WO2013177005A1 - Metabolic syndrome and chronic disease treatments - Google Patents

Description

METABOLIC SYNDROME AND CHRONIC DISEASE TREATMENTS

CROSS-REFERENCE TO RELATED APPLICATION

[0001J This application claims priority to US Provisional Application Seriai Mo. 61649444 fiied May 21, 2012, which is i corporated herein by reference to the extent not inconsistent herewith.

BACKGROUND

[0002] Despite progress with diagnostic tools, vaccines, antibiotics, and surgical techniques, most of the diseases that have plagued mankind for centuries continue to do so. Annually, cancer kiifs hundreds of thousands in the US and millions worldwide. Autoimmune diseases are epidemic. Sepsis ki!ls tens of thousands of Americans every year and is increasing. H!V has infected millions of people worldwide and, even though retroviral drugs will lengthen fife, most infected people will die of the disease. With the appearance of influenza strains similar to the Spanish Flu and the difficulty of developing effective vaccines, there is a potential for a pandemic. Atherosclerosis will kil! 50% of the inhabitants of industrialized countries, and neurological diseases from autism and ALS to Parkinson's and Alzheimer's disease are becoming ever more widespread.

[0003] A treatment is needed that will not just palliate but cure many if not ali of these diseases, a treatment that can be applied after the appearance of the disease, is non-invasive, essentiaify non-toxic, of brief duration, inexpensive, familiar to clinicians, and simple to apply, one whose effectiveness can be easily demonstrated, and that can be quickly made available worldwide.

[0004] The availability of such a treatment will enable more people to live healthier, longer, more productive fives, and save trillions of doifars in the US alone.

SUMMARY

[0005] Metabolic Syndrome is found in many disease situations from cancer to cardiovascular disease to cataracts to Parkinson's disease to sepsis and autoimmune disorders. Provided herein is a treatment for metabolic syndrome and its associated diseases based in the inventor's discovery of the relationship between Metabolic Syndrome, chronic inflammation and the immune system cascade. The

inflammation occurs because, while the body was stiSi fighting or recovering from a prior antigenic challenge, a second infection occurred. The body can only deal with one antigenic challenge at a time. The cytokine and endocrine response to the first challenge is suppressive to the clone(s} of lymphocytes selected by the second challenge. Only the innate immune system can respond to the second challenge, and it is inadequate. If the secondary challenge is from a virulent pathogen, the result can be a fulminant infection, sometimes fatal, if it is a weak pathogen, the result will be a chronic infection, if the secondary challenge is vigorous and happens while the response to the first is moving into the adaptive phase, autoimmunity will occur in the first infection,

[0006] Chronic inflammations and autoimmune diseases interfere with the adaptive response the body normally makes to antigenic challenges. The result is that a person with either chronic inflammation or autoimmunity is unable to deal effectively with further challenges and will develop stiil more chronic inflammations, autoimmune diseases or be unable to deal with a serious challenge such as H1 1 influenza.

[0007] immune suppressants can reduce symptoms but not cure the disease. However, insulin is a powerful stimulant to lymphocytes and can awaken ceils rendered inert by the cytokine/endocrine mix. Selected lymphocytes are activated and secrete cytokines to terminate the innate phase and re-start the adaptive phase. Pathogens are destroyed, tumors eliminated and inflammations disappear,

[0008] Sepsis, cancer, and other conditions such as chronic diseases and the accompanying metabolic syndrome are due to the failure of the adaptive immune system to activate so as to fully destroy a pathogen or tumor. Such diseases can be cured by stimulating anergic lymphocytes to activate and perform their normal functions. This is done by an infusion of insulin to maintain blood levels mimicking those occurring during the adaptive immune phase of a primary infection. Provided herein is a method of stimulating adaptive immune cascade activity in a patient in need thereof, said method comprising administering insulin in a pharmaceuticaify acceptable carrier to said patient via continuous intravenous infusion in amounts sufficient to maintain the patient's blood insulin level at about 15 to about 25 μυ/mi above their normal fasting pre-treatment level for a period of time sufficient to stimulate adaptive immune cascade activity in said patient,

[0009] A summary of the mechanisms and treatments for several conditions resulting from stalled immune cascades are provided below:

[0010] Development and Treatment of Chronic inflammation

• Chronic inflammation develops because lymphocytes selected by pathogens become anergic, because:

• While fighting one infection, patient develops a second infection.

• Endocrine, cytokine mix supporting first infection suppresses lymphocytes in second infection,

• Only innate system functions, producing inadequate, harmful inflammation, which becomes chronic.

Afiermath

• Hormonal mix supporting chronic infection causes insulin resistance, rising levels of insulin, and metabolic syndrome.

• Anergic lymphocytes remain anergic.

• Adaptive responses to future infections reduced; more chronic inflammations develop. Treatment

• Patient infused 48-96 hours with .lU/kg hr o .15U/kg/hr of insulin and glucose and potassium. Blood insulin is raised by an increment of 15-25pU/ml above the patient's normal fasting pre-treatment insulin level and maintained at this level during treatment. • Anergic lymphocytes are activated, destroy pathogens, down -regulate innate response, initiate hea!ing.

[0011] Development and Treatment of Cancer

• Because of an infection or chronic inflammation, immunity is suppressed, permitting ce!i to mutate, become cancer,

• Cance releases growth factors, causing brain to think there is a healing wound to support.

• Brain commands endocrine mix favoring growth, suppressing immunity.

• Body sinks into healing mode, suppressing immunity, feeding tumor.

Treatment

• Patient infused 48-96 hours with .lU/kg/hr or .15U/kg/hr of insulin and glucose and potassium. Blood insulin is raised by an increment of 15-25_tuU/mS above the patient's normai fasting pre-treatment insulin level and maintained at this level during treatment.

• Anergic lymphocytes are activated, destroy tumor, initiate healing.

[0012] Origin and Treatment of Autoimmune Diseases

• Patient is in beginning of adaptive response to a first microbial infection.

• Insulin levels are beginning to rise. Lymphocytes are beginning attack.

• Secondary infection develops, provokes stron innate response.

• Brain is deceived by shower of innate supporting cytokines from second infection into returning to endocrine support of innate phase, suppression of adaptive. Adaptive response to first infection stops, sinks back into innate phase.

• In first infection activated lymphocytes specific to antigen are inadequate to dear the body of microbes bu continue to bind to infected cells, release anti-bodies and cytokines to attract innate cells. First infection becomes autoimmune. Lymphocytes support continuing attack by innate ceils.

• Second infection becomes chronic inflammation.

Treatment

• Patient infused 48-96 hours with .2U/kg/hr or ,15U/kg/hr of insulin and g!ucose and potassium. Blood insulin is raised by an increment of 15-25LiU/mi above the patient's normal fasting pre-treatment insulin levei and maintained at this level during treatment.

• Anergic lymphocytes are activated in autoimmune disease and chronic inflammation, destroy pathogens, downregu!ate innate responses, initiate healing in both.

[0013] Development and Treatment of Fulminant infections

• Patient is fighting or recovering from first challenge (infection or trauma}.

• A second challenge in the form of an infection {e.g., flu} by aggressive microbe invades body, innate system activates.

• Endocrine mix supporting first infection or recovery from the trauma is immunosuppressive. • Selected lymphocytes cannot activate in response to second challenge.

• Second infection rages.

• innate cells {e.g., neutrophils, monocytes} try vainly to sto first challenge, become harmful to organs.

Treatment

• Patient infused 4S- 6 hours with .lU/kg/hr or .15U/kg/hr of insulin and glucose and potassium. Blood insulin is raised fay an increment of

above the patient's normal fasting pre-treatment insulin level and maintained at this level during treatment.

• Anergic lymphocytes are activated, destroy pathogens, down -regulate innate response, initiate healing.

BRIEF DESCRIPTION OF THE FIGURES

[0014] Figure 1 diagrams mechanisms of chronic inflammation, metabolic syndrome and future antigenic challenges.

[0015J Figure 2 diagrams mechanisms of antigenic competition.

[0016J Figure 3 diagrams mechanisms of chronic inflammation's interference with immune cascades and its resultant contribution to cancer.

[0017J Figure 4 diagrams mechanisms of stalled immune cascades and their effect on autoimmune diseases.

DETAILED DESCRIPTION

[0018] Provided herein is a method of stimulating adaptive immune cascade activity in a patient in need thereof, said method comprising administering insulin in a pharmaceutically acceptable carrier to said patient via continuous intravenous infusion in amounts sufficient to maintain the patient's blood insulin level at about 15 to about 25 μυ/mi greater than the patient's pre-treatment fasting blood insulin level for a period of time sufficient to stimulate adaptive immune cascade activity in said patient. The patient can be a human or other mammal.

[0019] Insulin is administered at the rate of between about 0.10 U/kg/hr and about 0.15 U/kg/hr or more to accompfish this result in typical adult humans in need of the present treatment. Administration of insulin can be initiated at about 0.10 U/kg/hr and increased as necessary to achieve the desired insulin b!ood levels. In embodiments, the patient's insulin blood levels are monitored at least about every three to four hours, and the rate of insulin administration adjusted as required to maintain the patient's blood insulin levels within the desired range. The insulin can be regular, human-made, insulin including commercially available brands such as Regular !fetin II^®, Humuiin^® R, and Novolin^® R. It can also be insulin from animals, such bovine or porcine insulin, especially when the patient is an animal. The insulin does not need to be fast-acting or ng-!asting, as the method hereof is performed using continuous intravenous infusion and was developed for the use of insulin having a normal rate of bioavailability. [0020] The immune response comprises a cascade of phases, an innate immune phase, followed by an adaptive immune phase, followed by a hea!ing phase. Each phase comprises its own cascade of events, all as more fuiiy described below. A patient in need of stimulation of adaptive immune cascade activity is a patient in which the adaptive immune cascade has not been substantially activated, or has stalled and faiied to proceed to heaiing phase. As more fuiiy described below, the immune system comprises an innate immune phase, an adaptive (also known as acquired) immune phase, and a heaiing phase. Each phase comprises a cascade of events, i.e., a series molecular, biochemical, and/or physiological processes occurring in a succession of stages each of which is closely related to or depends on the output of the previous stage. The normal progression of an immune cascade can become stalled or inhibited when one or more processes required for norma! activity of the cascade faii to adequately occur. To "stimulate adaptive immune cascade activity" as used herein means to cause the adaptive immune system to normally progress, activating immune cells that eliminate or prevent pathogenic growth.

[0021] Patients in need of stimulation of adaptive immune cascade activity have an initial blood insulin level less than normal, e.g., about 25 pU/mi or less. The patient's "initial" blood insulin level is defined as the patient's fasting blood insulin level immediately prior to treatment using the methods hereof. Patients generally have a final (after-treatment} blood insulin level greater than about 25 μϋ/mi, and in embodiments, e.g., in obese patients, greater than or equal to about 40 μυ/mi. or higher.)

[0022J CD4 cells are T-heSper lymphocytes, which lead the attack against infections. CDS cells are typically cytotoxic T-!ymphocytes, which carry a CDS marker. Normal healthy humans typically have a CD4:CDS ratio of between about 1.5 to about 2 to 1. Lower ratios indicate that the adaptive immune phase is insufficiently active, Higher-than-normal CD4:CD8 ratios indicate that the adaptive immune system is activated. Patients in need of stimulation of adaptive immune cascade activity often have a !ower-than-normal initial CD4:CDS ratio. (The "initial" CD4:CDS ratio is the CD4:CD8 ratio prior to administration of insulin in the present methods.} However, some patients in need of stimulation of adaptive immune activity {e.g., patients with autoimmune diseases such as active lupus and multiple sclerosis} can have a norma! or slightly higher-than-normal initial CD4:CD8 ratio, such as 2:1, 3:1, 4:1 or 5:1], indicating partially-activated adaptive immune cascades in which further activation is still needed for production of effective cytotoxic T-!ymphocyte activity to ameliorate the patient's condition.

Patients having chronic inflammation can have initial CD4:CDS ratios of about 2 to 3 to 1.

[0023] The methods provided herein are considered to have been successful when the patient has a final CD4:CDS ratio that is both higher than norma! and that is higher than the patient's initial CD4:CDS ratio prior to treatment. {The "final" CD4:CD8 ratio is the CD4:CDS ratio after completion of the treatment method hereof.} CD4:CDS ratios much higher than normal have been achieved by the methods hereof, e.g., greater than or equal to: about 10:1, about 15:1, about 30: 1, 45:1 and up to 70:1 or higher. The higher the ratio the more activation of the adaptive immune system has been achieved. In embodiments hereof, the patient's final CD4:CD8 ratios are measured at the completion of the insulin administration, and in embodiments the patient's initial CD4:CDS ratios are measured prior to beginning insuiin administration,

[0024] The patient is not typically considered to be in need of stimulation of adaptive immune activity by the administration of insulin unless the patient's insulin blood levels are less than about 25 μΐί/ml. In obese patients insulin levels iess than about 30 are considered to indicate need of stimulation of adaptive immune activity by the administration of insulin. In embodiments, prior to beginning administration of insulin the patient's insulin blood level is tested,

[0025] The method comprises continuous intravenous infusion of insulin, so as to "damp" (maintain) the patient's blood insulin level at about 15 to about 25 pU/rnl above the patient^'s pre-treatment normal blood insulin ievei. The rate of insulin administration can be varied in order to lamp the patient's biood insu!in levels within the desired range. The term "blood insulin ievei" refers to the level of insulin measured in a fasting patient's blood or serum. The term "plasma insulin level" is used synonymously with the term "biood insulin level." The term "continuous" with respect to the infusion of insulin means that insulin administration is kept up without interruption except for (1] possible brief interruptions if a patient's blood insulin ievei exceeds the desired range, such interruptions lasting onfy long enough for the patient's insulin ievei to return to the desired range; and/or {2} longer interruptions required if a patient develops a dangerously-high fever, these fonger interruptions lasting only long enough for the patient's fever to return to non-dangerous ieveis. in contrast to typical medical procedures involving intravenous insulin infusion, administration of insulin in the present method is not interrupted for the purpose of correcting the patient's blood glucose levels, if the patient's glucose ieveis drop below normal, additional glucose is administered,

[0026] Maintaining the patient's insuiin ieveis about 15 to about 25 μϋ/ml above the patient's pre- treatment norma! blood insulin level typically results in the onset of a fever within several hours, e.g., about four to about twelve hours. The method hereof is performed for at least a period of time sufficient to produce a fever and possibly other fiu-Sike symptoms, such as aching muscles and unusuai tiredness, in the patient. A "fever" is a temperature above the normal temperature of the patient. In humans the norma! temperature is considered to be 9S.6 ^,F, however different individuals may have lower or higher norma! temperatures. Temperatures about 3 ^,F above the patient's norma! temperature {e.g., about 101,5 °F to about 102 ^aF in an aduft human whose normal temperature is about 98,6 °F) are generally considered indicative of a fever.

[0027] if the patient's fever does not become dangerously high {e.g., over about 102 to about 104 °F for an adult human},, with consequent risk of permanent brain or other damage to the patient, insulin administration can be continued without interruption until the patient's fever returns to normal, and thereafter for at least about four to about eight hours, insulin administration can be performed for a total of about 48 to about 96 hours to ensure that the patient's adaptive immune cascade has been activated, in the event that insulin administration has been interrupted due to a dangerousiy-high fever,, insulin administration is resumed when the patient's temperature drops to nondangerous levels. The insulin administration can be continued until the cumulative time during which insulin administration has been performed reaches about 48 to about 96 hours.

[0028] The patient's glucose blood levels are periodically monitored, in embodiments by testing glucose blood levels once an hour, while insulin is being administered, Sufficient glucose is administered to maintain norma! blood glucose levels in the patient, e.g., between about 80 mg/d! and about 120 mg/di in humans. Glucose can be administered enterai!y or parenteraily in the form of medical glucose preparations known to the art. Supplementary glucose can also be administered in the form of food such as candy bars and other sugar-containing foods. Glucose is administered in a dosage high enough to maintain normaf to high blood glucose levels but not so high as to cause severe hyperglycemia or diabetic coma. In embodiments gfucose is maintained at levels slightly above normal, e.g. , more than about 120 mg/di u to typical post-meal levels of about 260, if the patient's renal , liver function and blood sugar levels are norma!, glucose administration can be started with 5% glucose (dextrose) in a physiologically acceptable soiution with minimal sodium. The glucose infusion can be maintained as long as necessary, typically at a rate of about 5 grams per hour per unit of insulin being administered.

Glucose is generally continuously administered to avoid hypoglycemia; mild hyperglycemia is not considered harmful.

[0029] The patient's potassium levels are also periodically monitored, in embodiments, by testing potassium levels in the patient's blood as is known to the art. In embodiments potassium levels are tested every six hours or less, !f the patient's blood (serum J potassium levels fall below normal, which in humans is about 3,5 to about 5,5 mEq/L (1 mEq/L potassium equals 39 mg/Lj, potassium in a pharmaceutically acceptable carrier is administered enteraliy or parenteraily by methods known to the art to adjust the patient's blood potassium levels to the desired range, In embodiments mild hyperkalemia (about 5.1 to about 6.0 mEq/L in humansj is maintained in the patient, as described in US Patent No, 6/143, 717, and administration of potassium is begun when the patient's blood potassium level fails to less than about 5.1 mEq/L Potassium can be administered in an amount of between about 10 mEq and about 300 mEq per 75 kilograms of body weight per day to keep the patient's potassium levels within the desired range,

[0030] Insulin, potassium and glucose are controlled separately, A single solution containing all three components would make such control difficult. Thus, it is recommended that separate intravenous solutions be administered, e.g. , in a piggyback arrangement as is known to the art.

[0031J In embodiments, the patient in need of treatment by the present method suffers from metabolic syndrome, a condition known to the art. The term "suffers from" as used herein carries its ordinary meaning in the art, i.e., that the patient has been diagnosed with the condition; or if the condition is undiagnosed, has symptoms indicative of the condition. The term "metabolic syndrome" is a name for a group of risk factors that occur together and increase the risk for coronary artery disease, stroke,, and type 2 diabetes. Metabolic syndrome is typically characterized by the risk factors of having extra weight around the middle and upper parts of the body (central obesity, sometimes described as an "apple-shaped" body}, and insulin resistance, in which the body cannot use insuiin effectively. Other risk factors include aging, genetic factors, hormone changes, and lack of exercise. Metabolic Syndrome features insuiin resistance, dyslipidemia, elevated blood glucose, high blood pressure, and frequently obesity, it is associated with a chronic inflammation, autoimmune disease, tumor or a wound that will not heal,

[0032J Metabolic syndrome may be caused by or accompanied by excess biood clotting and low levels of inflammation throughout the body. Diagnostic criteria differ, but the World Health

Organization currently diagnoses metabolic syndrome when one of the following: diabetes meifitus, impaired glucose tolerance, impaired fasting glucose and insulin resistance, is present and two of the following criteria are present: blood pressure 140/90 mmHg, dyslipidemia: triglycerides (TG): >1,695 mmol/L and high-density lipoprotein cholesterol (HDL-C) < 0.9 mmo!/L in a male) and < 1,0 mmol/L in a female, central obesity with waist:hip ratio > 0,90 in a male and > 0.85 in a female, or body mass index > 30 kg/m2, and microalbuminuria with urinary albumin excretion ratio≥ 20 pg/min or albumin reatinine ratio≥ 30 mg/g. The term "metabolic syndrome" as used herein applies to the condition as diagnosed by any criteria known in the art. Metabolic syndrome is thought to be a precursor to, and present in a wide range of diseases, including type 2 diabetes, cardiovascular disease, stroke, cancer, polycystic ovary syndrome, fatty liver disease, gout, and asthma.

[0033] Metabolic Syndrome represents an attempt by the body to transfer nutrients from the reservoir of peripheral tissues to those stressed tissues. Insensitivity to insulin causes peripheral tissues to lose amino acids, lipids, glucose and sons into the blood, in time the patient may develop on- Insu!in-Dependent Diabetes Me!iitus. The stressed tissues access the nutrients by means of the growth hormone/IGF- 1 system, In short, where there is a chronic inflammation, autoimmunity, healing wound or cancer, there is metabolic syndrome,

[0034] Metabolic Syndrome develops most often when a person is challenged by pathogens and selected lymphocytes fail to activate completely and destroy the offending pathogen and, instead becoming anergic.

[0035] Since the less efficient innate system cannot by itself deal with the threat, infections become chronic, tumors grow and wounds do not heal. Selected lymphocytes become anergic. Stress, various drugs, previously-existing infections (antigenic competition) and unhealed wounds can interfere with the full activation of selected lymphocytes. The most common reason that lymphocytes become anergic is antigenic competition. If a patient is challenged by a new infection while still fighting a previous one, the patient cannot mount a strong acquired defense against the second infection.

S [0036] !f the response to the first infection is in the innate phase, high levels of Cortisol, and INF will reduce the capacity of selected iymphocytes in the second infection to proliferate and differentiate. The result is chronic inflammation.

[0037] If the response to the first infection is in the acquired phase when the second infection begins, higher levels of insulin and Cortisol in addition to anti-inflammatory cytokines will prevent newly- selected lymphocytes in the second infection from activating. Again, the result is a chronic

inflammation.

[0038] !f the response to the first infection is in the healing phase, as after surgery, action fay T-regs, high levels of TGF , and 11-10 will prevent activation of Iymphocytes responding to the second infection, producing Metabolic Syndrome, and permitting it to become chronic , or if the infection is fulminant, leading to sepsis,

[0039] If infection #2 is severe and occurs while the response to infection #1 is moving into the acquired phase, so many cytokines will be released by damaged tissues in the second infection that there will be an interruption in the cascade in the first Infection. Insulin secretion is disrupted; CD4 and CDS ceils do not fully develop while antigen-specific Th-17 cells continue to summon PMNs and monocytes to the area. Levels of SL-2 drop and those of TGF and IL-10 do not rise high enough to stop Th-17 cells. Pathogens survive to continue tissue destruction. The result is autoimmunity in the first infection, chronic inflammation in the second and Metabolic Syndrome.

[0040] When a chronic inflammation or autoimmune disease is established, the brain will command an endocrine mix to support the immune response. As we have seen,, that mi Is always suppressive to Iymphocytes selected to deal with new infections. In effect, the patient will be unable to mount an effective lymphocyte response to new challenges. Thus, as people age, they may accumulate chronic inflammations, autoimmune diseases or cancers. In addition, the insulin resistance causes levels of glucose to rise, followed by a rise in insulin and belly fat.

[0041] Suppression of Inflammation produces only palliative effect. The cure for metabolic syndrome includes destruction of the pathogen or tumor; suppression of the innate response; and disarming of active lymphocytes and permitting normal healing.

[0042] Full activation of lymphocytes selected by antigen in the chronic infection, autoimmune disease or cancer, means the lymphocytes will run their normal course of down-regulating innate ceils, destroying pathogens, transforming into T-regs, and becoming memory cells or becoming apoptotic. Such activation of iymphocytes cannot be achieved with cytokines, whose actions are not fully understood and whose use is dangerous.

[0043] Infusion of insulin at the proper level for 48 to 96 hours stimulates Iymphocytes to complete their full cycle. The patient's cancer, chronic inflammation, autoimmune disease or other condition associated with metabolic syndrome will be ameliorated and the patient will be more able to respond normally to new challenges. [0044] !n embodiments_,, the patient in need of treatment by the present method suffers from chronic inflammation, a disease condition known to the art. Chronic inflammation is associated with virtually all chronic degenerative diseases, autoimmune diseases and cancer, it is common for patients to have two or more different autoimmune and/or autoinfiammatory diseases at the same time. Chronic inflammation, e.g., as a low level of inflammation through the body, is often present in metabolic syndrome and suppresses the adaptive immune system so that these diseases can develop. A high- sensitivity cardiac reactive protein (HSCRP) test, which is measured in mg/L (with a range of <1.0 mg/L being a low relative risk for "cardiovascular disease events" to >3.0 mg/L being a high relative risk), can identify chronic inflammation. An inflammatory marker test for inter!eukin 6 (!L-6) is also useful with the HSC P test to identify chronic inflammation and can also predict enhanced risk of developing type two diabetes. Testing of CRP, IL-6, tumor necrosis factor (T F) and interSeukin 1 β (III β) and/or InterSeukin 8 {ILS} is also used to diagnose chronic inflammation,

[0045] Chronic inflammation indicates the adaptive immune cascade is not properly activated, and the innate immune system is giving signals to the brain to keep the innate system active and suppress the adaptive immune cascade. Chronic inflammation is associated with allergy (inflammatory cytokines induce autoimmune reactions); Alzheimer's (chronic inflammation destroys brain ceils); anemia (inflammatory cytokines attack erythropoietin production); aortic . valve stenosis (chronic inflammation damages heart valves); arthritis (cells of the innate immune system stimulated by inflammatory cytokines destroy joint cartilage and synovial fluid); cancer (chronic inflammation suppresses adaptive immunity and permits cancers to develop); congestive heart failure (chronic inflammation contributes to heart muscle wasting); fibromyalgia (inflammatory cytokines are elevated) fibrosis (inflammatory cytokines attack traumatized tissue); heart attack (chronic inflammation contributes to coronary atherosclerosis}; kidney failure (inflammatory cytokines restrict circulation and damage nephrons); lupus (inflammatory cytokines induce an autoimmune attack); pancreatitis inflammatory cytokines induce pancreatic cell injury); psoriasis (inflammatory cytokines induce dermatitis); stroke (chronic inflammation promoted thromboembolic events); and surgical complications (inflammatory cytokines prevent healing), !n all these there is no adaptive immune response to end the pathogenic challenge.

[0046] in embodiments, the patient in need of treatment by the present method suffers from at least one chronic infection, which is typically a "secondary infection," i.e., an infection by a microorganism {e.g., virus, bacteria, or fungus) that follows an initial infection by another microorganism. As discussed below, such secondary infections are often chronic. Stimulation of adaptive immune cascade activity by the methods hereof allows antibodies and/or T-ceils specific to the microorganisms causing the second infection to be produced so as to resolve the secondary infection,

[0047] in embodiments the patient suffers from one or more tumors, or the patient may suffer from a healing wound, e.g., as a result of accidental trauma or surgery, and has subsequently contracted an infection by a microorganism. Such patients are typically in the healing phase of the immune response. As discussed more fully below, during the healing phase of the immune response, the adaptive immune cascade is suppressed, and patients are especially susceptible to infection. Tumors, which the body- treats like healing wounds, can be shrunk by the methods hereof by stimulation of the adaptive immune cascade to activate tumor-specific immune ceils. Chronic infections are also ameliorated or completely cleared by adaptive immune cell attack on the pathogen causin the infection as a result of the methods described herein.

[0048] in embodiments, the patient in need of treatment by the present methods suffers from an autoimmune disease. Many autoimmune diseases involve the presence of pathogens. Autoimmune diseases include: Active chronic hepatitis (HYBsAg negative); Acute disseminated encephalomyelitis {ADEM); Acute hemorrhagic leukoencephalitis {Hurst's disease); Agammaglobulinemia, primary; Allergic asthma; Allergic asthma; Aiiergic eczema; Aiiergic rhinitis; Alopecia areata; Ankylosing spondylitis'; Anti- GBfvl/anti-TBM disease; Antiphosphoiipid antibody syndrome {APS}; Arteriosclerosis; Atherosclerosis; Autism; Autoimmune Addison's disease; Autoimmune aplastic anemia; Autoimmune atrophic gastritis; Autoimmune dysautonomia; Autoimmune hemolytic anemia; Autoimmune hepatitis; Autoimmune hyper Sip idem ia; Autoimmune inner ear disease (A; ED), Autoimmune interstitial cystitis; Autoimmune lymphoproiiferative syndrome {ALPS}; Autoimmune myocarditis; Autoimmune polyglandular syndromes, Types 1, II & 111; Autoimmune progesterone dermatitis; Autoimmune thrombocytope ic purpura (ATP); Autoimmune thyroiditis; Baio disease; Behcet's disease; Bullous pemphigoid; Castleman disease; Celiac disease-sprue; Chagas disease; Chronic fatigue syndrome; Chronic inflammatory demyefinating polyneuropathy {CIDP}; Churg-Strauss syndrome; Cicatricial pemphigoid; Cogan's syndrome; Cold agglutinin disease; CREST syndrome; Crohn's disease; ; Cryptogenic cirrhosis;

Dermatomyositis; Oevic's disease {neuromyelitis optical; Diabetes, type 1; Discoid lupus; Discoid lupus erythematosus; DressSer's syndrome; Eosinophilic fasciitis; Erythema nodosum; Erythema nodosum; Essential mixed cryoglobulinemia; Evans syndrome; Fibrosing alveolitis; Food allergies;

Glomu!eronephritis; Goodpasture's syndrome; Graves' disease; Guiiiain-Barre syndrome; Hashimoto's thyroiditis; Henoch-Schoniein purpura; Herpes gestationss; Hypogammaglobulinemia; idiopathic leukopenia; idiopathic thrombocytopenic purpura; IgA nephropathy; insulin-dependent diabetes meliitus; Juvenile arthritis; Kawasaki syndrome; Lambert-Eaton myasthenic syndrome; Lambert-Eaton myasthenic syndrome; LeukocytocSastic vasculitis; Lichen planus; Lichen sciierosus; Ligneous conjunctivitis; Linear IgA disease {LAD}; Lupus nephritis; Lyme disease; Male infertility; Mented:'s disease; Microscopic poiyangiitis; Mixed connective tissue disease {MCTD}; Mooren's ulcer; Muchs- Habermann disease; Multiple sclerosis; Myasthenia gravis; Narcolepsy; Non-length-dependent small fiber sensory neuropathy; Ocular cicatricial pemphigoid of the immune system against the body itself:; Palindromic rheumatism; Para neoplastic cerebellar degeneration; Paroxysmal nocturnal

hemoglobinuria {PNH); Pars planitis {peripheral uveitis); Parsonnage-Tu rner syndrome; Pemphigoid; Pemphigus vulgaris; Pernicious anemia; Phacogenic uveitis; POEMS syndrome; Polyarteritis nodosa; Polymyalgia rheumatics; Polymyositis; Postmyocardiai infarction syndrome; Postpericardiotomy syndrome; Premature menopause; Primary biliary cirrhosis; Primary myxedema; Progesterone dermatitis; Psoriasis; Psoriatic arthritis; Pulmonary fibrosis, idiopathic; Pure red ceSi aplasia; Pyoderma gangrenosum; Raynaud's disease; Reflex sympathetic dystrophy; Reiter's syndrome; Relapsing polychondritis; Restless leg syndrome; Rheumatic fever; Rheumatoid arthritis; Sarcoidosis; Schmidt syndrome (autoimmune polyepdocrsne syndrome); Scieritis; Scleroderma; Sjogren's syndrome; Stiff person syndrome (in some cases); Subacute bacteriai endocarditis (SBE); Subacute bacteriai endocarditis (SBE); Sympathetic ophthalmia; Systemic lupus erythematosus fSLE}; Takayasu's arteritis; Temporal arteritis/giant ceil arteritis; Testicular autoimmunity; Thyrotoxicosis; To!osa-Himt syndrome; Transverse myelitis; Ulcerative colitis; U differentiated connective tissue disease (UCTD), Uveitis; Vasculitis; Vitiligo; and Wegener's granuiomatosis. Pathogenic microorganisms have been impiicated as causative agents of many autoimmune diseases, and amelioration of these diseases by the present methods is believed to occur because of adaptive immune cell attack on pathogenic causes of the diseases,

[0049] In an embodiment, a method of stimulating immune cascade activity in a patient in need thereof is provided. The method comprises: determining that said patient's initial blood insulin level is less than about 25 μϋ/mi, e.g., using commercially available ELISA kits in real time. The method also comprises determining the patient's initial CD4:CD8 ratio, then administering insulin to the patient via continuous intravenous infusion at a rate sufficient to move potassium into the cells, especially, the lymphocytes. When a lymphocyte kills another ceil, the lymphocyte loses Its surface charge and injects perforin into the cell it is kiiling. Potassium rushes out of the lymphocyte cell, and then the lymphocyte must pump potassium back in in order to remain active, and to produce the maximum number of insulin receptors. This is possible when insulin is infused at a level sufficient to maintain a desired biood insuiin levei in said patient of about 15 to about 25 μϋ/mi above the patients normal pre-treatment blood insulin level for about 48-96 hours. Insulin should not be administered at rates so high that the lymphocytes reduce the number of insulin receptors,, which typically happens when insulin blood levels are greater than about 40 μυ/ml. Reduction of insulin receptors leads to immunosuppression. The rate of insuiin infusion herein is typically about 0,10 to about 0.15 U/kg/hr, The insulin is administered so as to raise the patient's blood insulin level to about three times norma! levels and stimulate adaptive immune cascade activity in the patient. The method also comprises periodically monitoring the patient's blood insulin, glucose and potassium le els and adjusting said rate of insulin administration to maintain the desired blood insulin level. Glucose is also administered in amounts sufficient to maintain the patient's blood glucose levels within norma! range; and potassium is administered to maintain mild hyperkalemia in the patient as shown by potassium blood levels between about 5,1 to about 6,0 mEq L. Insulin administration can be interrupted in the event said patient develops a dangerously high fever and resumed when the patient's temperature drops to a non-dangerous level. Administration of insulin is continued for at least about four to about eight hours after the patient's fever returns to normal. The method can also include measuring the patient's final CD4:CDS ratio after administration of the insulin, wherein the patient's final CD4:CD8 ratio is both greater than the patient's initial CD4:CDS ratio and greater than or equal to about 3 :1.

[0050] Further provided herein is a system for stimulating adaptive immune cascade activity in a patient in need thereof, said system comprising: (a) insulin in a suitable pharmaceutical carrier for intravenous infusion in an amount sufficient to stimulate adaptive immune cascade activity in said patient when administered to said patient by intravenous infusion over a period of at least about 48 to about 96 hours; (bj at least one biood insulin test apparatus; and {c} instructions for administering the insulin for the purpose of stimulating adaptive immune cascade activity in a patient in need thereof.

[0051J The system can be scaled for a singie patient or can be scaled for a clinic accommodating multiple patients for treatment using the methods hereof. Insulin, glucose and potassium can be supplied in convenient dosage forms in quantities required for performing the method for single patients. Test apparatuses, such as test kits, can be packaged for singie patients,, or laboratory-sized test equipment can be provided to accommodate a number of patients. Apparatuses for administering insulin intravenously, and for administering glucose and potassium are known to the art and commercially available for each patient to be treated by the systems hereof. Quantities of equipment and pharmaceutical preparations are readily calculated by those skilled in the art to provide for adequate and complete performance of the methods hereof.

[0052] Blood insulin test apparatuses are known to the art, e.g., the insulin ELISA kit of Dako

Corporation, Carpinteria, CA.

[0053] Pharmaceutically acceptable insulin preparations are available commercially through medical suppliers, as described above. In embodiments the insulin is provided in standard size {e.g., 11) intravenous bags. Quantities and convenient packaging for the reagents used in the method are readily calcuiated and procured by those skilled in the art. A total amount of insulin required for a single patient is between about 350 and about 2100 Units, depending on duration of the insuiin infusion and the patient's weight, in embodiments at least about 2100 Units of insuiin per patient is provided. If patients are overweight and require even higher amounts of insulin, the system can comprise such further amounts, as can be readily estimated by one skilled in the art. Analogs of regular insulin having the effects described herein for regular insulin can also be used in the methods hereof.

[0054] Apparatuses for administering insulin via continuous intravenous infusion are also known to the art and commercially available through medical equipment suppliers. Standard intravenous drip apparatuses can be used, e.g, the Alans UK Ltd. intravenous infusion pump.

[0055] The system provided herein can also comprise at least one blood glucose test apparatus (glucose monitor). Such glucose monitors are widely commercially available, e.g., the One Touch³ glucose monitors of LifeScan, Inc., Wayne, PA. [0056] The system can a!so comprise pharmaceutical acceptable glucose suitable for enteral administration, such as candy, or for parenteral administration, inducting intravenous administration, in an amount sufficient to maintain the patient's biood glucose at norma! ieveis during administration of said insuiin over a period of at least about 48 to about 96 hours. Pharmaceutically acceptable glucose is widely commercial iy available, e.g., Hospira 5% dextrose solution, Hospira, !nc,_; Lake Forest, !L. The glucose is provided in an amount sufficient to maintain the patient's blood glucose at normal levels during administration of said insulin over a period of at least about 48 to about 96 hours, A totai amount of glucose required for a single patient is between about 150 and about 6000 g, depending on duration of the insulin infusion and the patient's weight. In embodiments at !east about 6000 g of glucose per patient is provided, if patients are overweight and require even higher amounts of glucose, the system can comprise such further amounts, as can be readily estimated by one skilled in the art.

[0057J Apparatuses for administration of glucose are known to the art and widely commercially available, and include standard intravenous infusion equipment. For example glucose administration can be done via piggyback components attached to the insulin infusion equipment. Apparatuses for administering glucose are known to the art. For example administration of potassium can be piggybacked onto the insulin infusion apparatus using standard intravenous components.

[0058J The system hereof can afso comprise at least one blood potassium level test, Blood potassium test apparatuses are known to the art, e.g., Medica Corporation's EasyElectrolytes test device or the Quantofix^® potassium test kit of Sigma-Aldrich. St, Louis, MO.

[0059] The system can also include pharmaceutically acceptable potassium preparations providing potassium in an amount sufficient to maintain the patient's biood potassium at normal levels during administration of said insuiin over a period of at least about 48 hours. Potassium is provided for each patient in an amount sufficient to maintain the patient's blood potassium at normal (3.5 mEq/L to 5,0 mEq/L} to mifdly hyperka!emic levels (5.1 mEq/mf to 6.1 mEq/m!} during the administration of the potassium over a period of at least about 48 to 96 hours. A total amount of potassium required for a singie patient is between about 120 and about 200 mEq, depending on duration of the insulin infusion and the patient's weight. In embodiments at least about 2000 mEq of potassum per patient is provided. If patients are overweight and require even higher amounts of potassium, the system can comprise such further amounts, as can be readily estimated by one skilled in the art. The potassium can be provided in a suitable pharmaceutical carrier in standard dosage forms including intravenous dosage forms.

[0060] Apparatuses for administering potassium are widely known and commercially available. For example administration of potassium can be piggybacked onto the insulin infusion apparatus using standard intravenous components. The system hereof can also comprise at least one thermometer for taking the patient's temperature.

[0061] The system hereof can further comprise at least one CD4:CDS ratio test apparatus. Such test apparatuses are known to the art and commercially available, e.g., flow eytometers from Partec GmbH of Munster, Germany, Becton Dickinson of California, Coulter Corporation, Florida, Guava Technologies, California.

[0062] Consider this list of unrelated diseases: AIDS, ALS, Alzheimer's Disease, Ankylosing Spondylitis, Asthma, Atherosclerosis, Atriai fibrillation, Autism, Benign Prostatic Hypertrophy, Cancer, Chronic Fatigue Syndrome, Chronic Obstructive Pulmonary Disease, Critical Care Polyneuropathy, Diabetes, I and li, Fibromyalgia, Glaucoma, Gulf War Syndrome, Guillain-Barre Disease, H1N1 influenza, inflammatory Bowel disease, Lupus, Macular degeneration, Multiple Sclerosis, Necrotizing Fasciitis, Obesity,

Parkinson's Disease, Psoriasis, Rheumatoid Arthritis, Schizophrenia, Scleroderma, Sepsis, Shingles, Toxic Shock Syndrome, Tuberculosis, Vitiglio, and others as described above, it may seem unlikely that such diverse diseases as those could have anything in common, much less all be successfully treated with the same therapy. But it once seemed preposterous that the extract of a moid could be effective against hundreds of infections caused by different species of bacteria. But penicillin did that. And it seemed unlikely that a naturally occurring hormone could become extremely effective in treating diseases as different as rheumatoid arthritis, alopecia, cancer and hypercalcemia. But Hench showed that cortisone is usefu! in those and almost two hundred other diseases even though the cause of the diseases was not known. But they had the unifying feature of excessive inflammation.

[0063J In a like manner, the diseases listed above are all associated with metabolic syndrome. While the definition of this condition in the literature is controversial, it features some combination of insulin resistance, elevated triglycerides, reduced high density lipids {HDts}, high blood pressure, belly fat, elevated C Reactive Protein, erythrocyte sedimentation rate, bloating, gas, erectile dysfunction and elevated fasting glucose. The term "metabolic syndrome" is used to herein to denote any of the conditions known to the art and listed herein as being associated with metabolic syndrome.

[0064] !t is submitted herein that metabolic syndrome is usually the result of a chronic inflammation [Jackson, Michael J. et aL] . The inflammation developed because the adaptive limb of the immune system failed to meet the pathogenic challenge, the syndrome represents the body's effort to divert nutrients from peripheral tissues to the metabolic compartment under duress, i.e., an inflammation, sepsis, autoimmune disease or cancer, and a chronic inflammation/metabolic syndrome reduces the body's ability to mount a robust adaptive response to future antigenic challenges, so that a patient may have several chronic inflammations or autoimmune diseases at the same time, such as rheumatoid arthritis and atherosclerosis [Meggs; Doran; Wasko],

[0065] Pathogens that would be shrugged off if the adaptive immune system responded normally can become anything from a debilitating chronic inflammation to a fatal disease. Take HIV. Fewer than 5% of those exposed become infected, while 98% of persons exposed to measles do. Both the measles and HIV viruses invade leukocytes, causing immunosuppression. The system clears itself of the aggressive measles virus, but it fails to clear the weak, inefficient HIV [Oldstone]. [0066] The question is why the Adaptive Phase did not meet the challenge of that weak virus. To understand that, and why the treatment proposed here that a naturally occurring hormone can cure many of these diseases, we must look briefly at the immune cascade. The cascade is of such complexity that no description can be definitive. And what is known has been reviewed in many places, so no attempt will be made to describe it fully, only to call attention to relevant features. It should be appreciated that a patient already suffering an immune challenge can become subject to a new infection in any of the three phases.

PHASE I. THE INNATE IMMUNE PHASE

[0067] Dinareifo and Molda er have summed up the Innate Phase well: "It is a rapid, primordial and ineff icient system aimed at containing microbial pathogenesis until the development of a more definitive acquired immune response," [Dinarei!o and Moldawer}. When a pathogen gains entrance to the body, the first response is probably activation of Toil-Like Receptors (TLRs) which alert the host to pathogens [Chen and Oppenheim], They contribute to activation of resident macrophages or dendritic cells, which then phagocytose pathogens. These cells present the pathogen's antigen in conjunction with the host's major histocompatibility complex (fvlHC) for recognition by lymphocytes [Bogen], Once activated by antigens, lymphocytes begin a rapid process of proliferation and differentiation. Differentiating lymphocytes express receptors for insulin-like growth factor (IGF-1), which contributes to their maturation. lnterleukin-17 (11-17} is secreted by T-helper-17 {Th-17} cells and promotes neutrophil maturation and chemotaxis [Louten et a!.}. Sometimes referred to as the interface between the innate and adaptive systems, these cells constitute a link between T-eeil activity and the accumulation of neutrophils locally in organs [Sergejeva and Linden]; !L-27 also has an effect on ceils of the monocyte lineage, which can play a significant role in pathogenic conditions [Sergejeva and Linden], Since they are lymphocytes that bind specifically to antigen, Th-17 cells serve as sentinels, releasing chemokines to attract cells of the innate system and cytokines to notify the brain what kind of challenge it is f acing in an infection and what kind of response is needed: basophil, neutrophil, eosinophil and/or monocyte.

[006S] Polymorphonuclear leukocytes fPfvlNs) soon arrive and begin to destroy the invader. These cells release cytokines that attract more PMNs and monocytes, thus upreguiating the innate phase,

[0069] If a localized response is prolonged or intense, enzymes released from dying neutrophils may iiquefy nearby host cells and foreign material alike [Parslow et a!.]. This attack by ceils of the innate phase can become injurious to host ceils, in fact, if it becomes chronic, the inflammation can cause asthma, nervous system disorders, fibrosis and rheumatoid arthritis [Chen and Oppenheim].

[0070] St has long been noted that cells of the innate immune system have a regulatory role in the developing adaptive immune phase [Fearon and Locksley], But it has not so commonly been recognized that by the secretion of cytokines, newly-selected lymphocytes exert n early and powerful control over the innate immune system from the beginning of the cascade, lnterleukin-1 (IL-l), interfeukin-6 (!L-6) and Tumor Necrosis Factor alpha {TNFct} are secreted by lymphocytes and antigen-presenting cells SAPCs; [Hirsc and Kroemerl and contribute to chemotaxis and activity of polymorphonuclear leukocytes. The cytokines are also swept through the body to various organs, including the liver and brain [DinareSlo and oidawer, p.17], interferon gamma (INFy) is secreted by lymphocytes and other cells and increases the antigenicity of host tissues [Shah et al.], preparing them for an attack by cytotoxi T-ceSis (CTLs}.

[0071] From the appearance of pathogens to the repiacement of damaged and dead tissues, the immune response is a constant battle between cells for dominance. For example, Th-17 cells develop more quickly than Th-1 and Th-2 ceils, and summon monocytes and PMNs to the scene. But as Th-1 and Th-2 cells multiply, they release IL-2 which stimulates the growth of other T helper cells and cytotoxic T lymphocytes (CTLS). As the proliferation advances, they come to outnumber Th-17 ceils and inactivate, kiil or transform them into iTreg ceSis. As IL-2 increases, numbers of Th-17 cells [Ad!er] and PMNs decline, and monocytes transform into macrophages. If the humoral threat is greater than the intracellular, more IL-4 than !L-12 is secreted and B cells proliferate faster than Th-ls, And there is the issue of timing. For example, in this stage when lymphocytes are maturing, TGFp is at low levels locally and supports the proliferation of those ceils. However, as we shall see later, in the healing phase, TGFp increases and becomes systemic, at which time it is a powerful antiimmune agent. In a similar way, insulin-like Growth Factor- 1 {IGF-2} supports maturation of developing lymphocytes [Johnson], but in the healing phase participates in the downregulation of adaptive immunity, !n these events, enormous energy and utilization of materials are required. That is achieved by changes in the endocrine profile,

[0072] Cytokines secreted by APCs and lymphocytes and damaged tissues induce an endocrine response including rising levels of Cortisol [Hirsch and Kroemer, lO ff], glucagon, catecholami es and growth hormone [Dinarelio and Moidawer; Berczi and Nagy, p. 100], This endocrine mix causes insulin resistance and catabo!ism in peripheral tissues. They release ions, lipids, glucose and amino acids into the metabolic pool from which they can be acquired by proliferating cells of the [Beisei], Thus, the endocrine system supports the function of the innate immune cells and the expansion of lymphocyte clones.

[0073] Paradoxically, this endocrine profile is immunosuppressive, exerting multiple inhibitory effects at the levels of both APCs and T cells [Hirsch and Kroemer, p, 3], However, since the antigen-selected clones of lymphocytes had already been activated before the mix developed, those clones (T helpers 1 and 2 (Th-1 and Th-2), Cytotoxic T Lymphocytes (CTLs) and B cells} are not suppressed but continue their proliferation and maturation, permitting the development of the adaptive immune phase,

[0074] PHASE !l. THE ADAPTIVE (ACQUIRED) IMMUNE PHASE

[0075] The second part of the cascade is the adaptive (acquired) immune phase. It features the efficient attack on the pathogen by lymphocytes specific to that pathogen. While lymphocytes proliferate and mature during the innate immune phase, the adaptive immune phase may be defined as the period during which lymphocytes become the predominant immune cells and act to clear pathogens from the body. Receptors for IGF-2 vanish and do not reappear for 48 hours [Segretin, ef al.}. T helper 1 cells release into the environment cytokines {e.g. lnterieukin-2, IL-12J that activate selected CTLs to eliminate host ceils that have been invaded by pathogens. T-he!per 2 cells secrete cytokines (IL4, !L-5) to activate B ceils. They transform into plasma ceils and release antibodies that bind to pathogens, making it easier for macrophages to engu!f and destroy them,

[0076] Two other events take place in this Adaptive Phase. First, cytokines, e.g., Snterieukin-10 (11-20) and interieukin-2 {IL-2}, released by helper T-ee!is also powerfully downregufate the innate immune response [Shah ef ai. p, 289], thus preventing further damage to the host [Dinarelio and Moida er], Levels of SL-1 and TNFa decline and inflammation recedes as lymphocytes swiftly destroy infected cells and circulating microorganisms. Of particular interest for the model presented here is the fact that IL-2, released by Th-1 CD4+ cells to activate CTLs has a suppressive effect on Th-17 ceils. Reduced levels of iL-17 slow the appearance of neutrophils and monocytes [Hammerich, ef ai.\.

[0077] Second, the endocrine mix changes. Glucagon levels rise to five times normal, contributing to insulin resistance in peripheral tissues and causing the liver to release more glucose into the blood. Most significantly, insulin increases to three times norma! levels [Ryan et αί Rayfield, et al.; ocha, et ai],

[0078] In addition, insulin receptors appear on proliferating lymphocytesfKrug et a!.; Helderman and Strom, 1977; Brown et at.; Berczi and agy p, 72], While naive lymphocytes have few detectable receptors for insulin, once activated they produce 6000 [Helderman and Strom, 197S]. Thus, the endocrine mix of the adaptive immune phase supports the full activation of antigen-selected and cytokine- stimuiated lym hocytes. The selected c!one(s) are able to acquire from the metabolic poo! the nutrients they need to proliferate and perform their function of eliminating targeted antigens. The rising levels of insulin and the cytokines released by lymphocytes also stimulate macrophages and natural killer {MK} cells to act aggressively [Costa Rosa, et al], but are anti-inflammatory.

[0079] The endocrine profile in this second phase is also immunosuppressive. Glucocorticoids continue to be high, suppressing proliferation of clones stimulated by any secondary infection, it is believed that lucocorticoids working synergisticaily with cytokines are mostly responsible for the immunosuppression. However, if insulin is high {>40}.tU/ml} when a new cascade begins, it can add to the suppression of newly stimulated T lymphocytes [fV!ito, N. et a!.; offler], This contributes to Antigenic Competition which will be discussed later.

[0080] Cells of the adaptive immune phase are elegantly specific and highly efficient killers as well as potent regulators of the immune cascade. But they are also more vulnerable to negative interference than cells of the innate immune phase. They In order to function properly, they must {1} bind tightly to antigen presented in the fv HC, {2) receive stimulation from cytokine(s), and {3} be stimulated by insulin, Lack of any one of these will cause functional inactivation [Rudd| or anergy, a reversible loss of function [Hirsch and Kroemer p, 4], PHASE til. HEALiNG PHASE

[0081] The third, healing phase, features deletion of lymphocytes that could cause autoimmunity, transformation of some activated lymphocytes into memory ceils, and restoration of damaged or destroyed tissue, Natural T-regu!atory cells (nT-regsj from the spleen appear in the circulation, causing apoptosis of armed lymphocytes. Some CD4+ Th-1 cells transform into induced T-regs (iT-regs) and join in the suppression of activated lymphocytes [Chen and Oppenheim]. Lymphocytes and monocytes secrete the potently anti-immuneJYansforming Growth Factor-β (TGF- {5} into the wound and circulation, inhibiting lymphocytes from further proliferating and attacking targets, but stimulating repair of damaged tissue. CDS cells also participate in the suppression of immunity, but their action is still not well understood Nelson].

[0082] The endocrine mix changes a third time. Insulin sinks to normal or even lower levels while counter-regulatory hormones and glucocorticoids continue to produce insulin resistance in peripheral tissues. The fiver and other tissues produce high levels of Insulin-like Growth Factor- i f IGF-1). Dividing ceils of damaged tissues produce receptors for this hormone and are therefore able to access the nutrients.

[0083] Thus, in ail three phases the endocrine mix is immunosuppressive and catafooiic, or at least anti- anabolic, and stimulates insulin resistance, in the healing phase of the immune cascade the effect is to preserve nutrients for repair of the wound and deny them to immune ceils, thereby further downregu- fating the immune response. Physiological concentrations of !GF-1 have a profoundly suppressive effect on fyrrtphocytes[Himt and Eardley]. Moreover, IGF-1 causes systemic production of Transforming Growth Factor-p^" fTGFp) to increase substantial !y. It is significant that when T-ceils are activated, receptors for !GF-1 on their surfaces vanish and there is a reduction of IGF-1 mRNA production by the activated T-cells, IGF-1 receptor re-expression reaches high levels after 48 hours [Segretin], Thus, when a T cell is activated it loses receptors for IGF-1 and displays about 6,000 receptors for insulin. After the 48 hours it needs to perform its function, the lymphocyte again expresses !GF-1 receptors and ceases its cytotoxic activity. During this healing phase the patient is extremely vulnerable to opportunistic infectious agents. HORMONES

[0084] So, whi!e the endocrine mix appearing in each of the above three immune phases is immunosuppressive, insulin, which appears in the adaptive immune phase {Phase Si}, provides a powerful stimulant to selected immune cell clones, in fact, insulin is as powerful a stimulus to adaptive immunity as Cortisol is a suppressor.

[0085] Insulin rises in the adaptive immune phase for onfy two to three days, to a tightly controlled level {30 ± 5 μμυ/mi) [Rayfiefd, et a!.} in the blood and exerts its effects only on lymphocytes already antigen-selected and cytokine-stimuiated. Insulin below this level fails to stimulate lymphocytes and above 40 μυ/mi becomes suppressive [Hunt and Eardley]. [0086] Even after so brief a description of the three endocrine mixes secreted during an immune cascade, it can be seen that hormones have a powerful effect on immunity. As one investigator concluded: "[Tjhe neuro-endocrine system is the highest regulator of immune reactions and has the capacity to regulate immunocompetence; to increase, suppress, and ba!ance immune reactions; to promote selectively either cell-mediated or humorai immunity; to initiate immunoglobulin ciass switch; to induce or abolish immunological tolerance; to maintain immunological responsiveness in privileged sites; and to correct the age-related decline of immune function," [Berczi and Nagy, p. 107]

CAUSES OF ADAPTIVE IMMUNE PHASE FAILURE

[0087J The question is: if metabolic syndrome is a consequence of a failure by the adaptive immune system to meet an antigenic challenge, what caused that failure?

[0088J Stress and various pollutants and drugs can diminish the immune response. But for the diseases discussed herein, the causes of adaptive immune phase suppression are typically the presence of a preexisting infection, a healing wound, or a tumor.

Antigenic Competition

[0089] The most common cause of adaptive immune phase suppression is antigen competition. When a patient is already battling one infection {#1} and is exposed to a second microorganism (#2), lymphocytes selected to meet the second challenge cannot activate because of the immunosuppressive endocrine mix. The response to infection #1 will usually continue, with selected lymphocytes for infection #1 activating and efficiently destroying the invading pathogens, although healing may be delayed. But, as we have seen, the endocrine mix from infection #1 is so suppressive that lymphocytes selected by Infection #2 cannot fully activate. Cortisol wilf be immunosuppressive to lymphocytes of infection #2 [Roitt, p. 169]. And If insulin levels have reached their peak, they add to the suppression of lymphocytes that have not been antigen-selected [Koffier]. In addition, if levels of IL-l, T Fa and IFN are high 24 hours before antigenic selection in Infection #2, activation of lymphocytes is interfered with prevented Op- penheirrt pp. 84 ff|, Lymphocytes in Infection #2 become anergic. And if Infection #1 is already in the adaptive phase, iymphokines will even reduce the proliferation and function of ΡΜΝε and monocytes. The primitive, inefficient innate phase, now weakened, is left to deal with the pathogens in Infection #2. The immune response to the second infection is reduced. The response to infection #2 will usuall continue and often it cannot rid the body of these pathogens and injurious inflammation caused by infection #2 becomes chronic,

[0090] Even after Infection #1 has fully resolved, the brain is still receiving messages from damaged tissues of Infection #2 that the body is host to an infection, it continues to support the innate immune phase with the endocrine mix described above for the innate phase, featuring glucocorticoids, glucagon, growth hormone, catecholamines and low insulin and thyroid. That is the endocrine mix that characterizes metabolic syndrome. In time, insulin levels will rise as the body tries to deal with hyperglycemia. Lymphocytes are not activated by the slow rise of insulin levels as they respond to this slow rise of insu- iin by producing fewer insulin receptors [ offler (2991)3, in some cases, the chronic inflammation will resolve ove time. In others, such as periodontal disease, sinusitis, irritable bowel syndrome, chronic fatigue syndrome, and neuropathies [Oldstone, p. ix], it may continue for years.

Consequences of Chronic inflammation

[0091] A serious consequence of this chronic inflammation is that so iong as it lasts, the patient will have metabolic syndrome and be unabie to produce a robust adaptive immune response to a new infection. The patient will accumulate other chronic inflammations, autoimmune diseases or cancers [Car- stenetes et a!.; Ami!].

[0092] Sn industrialized countries, 40% of the populace have metabolic syndrome by age 60. Elderly people often accumulate several chronic inflammations over the years that cannot be resolved by the innate immune system. So chronic inflammations accumulate for persons with metabolic syndrome. Persons with one chronic inflammation are more likely to have another, or to develop an autoimmune disease [Svleggs, pp 6-9].

[0093] Healthy young persons can also be victims of inappropriate inflammations. For example, if a young adult is fighting one infection and is exposed to H1N1 influenza, he will be unable to deal effectively with the flu. The virus will multiply, sometimes with fatal results. Or if the f!u was Infection #1, and another infection was secondary, the latter can become virulent or chronic, depending on the kind of microorganism involved.

[0094] Another example of the immunosuppressive consequences of metabolic syndrome is HIV, Sn Africa and many other underdeveloped areas,, residents carry within themselves a number of chronic infections. When exposed to the inefficient HIV, they cannot mount a lymphocyte defense and AIDS becomes one more chronic disease to afflict the patient, this time fatally. In the United States it has been a mystery why AIDS is virtually confined to homosexuals and substance abusers, even though other populations have been exposed, But both those groups were often afflicted with other chronic diseases,, such as hepatitis B, enteric diarrheal diseases such as amebiasis and giardiasis_,, and sexually transmitted diseases such as gonorrhea and syphilis [Oidstone, p. 268]. Such chronic infections cause metabolic syndrome with the accompanying suppression of the acquired immune phase, which permits H!V to become established.

[0095] Where there is a chronic inflammation, there is some degree and type of metabolic syndrome, and where there is metaboiic syndrome there is vulnerability to new infections. Treating symptoms to reduce the inflammation can have a palliative effect but does nothing to resolve the disease. Cortisone can give relief to those who suffer from rheumatoid arthritis or lupus but cannot cure the disease. A way that amelioration or cure of chronic inflammation caused by secondary infections can be effected is by stimulating the selected but anergic lymphocytes to activate, suppress the inappropriate chronic inflammation (innate immune phase), destroy the pathogen and initiate healing. This can be done by administration of insulin, as described below, insulin can provide that stimulation. Autoimmunity

[00&6J There has been much discussion of the similarity of autoinfiammation (chronic inflammation} and autoimmunity, in rheumatoid arthritis, which is considered an autoimmune disease, ceils of the adaptive immune system are present, but there is a dearth of cytokines from those cel!s [DinareiSo and Moldawer, p. 110}. The damage done to tissues is more like that caused by the innate immune system. Autoimmune diseases are chronic, while an attack by lymphocytes against pathogens is so deadly that once it begins the pathogen is cleared from the circulation in hours. Why does the immune system of a mature adult suddenly attack the self after years of norma! tolerance? Healthy persons possess autoreactive immune ceils, yet those ceils do no harm, in fact, Michael Schwartz and colleagues have demonstrated that the same cells that produce autoimmune disease play a protective role in defending the self against trauma in the C S [Schwartz and ipnis]. Self-reactive cells play an important rofe in the "clean up" after an insult. Under the influence of T-reg cells, they normally transform into T-regs, die, or become anergic.

[0097] Strictly speaking,, it is improbable that there is such a thing as autoimmunity. It is more like!y that the cells of the pancreas (or brain or kidney, etc,} have become infected with a virus and leukocytes are trying to kii! infected cells. Suspicions are increasing daily that autoimmune diseases are caused by microorganisms, St has recently been suggested that Heliobacter pybri may trigger Parkinson's [Saey]. Increasingly, there is specufation that schizophrenia and bipolar disorder are due to infection with a virus [Ewald, p, 155]. Atherosclerosis is considered by some to be an autoimmune disease [Ewald, p. Ill], or due to an infection [Weber]. And it has long been known that the development of Insulin-Dependent Diabetes tvlellitus, rheumatoid arthritis, Reiter's syndrome, Gui!iain-Barre Syndrome and Multiple sclerosis are preceded by a viral or bacteria! infection or vaccination [Baker; Stove and ZarnviS; Dianare!io and Moldawer p, 131], As one author has put it, "For the few common diseases in which autoimmunity is well understood, an infectious agent is the cause of the trouble, " [Ewald p. 1123. 8"t if this is true, why does the Adaptive System not quickly clear the system of the microorganism? Because of the existence of a chronic inflammation and its accompanying metabolic syndrome that prevents the appropriate clone(s} of lymphocytes from activating.

[0098] And yet, for ail their similarities,, autoinfiammatory and autoimmune diseases are different. Autoimmune diseases are transferable to a healthy animal by transplanting T-ce!Ss or antibodies from a sick animal [Kodama; Koarada; George],

[0099] in terms of the model presented here, autoinfiammatory disease is the result of the immune cascade being stalled in the Innate Phase and unable to enter the Adaptive Phase as seen in Infection #2 of antigenic competition. There are no lymphocytes present to restrain the innate response or to destroy remaining pathogens. Autoimmunity is defined as the cascade being stalled in the Adaptive Phase and unable to enter the Healing Phase, The question is how to move both cascades ahead in the normal way, ending with the appearance of T-regs.

2¹? [00100] In the present mode!, autoimmunity is also considered to be the result of antigenic competition, if the response to infection # I is well along in the adaptive phase but Infection #2 is significant, the brain will interpret the messages it is receiving from damaged tissues (from infection #2} that it is time to reduce the insulin secretion but too early to secrete IGF-1 and to move to the healing phase. Proinflammatory cytokines and endocrines will continue. iL-6 is linked to autoimmune disease [Hammond and Poltergeist, p. 323], If iL-6 remains high in the circulation, and TGFjS rises, instead of naive T lymphocytes being transformed into the T-regs that prevent autoimmunity, they become the proinflammatory Th-17 f!vlucida et ai. v, 34]. Of the T-cei! clones established from synovial tissue of patients with rheumatoid arthritis, nearly all Th-I and Th-0 clones produced IL-17 . . , ," [Dinare!lo and Moldawer, p. 77] . It is important that in autoimmune diseases such as rheumatoid arthritis and !upus, IGF-1 levels, the sign of the hea!irtg phase, and insulin, the sine qua non of a robust lymphocytic response, are both low.

[00101] in fact, oitt et ai state that "the erosion of cartilage and bone in rheumatoid arthritis is mediated by macrophages and fibroblasts, which become stimulated by cytokines from activated T-ceSis and immune complexes generated by a vigorous immunological reaction within the synovial tissue . . . . '^* and go on to say that "it is difficult to identify a role for the T-cei! as a pathogenic agent as distinct from a T-helper function in the organ specific disorder." [Roitt]. Furthermore, IL-2-deficient mice which also lack CD-8T-celis stifl develop colitis even with accelerated kinetics [Nelson], As Dinarello and Moldawer have said, "[Tjhere is now growing recognition that persistent activation of the innate immune system occurs in a variety of autoimmune diseases including rheumatoid arthritis. This prolonged activation leads to the conditional complaints, metabolic abnormalities, and destruction and remodeling of tissues experienced by patients with chronic and uncontrolled progressive disease." [Dinarello and Moldawer p, 16], So, if the second infection is significant and occurs at an inopportune time, it can disrupt the normal response to the first infection, causing it to degenerate into a chronic, autoimmune reaction,

[00102] B. Nelson reported that in seeking to know just how important SL-2 was to the immune response engineered mice that did not produce the cytokine, he was surprised to find that the mice were still able to deal with viral infections. And he was even more surprised to find that ail the mice later developed an autoimmune disease [Nelson]. So !L-2 was apparently more important as a protection against autoreactive cells than as a stimulus to immunity. In addition, Nelson found that the autoimmune reaction always involved a pathogen. For example, many of the mice developed fatal colitis, but in mice bred in isolation from intestinal flora, the animals did not develop the disease [Nelson]. It is submitted herein that autoimmunity develops when Infection #2 causes such damage to tissues that the brain is deceived by a shower of cytokines into thinking it is premature to proceed to the adaptive phase in infection #1 and stops it in progress. Thus, there is insufficient !L-2 to induce full maturation in CD4 and CDS cells, Th-17 ceils are unrestrained, and continue to summon innate ceils to the affected organ. While they are unable by themselves to resolve the infection, they damage host tissues. [00103] A way to rid the body of a harmful autoimmune disease is therefore to restart the stalled cascade, immunosuppression will not do that, Schwartz and Kipnis have rightly concluded ". . . for the treatment of autoimmune diseases, our findings argue in favor of therapy based on immunomodu!ation instead of immunosuppression [Schwartz and Kipnis}.

[00104] Administration of insulin as described herein provides such immunomodulation. T helper ceils will reactivate, and secrete !L-2 and other lymprtokines to downregulate the innate attack, stimulate lymphocytes to destroy pathogens and produce T-regs to shut down the entire immune reaction and let healing proceed.

Healing Wound

[00105] Just as antigenic competition can cause paralysis of the adaptive immune system, so can healing, with serious consequences. It has long been recognized that if injured, the body of a host will cannibalize other tissues to provide a wound with the nutrients it needs to heal. To effect this, the brain changes the endocrine balance, as we have seen, to one featuring low insulin, high SGF-1 and growth hormone and continuing higher-than-normaS levels of glucocorticoids. TGFp also rises in the circulation, further suppressing immunity and stimulating cellular growth. Since this hormone mix produces insulin resistance in peripheral tissues, glucose levels rise in proportion to the severity of the wound, providing the energy needed by the rapidly-dividing cells of wounded tissues. As the wound heals, glucose levels drop and eventually return to normal.

[00106] During this healing phase, if the patient is infected with a microorganism, the innate immune system will be able to mount a defense, but the more sensitive lymphocytes are rendered anergic by the lack of insulin and the rise of IGF-1 and TGFp. If the microorganism is virulent, sepsis will be the result, since lymphocytes will be unable either to destroy the pathogen or to restrain the innate immune response. Monocytes and polymorphonuclear leukocytes {PMNs}, not under the regulation of lymphocyte-derived cytokines, can multiply explosively, damaging organs and even causing death. If the infection is less serious, it will become a chronic inflammation. The method provided herein to terminate a harmful infection that develops during recovery from a wound is to enlist the assistance of lymphocytes that have been rendered anergic by lack of insulin stimulation. This can be done by infusion of insulin during and after surgery, providing exogenously the materials needed by the lymphocytes while the body devotes endogenous resources to healing.

Cancer Treatment

[00107] "A systemic disease demands a systemic cure [Mukherjee]. But what kind of systemic therapy could possibly cure cancer?" The answer is immunity. Activated lymphocytes, macrophages and natural killer ceils can relentlessly hunt down all malignant ceils and kill them. But this can happen only if selected lymphocytes are roused from their anergy. Cytokines administered alone or in combination are too toxic [Bjarne et at], and their actions cannot safely be predicted. One has only to think of the TGN 1412 trial in which six young volunteers received a very smai! dose of anti-CD-28 and within minutes almost died [Suntharaiinjam ef si.].

[00108] It is established that lymphocytes are cbemotacttcally attracted to a tumor and infiltrate it. But then the high levels of TGFp produced by the tumor transform some T-celis into T-regs and cause anergy in the others. But when the energy of selected clones is overcome and the adaptive system is restarted, a povverfu! immune response will quickly destroy the tumor. The treatment disclosed herein can rouse such inert,, anergic lymphocytes.

[00109] The present investigator developed the model of immunity disciosed herein while working in the fie!d of oncology. Seeking the reason the immune system did not destroy tumors, he noted that the endocrine and metabolic environment of the body during an infection was different from that during recovery from a wound. In addition, the endocrine mi when the patient is host to a tumor is identical to that when the patient is recovering from an infection, injury or surgery. He concluded that the brain was "deceived" by growth factors produced by the tumor into "thinking" there was a wound to heal, and the brain therefore commanded the hormonal mix that caused peripheral tissues to be cannibalized of nutrients which were provided to the tumor/wound [Homburger]. Just as a chronic inflammation means the immune cascade is stuck in the innate phase and cannot enter the adaptive phase, and as an autoimmune disease means the cascade is stuck in the adaptive phase, a tumor means the cascade is stuck in the healing phase, producing another version of metabolic syndrome.

[00110] This inventor hypothesized that if the endocrine environment could be changed to that whichexists during a primary infection, inert lymphocytes would activate and destroy the tumor.

Sepsis

[00111] Sepsis occurs when the body cannot produce a robust adaptive response to a potent microbial challenge. Most commonly, it happens when the body is in the recovery mode, as after surgery, when immune suppression is greatest. The endocrine mix is powerfully immunosuppressive because the body is devoting metabolic resources to healing. Insulin is low. As the new pathogens arrive, they are phagocytosed by dendritic cells (DCs) and macrophages and presented to selected lymphocytes, which bind poorly, and begin inadequate differentiation and proliferation [Louten, Sergejeva]. IGF-1, ordinarily secreted in high amounts during healing phase, falls as SL-1, TNFa, fFN, TGFp and IL-6 levels rise. !L-6 even rises as high as 7,500 times normal. This mix of cytokines produces greater numbers of Th-17 cells which secrete !L-17, summoning ever more PMNs and monocytes. Since lymphocytes specific to the pathogen are anergic and release no 11-2 and 11-10, T-regs do not develop. Without that restraint the innate system goes wild.

[00112] irnmunoenhancement is an effective treatment. Insulin will provide anergic lymphocytes the stimulus they need to attack the pathogens and release 11-10 and il-2 to restrain the innate phase. CTLs will attack infected cells and plasma cells will release antibodies to bind to humoral pathogens, insulin also stimulates phagocytosis by macrophages fWeeker]. Obesity

[00113] It is commonly thought that obesity causes metabolic syndrome and fat produces inflammation. For example, it is known that obesity is accompanied by impaired T-eell numbers and proliferation. Many interpret this to mean that obesity dovvnreguiates immunity. However, the opposite is faeiieved to be true. The existence of a chronic inflammation is the cause of much obesity. Inflammatory mediators have the potential to impact a surprising range of diseases, including obesity and its associated metaboi- ic syndrome fZuniga et ai.]. Inflammation causes metabolic syndrome and insulin resistance, which in turn causes some degree of hyperinsulinemia, causing hunger and storage of glucose in fat. insulin need not be very high to cause this effect [Taubes; Rodin],

[00114] The reason obesity is increasing so rapidly is that more people have chronic inflammations. In fact, all the diseases listed here that are associated with metabolic syndrome are increasing. This is faeiieved to be so because people live in such propinquity. Also, there are so many over-the-counter drugs to suppress symptoms that people return to work or school before they have fully recovered from a disease such as influenza and are then susceptible to a secondary infection, it is also possible that the patient does not take the full course of antibiotics or goes out in public before having fully recovered. Vaccination

[00115] The concept of antigenic competition sheds light two of the mysteries surrounding vaccination. It long has been known that vaccinations are sometimes followed in a few days by an iilness. Sometimes it produces little more than a malaise and is attributed to the vaccination itself. Other times it can be a serious illness, After the mass vaccinations for swine flu a significant number of people fell victim to Guiliain-Barre syndrome. And parents of children with autism often maintain that their children were healthy until they received one of the standard childhood vaccinations. They blame the vaccination for their children's autism. But extensive studies have failed to find any causal connection between the two. Still, parents continue to describe a normal child before vaccination, then an illness with a high fever followed by their child sinkin into autism. This author suggests that while the vaccination did not cause the autism, it did suppress the child's immune system for a time, permitting an infection unrelated to the vaccination to take hold,

[00116] As we have seen, the body can mount only one adaptive response at a time, it must be remembered that when a person is vaccinated the body goes through a full blown immune response, from the innate phase through the adaptive phase and even into recover/. The antigen must be phagocy- tosed by dendritic cells, and presented to lymphocytes. T and B cells must perform their work and then become memory cells or undergo apoptosis. Admittedly, a vaccination is not as challenging as the response to an infection, but it still leaves the patient vulnerable to a new pathogen. As we have seen above, the result will vary with the pathogen. But the person who becomes victim to an infection while the body is dealing with the vaccination will be left with a chronic inflammation or autoimmune disease. The chronic disease can be effectively dealt with by restarting the immune process, as described in the treatment section be!ow. The problem can be avoided if it is recognized that during the period folio - ing a vaccination the patient is vulnerable to infections. Children should not be permitted to go to school or play with others for a few days. Adults should not go to work or be in a crowd.

[00117] In addition, the concept of antigenic competition sheds important light on the reason some people react weakly to a vaccination. If a person harbors a chronic inflammation, as we have seen, his ability to mount a strong adaptive response to new antigenic challenges is compromised, in the same way, the patient will respond weakly, if at all, to the vaccine. People with chronic inflammations should be treated as described below before accepting vaccinations.

Conclusion

[00118] in conclusion, sepsis, cancer, chronic diseases and the accompanying metabolic syndrome are due to the failure of the adaptive immune system to activate fully and destroy a pathogen or tumor. Metabolic syndrome is a neuroendocrine response that is not only immunosuppressive but also has its own harmful side effects such as Cushing-!ike hypercortisoiism [Anagnostis], Such diseases can be cured by stimulating anergic lymphocytes to activate and perform their normal functions of downregulating the action of polymorphonuclear ieukocytes and monocytes, destroying pathogens and then promoting healing. . This is done by an infusion of insulin to maintain biood levels mimicking those occurring during the adaptive phase of the immune response to a primary infection.

TREATMENT

[00119] To propose that increasing insulin levels for 24-96 hours will restore systemic immunity to such potency that hundreds of chronic diseases will be cured may seem bold, since patients suffering from many of those diseases already have elevated insulin levels. Of course, cancer patients have low insulin values because they are in the recover/ phase, as described above. But many patients harboring a chronic inflammation have higher levels of the hormone than is needed to trigger a potent adaptive response in norma! people, That is particularly true in the classic form of metabolic syndrome in which the patient is obese. But the treatment described below is effective in restoring immunity and ending chronic inflammation even in the obese.

[00120] offler et. at, studied the effect of hyperinsu!inemia on afloactivated lymphocytes from normal and obese subjects, !t had previously been established that insulin did not either affect the binding of lymphocytes to antigen presented them or decrease the absolute number of cytotoxic T lymphocytes. It was also known from previous studies that insulin at physiological levels enhances cytotoxicity of those cef!s [Koffler (1991)], And it has been shown that since lymphocytes could sense the level of insulin in a culture before activation but could not participate in any feedback control over secretion of the hormone, they adjust to rising levels of insulin by increasing or decreasing the number of receptors. The investigators hypothesized that there were immunological consequences of that adjustment in receptor numbers [Koffler (1991)], [00121] Using the eug!ycemie/hyperinsuiinernic ciamp technique they created hyperinsulinemia and eug!ycemia in normal and in obese subjects. As expected, after sensitization to the antigen but before the hyperinsulinemia, normal subjects produced 6752 receptors; but after 4 hours of hyperinsulinemia, the number shrank by 75% to 1665 and "sensitized cytotoxic T-!ymphocyte killing was markedly reduced." Koff ier et αί stated: "in stark contrast was the absence of clamp-related changes in cytotoxic T- fyrnphocyte function observed in assays of cells removed from obese subjects." The number of receptors displayed on these cells after antigenic challenge but before the damp was begun were 33% fewer than those from norma! subjects; but there was no further reduction after the hyperinsulinemia, in addition,, while the killing response of lymphocytes from obese subjects before the ciamp was less than that from norma! subjects, there was no statistically significant further reduction in cytotoxicity after the hyperinsulinemia. [Koff!er {1991}3- So hyperirtsulinemia radically decreased function of selected lymphocytes from normal subjects, but had no effect on cells from persons with pre-existing elevated insulin.

[00122] As was mentioned bef ore, a naive, i.e., unseiected, lymphocyte can sense that the level of insulin is too high and, when stimulated by antigen, reduce the number of receptors it will present in order to protect against overstimulation. Lymphocytes must learn to do this because insulin levels are subject to many spikes, as after meals. If the rise in the hormone is acute the newly-selected cells produce so few receptors they cannot activate and perform their killing. But If the rise has been chronic, the lymphocytes have had time to adjust, present the appropriate number of receptors, and mount a defense against antigenic challenges. Thus, obese patients or others with a form of metabolic syndrome can still mount at least a weak adaptive response to a new antigenic challenge. The response is strong enough to preserve life in most infectious challenges but may leave the patient with another chronic inflammation. The response is not normal because, as explained previously, metabolic syndrome causes production of an immunosu pressive mix of cytokines and hormones.

[00123] So cells rendered anergic months or years earlier by the cytokine and endocrine mix produced in response to a previous infection as described earlier have had time to adjust to slow rise in the insulin as the body responds to resistance in peripheral tissues. The anergic lymphocytes adjust to what is becoming a new norma! by down-regulating the number of receptors they present. But they retain their capacity to activate fully if they receive the correct signal. If the host responds to a new challenge, whatever surge of insulin that may happen does not act as a signal for them to come out of their anergy, because prior to whatever insulin occurred there was a surge in Cortisol to add to the already higher than normal levels. While there can be some activation of the clone selected by the new antigen, anergic lymphocytes cannot activate. However, no surge of Cortisol accompanies the additional increment of insulin infused in this treatment. Lymphocytes that have downregu!ated the number of receptors they present can respond to the signal, activate, attack the pathogen causing the chroni inflammation, release cytokines to downregu!ate the harmful innate response, and carry forward the cascade into the healing phase. Thus, the treatment for those with pre-existing hyperinsuiinemia is the same as for cancer patients who have hypoinsuiinemia.

[00124] The treatment itself is simple, but Sike all simpie things, must be well understood and carefully executed. As explained in the section on cancer, insulin, potassium and glucose are administered intravenously, with insulin maintained at about 15 to about 25 μϋ/m! above the patients normal pre- treatment fasting blood insulin level for about 24 to about 48 hours or longer, e.g., about 96 hours, to be maximally effective, if insulin is not administered by infusion, the liver will be able to counter what is being done by extracting and dismantling the insulin. Usually insulin is administered at this level will bring blood insulin to the target level. The same dose will increase plasma levels of insulin by 15- 25 iU/m! in obese subjects and activate anergic lymphocytes. After meals, it will spike, but the brief increase will not affect the immune response. Glucose and potassium can be adjusted to avoid hypokalemia and hypoglycemia. Of course, individuals vary in their sensitivities to insulin and the physician may have to make adjustments in the dose being infused; but the amount recommended here, when infused, has been shown to move potassium from plasma into the ceils. This enables the enzymatic reactions necessar for final activation. The same dose raises insulin by the same increment in patients suffering from hypennsuiinemia,

[00125] if a patient's glucose level falls to about 100 mg/dl, glucose administration should be increased, if a patient's potassium blood level fails below about 4 mEq/L, the dose being administered must be increased to bring the level to at least about 5 mEq/L, and in embodiments at least about 6 mEq/L Usually, insulin infused at about 0,1 U/kg/hr will bring blood insulin levels to the target level. A rule of thumb is to administer about 5 grams of glucose per unit of insulin being infused.

[00125] If the patient does not develop a fever within 12 hours, insulin can be increased to 0,15 U/kg/hr. insulin levels can be checked before breakfast lunch and dinner. Glucose can be checked every one to two hours. If the patient becomes hypoglycemic, glucose administration is increased; but the insulin dose is not altered. The patient will become feverish and develop mild flu-like symptoms. This is a sign that the immune cascade has re-started. Of course, in case of septic patients, they will al eady be febrile since the body is in the innate phase of the immune response. However, their insulin level will be low and this treatment will move them from the innate to the adaptive phase.

[00127] In cancer treatment, a fever is a sign that the immune response has begun, if the fever should rise to a dangerous SeveS, it is because the tumor is being destroyed and the patient's liver cannot extract and destroy the toxins rapidly enough. Treatment is suspended until the fever has declined, then resumed. The method should be supervised by an internist skilled administering insulin or an experienced endocrinologist.

[00128] Insulin plasma levels to be maintained during insulin infusion should be high enough to stimulate the adaptive immune system but not so high as to interfere with lymphocyte functionality, in gen- era! blood insulin levels insulin levels 15-25 mU/mi above the patient's norma! pre -treatment insulin !eve!s should be maintained during the treatment.

[00129] !n summary, the treatment method is to administer insulin at 0,1 U/kg/hr, which can be increased to 0.15 U/kg/hr if no fever develops within 12 hours, for a period of 48 to 96 hours in order to raise and maintain the patient's p!asma insulin levels 15-25 μϋ/mi above the patient's normal pre- treatment plasma insulin level.

[00130] Patients who can benefit from this treatment irtc!ude all patients with metabolic syndrome no matter what their norma! pre-treatment pSasroa insuSin level is. Many markers for metabolic syndrome are known to the art. For example,, patients with higher-than-norma! inflammatory markers such as IL-6, even if they have higher-than-norma! levels of insulin, can he successfully treated. More specifically, patients who can benefit from the treatment hereof include: all patients with cancer; ail patients with sepsis; all patients with chronic inflammation, and a!! patients with autoimmune disease.

[00131] in addition, all patients with acute infectious diseases and fasting plasma insulin levels greater than 40 mU/m! (which high insulin leve!s indicate that a norma! adaptive immune response is being prevented} can benefit from the treatment.

[00132] Patients who develop an infection after receiving a vaccination which turns into a chronic inflammatory condition are among those who will benefit from receiving the treatment as soon as possible. In addition, patients who wish to receive a vaccination, such as many e!deriy patients, who already have an infection or chronic inflammatory condition should be treated by the method hereof before receiving the vaccination.

[00133] Patients in need of the treatment hereof are considered herein to be ail patients who can benefit from the treatment,

[00134] Patients who should not be treated by this method are patients with acute infectious diseases and fasting p!asma insulin levels of 25 pU/mS or more and less than about 40 μϋ/mi. Such insulin levels indicate the patient is probably already mounting a norma! adaptive immune response and the treatment could incapacitate the lymphocytes involved in this norma! response. However, if the patient also has a history, or strong signs of metabolic syndrome, and fasting insu!in levels of about 35 or greater μυ/ml, then the patient can benefit from the treatment method hereof.

[00135] Persons who should not be treated by these methods include those who have received a transplant; persons with advanced brain tumors that are like!y to swell; persons with unduly large tumor burdens as tumor disintegration might produce dangerously high !eve!s of toxins; persons with kidneys unable to process the fluids; persons with insulin a!!ergy; and persons with fasting insu!in !eveis at or above target !eve!,

[00136] The following examples are illustrative, and not limiting. The scope of the claims is defined by the elements recited in the claims and equivalents thereto. EXAMPLES

Example 1. Need for continuous insulin infusion [00137] FDA and i B permissions were received for human tests. Volunteer patients protested against hospitalization, and it was reluctantly agreed to let them be treated as out-patients. They received one shot of long-lasting insulin in the morning and g!ucose and potassium pills to take during the day. They all responded with flu-like symptoms and a rise in the CD4/CD8 ratio from sub-normal to as high as 71/1. Analysis of the data showed that only occasionally for short periods did insulin levels in the biood rise to targeted levels. A patient would be given a certain dose of insulin one morning and his biood ievei would rise to 24. The next day after receiving the same dose, his b!ood level would drop to 12. It was hypothesized that the body was resisting our treatment, trying to hold levels at the lower-than- normaf levels common for cancer patients.

[00138] This example indicates that intravenous infusion of the cocktail of glucose, insulin and potassium 24 hours a day ensured effective treatment. Insulin infusion for at feast about 24 hours, and up to about 48 to about 96 hours or more can be required depending on the patient's response.

Example 2. Metastatic breast tumor shrinkage

[00139] Mrs. A., a SS-year-oid mother of five, presents with metastases of breast cancer to the lungs, bones and mastectomy scar. She is anorectic and cachectic, short of breath and walks sfow!y with assistance of her husband. He explains that she has endured a radical mastectomy, oophorectomy and hormonal therapy. He reports that she refused further conventional therapy but was persuaded by her oncologist to accept this treatment because it uses on!y "natural" materials. After a fu!i explanation of the treatment, she agrees and enters the hospital the next morning. Fasting blood test shows insulin feve! of 7 μϋ/mf, glucose of 125 mg/di and potassium of 4.5 mEq/L Her CD4/CD8 ratio is 1.2/1.

[00140] infusion is begun at 8:00 am of insulin at 0.1 U/kg/hr (4.5 U/hr), glucose at 22 g hr, and potassium at 2 mEq/hr. She sleeps most of the morning but is awakened at 12:00 pm for lunch. She feels feverish and says she hopes she does not have the flu. It is explained to her that it is more likely that the immune system is actively attacking her tumors. She nods stoically. Her temperature at 2:00 pm is 100.5 ^C'F, She sleeps most of the afternoon, awakens at 4:30 pm complaining that she is "burning up," aches ail over, particularly in the upper legs, and is finding it harder to breathe. Pre-prandial tests show insulin at 32 μυ/mi, glucose at 135 mg di, and potassium at 5.6 mEq/L. The tumors on her mastectomy scar are swollen and tender and she agrees to aspiration. Microscopic examination shows them filled with a clear liquid and many lymphocytes and macrophages. She watches television with her husband and falls asieep by 9:00 pm. She awakens at 4:00 am when more biood is drawn and says she is very hot. Her temperature is 102 °F, Her gown is sweaty,

[00141] She is awakened at S:00 am for the drawing of biood and for breakfast. Afterwards, she accepts a sponge bath and change of gown. She drinks some juice and eats a few bites of oatmeal. Her serum insulin level is 34 μϋ/mf and her temperature 100,5 °F, Later, it is learned that her CD4/CD8 ratio at this point is 18. A finger stick reveals her glucose level has dropped to 30 mg/di and glucose administration is increased to 25 g/L. she feels no side effects from the hypoglycemia. [00142] Her children come to visit and she insists on walking them to the elevator, pushing her pump ahead of her. Back in bed, she sleeps untif 12:00 pm when she eats half her iunch. Her temperature has fallen to 99.7 °F, insulin is 30 μϋ/ml and her CD4/CDS ratio is 30/1.

[00143] She insists on getting out of bed to urinate and says to her nurse, "I am afraid to admit it, but ί feel better."

[00144] At 6:00 pm, she eats most of her meai. Her temperature is 98.6 ^JF, blood insulin level is 26 μυ/mi and her CD4/CDS ratio is 48/1. She watches TV with her husband until 10:00 pm, then sleeps.

[00145] Awakened at 7:00 am, she says, "That is the best night's sleep I have had in weeks." Her temperature is normal, the catheter is removed and she takes a shower on her own. Her insulin level is 22 μυ/rnl and her CD4/CDS ratio is found later to be 53/1. She eats a fuiS breakfast and is examined by her doctor who says the two tumors on her scar now Sook like collapsed blisters. She says she feels no pain and can breathe normally. She is instructed to return in a week for an exam and MR!.

[00146] When she reports for her examination one week later, she says she has been eating ' ike a pig" and fee!s good. The MR! shows no sign of tumors in her !ungs or femurs, insulin, glucose and potassium levels are norma!. CD4/CD8 ratio is found to be 62:1.

Example 3. HINl-associated acute respiratory distress syndrome {ARDS}

[00147] A thirty-two year old white woman appears at the emergency room with ciear case of seasonal flu. She is given aspirin and cough suppressant and toid to stay in bed untif she feels better. Four days later she returns with the assistance of a friend. She is in distress, unable to walk alone, breathing with difficulty, bareiy conscious. Her friend says she had recovered from the f!u and returned to work as a legal secretary, then suddenly co!fapsed. She is hospitalized in the ICU, diagnosed as suffering from H1 1 complicated by ARDS. Tests show profound depletion of both CD4 and CDS cells, blood insulin level of S μυ/mi, temperature 101.5 ^aF, The emergency physician sends her to the ICU to be treated with this intensive insulin therapy. She receives 0.1 U/kg hr of regular insu!in, 2 mEq potassium chloride per hour and enough glucose adjusted to produce a slight hyperglycemia (125 mg/di/. Ali materials are infused. At three hours her temperature is 101.8 °F. Tests at 8 hours show blood insulin level at 32 μυ/ml , glucose steady at 125 mg/d! and her CD4/CD8 ratio at 15/1, temperature 101.2 ^" F. She remains unconscious.

[00148] At 24 hours she awakens, is confused but asks for a bed pan and urinates normally. She drifts off to sleep immediately. Her temperature is 100.2 °F. At 36 hours her temperature has fallen to 99.5 °F and her breathing has improved. Her CD4/CD8 ratio is 42/1 and her b!ood insu!in is 30 μυ/mi.

[00149] At 42 hours she opens her eyes, blinks, asks where she is. When toid she nods, closes her eyes and goes back to sleep. Her temperature is 99 °F. At 49 hours she awakens, asks for water and stays awake. Her temperature is normal. She is offered food and asks for chicken noodle soup, slowly eats it and goes back to sleep. At 54 hours she is disconnected from her i.v. Her b!ood insu!in is 22, temperature normal, CD4/CD8 ratio is 44/2, She leaves the hospital 3 days later, accompanied by her friend. Her further recovery is uneventful.

Example 4. insulin-Dependent Diabetes Mei Situs

[00150] A 23-year-oid white man presents with Type I Diabetes ten weeks after a bout with coxsackie B4 virus. He is admitted to the hospitai for treatment. Tests show 10-20% of his beta cells remain. Fasting insulin level is 3 μυ/rni, glucose is 215 mg di and K+ and temperature are normal His CD4/CDS ratio is 4/1.

[00151] Treatment is begun at S:00 am. Regular insulin is infused at 0.1 U/kg hr, glucose at 2 grams per hour and potassium at 2 mEq per hour. He walks up and down the hallway, pushing his pumps ahead of him, then watches TV. At 12:00 pm, his insulin is 25 μϋ/mi, K+ normal and glucose 250 mg/d!.

[00152] Administered glucose is reduced to 1 gram per hour. His temperature is 99.2 °F. He eats a normal funch. At 4:00 pm he complains that he feels hot and sick. His temperature is 101.2 °F. At 6:00 pm, insulin is 30 μϋ/mi, glucose 142 mg di, his temperature is 101,5 °F and his CD4/CDS ratio is 14/1. He has no appetite but accepts some soup, reads, watches TV, and sleeps.

[00153] He awakens at 7:30 am complaining that he feels sick. His insulin level is 28 μϋ/ml, glucose 130 mg/di, temperature 100.1 °F. When urged he eats some cereal and drinks orange Juice. At noon his insulin is 25 pU/mi, glucose 125 mg di, temperature 99.7 ^C'F, CD4/CDS 22/1. He walks the halls and reads. At 6:00 pm he says he feels much better, that his bug must have been a 24-hour variety. His temperature is normal, insulin 23 μυ/ml, glucose 115 mg/di and CD4/CD8 23/1,

[00154] The next morning his catheter is removed. His glucose le vel is checked every two hours for that day and night. It never rises above 116.

[00155] The next morning his fasting insulin level is 11 μϋ/ml, glucose 100 mg/di, and CD4/CDS ratio 12/1. He is instructed to test his glucose level regularly, as he had been doing, then report back in a week. At his return he says he feels good, his glucose levels have been normal. His fasting insulin level is 12 μΙΙ/ml, glucose and K+ normal, CD4/CDS ratio 4/1. Tests show 25-35% of his beta cells are functioning. Follow-up three months later shows all values normal and he has recovered 75% of his beta cells.

Example 5. Parkinson's Disease

[00156] A seventy-two year old retired army colonel presents with Parkinson's disease. He exhibits postural instability, muscular rigidity and expressionless face. His right hand trembles when at rest. He was treated initially with ievodopa but became unresponsive. Dopamine agonists were prescribed and taken for six months bu caused hallucinations and impulse disorder. For a year he has taken no medication. He is accepted for treatment.

[00157] Tests prior to treatment show normal temperature, fasting insulin level of 6 ?U/ml, glucose of 115 mg/di, and normal potassium. His CD4/CDS ratio is 3/1. A catheter is inserted in his left arm and treatment begun at 8:00 am. He receives 0.1 U/kg regular insulin, 2 mEq + and 2 grams of glucose per hour. At noon he is found to have a giucose level of 75 rng/dl, his glucose is raised to 4 grams per hour and he is urged to eat a candy bar. There are no side effects. He eats a light lunch at 1:00, fed by his wife, watches TV, then dozes for an hour. Pre-dinner insulin fevel at 6:00 pm is 26 ?U/ml, g!ucose 116 mg dl, normal K+ and temperature 99.9 oF. He eats a normal dinner, watches TV, visits with wife, daughter and grandchiidren, complains that he feeis hot and that his tremor is worse,

[00158] Next morning at 8:00 b!ood insulin is 31 ?U/mi, glucose 120 mg dl, K+ normal, CD4/CDS ratio 9/1, He eats normal breakfast, complains that he is still hot but gets out of bed by himself and goes to the bathroom. He is walking more steadily. He gets back in bed, stares at his right hand. There is no tremor. He grunts, watches TV. Before dinner, his insulin level is 30, CD4/CDS ratio is 16/1, temperature is 98.6 oF. He feeds himself. The next morning his insulin is 29 μϋ/mf, CD4/CD8 20/1. He eats a norma! breakfast and says he wants to go home. The catheter is removed. He insists on dressing by himself, walking to the front desk without assistance, and says to his physician, "By God, I think you fellows may have something here, i fee! good."

[00159] At his check-u in two weeks, all tests are normal, As he rises to leave, he turns and says, "By the way, ! had my annua! eye examination Tuesday, The doctor said my cataracts are gone,"

[00160] A!l references cited herein are hereby incorporated by reference to the extent not inconsistent with the disclosure hereof for purposes of enablement and written description. Although the description herein contains many specificities, these should not be construed as limiting the scope hereof but as mere!y providing illustrations of some of the presently preferred embodiments. For example, dosages iliustrated in the Examples can be adjusted as required to maintain appropriate biood levels of insulin, giucose and potassium, by one of ordinary skill in the art without undue

experimentation. Thus the scope of the invention should be determined by the elements of the appended claims and their equivalents, rather than by the examples given,

TABLE 1 SUMMARY OF NORMAL CASCADE PHASE t, INMATE PHASE

1. Pathogen invades, damages tissues; tissues release interferon.

2. Dendritic cells and resident macrophages phagocytose pathogens.

3. Dendritic cells, macrophages present antigen combined with Major Histocompatibility Complex (MHC), secrete il-l, il-6, !L-S. IL-23, il-15, tumor necrosis factor, ehemokines.

4. Monocytes, polymorphonuclear {PivlN} cells arrive, phagocytose pathogens,

5. CD4 lymphocytes bind to antigen presented by antigen presenting cells (APCs).

6. CD4 cei!s develop into Th-1 , Th-2, Th-17, begin expansion of clones,

7. Th-1 ce!fs secrete !L-12, interferon gamma (!FNQJ activate macrophages [Hammerich, et a!.].

8. Th-2 ce!ls secrete fL-4, IL-5, !L-13 [Hammerich et a!.}.

9. Th-17 cells differentiate in presence of TGFp and IL-6 or ll-ΐβ and SL-23.

10. Th-17 ce!!s secrete !L-17, recruit PM s and monocytes from bone marrow [Cosmi, L., et a!.}.

11. Th-1 cells produce IL-2, growth factor for lymphocytes, T-regulatory ceils and natural killer i ) ceils; down-regulate Th-17 and innate cells,

12. CDSs bind to antigen, begin proliferation and differe tiation.

13. Cytokines bind to receptors in the brain.

14. Brain commands increase in: Growth hormone inhibits peripheral glucose uptake, stimulates giuconeogenesis f Inoue et al.J, Cortisol inhibits peripheral use of glucose , enhances production,

Catecholamines enhance giycogenoiysis , increase giuconeogenesis

Glucagon increases production, release of giucose.

Mix produces insulin resistance, hyperglycemia, ioss of amino acids, lipids, ions from peripheral tissues.

Mix is imm nosuppressive but does not affect clones of lymphocytes already selected, differentiating and proliferating. They are able to access the nutrients lost by peripheral tissues. Body temperature, erythrocyte sedimentation rate (E5R), C Reactive Protein (CRP) levels rise. PM s and monocytes attack pathogens, also damage heaithy tissue.

Th-17s reach maximum expansion. As levels of Transforming Growth Factor beta (TGFp) rise, Th- 17s begin transformation into Th-ls or induced T regulatory cells (iTregs).

CD4 cells are expanding rapidly , differentiating into Th-1 or Th-2, in proportions corresponding to magnitude of humoral or intracellular challenge.

CDS cells differentiate into CTLs. Natural Killer ceils, Natural Killer T cells expand, differentiate. B cells become plasma cells, manufacture antibodies.

Lymphocyte clones reach point of maximum expansion, differentiation under influence of IL-2. Th-17 cells continue decline due to rising levels of IL-2, fL-4, IFNQHammerich et a!,],

Lymphocytes lose receptors for IGF-1 [Smith).

Brain receives signal from rising levels of 11-2, that lymphocyte compartment is at maximum, commands change in endocrine mix.

TABLE 2, SUMMARY OF NORMAL CASCADE PHASE if, ADAPTIVE PHASE Selected lymphocyte clones are differentiated and expanded. Lymphocyte compartment is optimal,

Rising levels of cytokines, IL-2, IL-S, IL-4, iL-12 and iFNj ]

Causes brain to command change in endocrine profile:

Insulin rises to three times normal.

Cortisol remains high, producing insulin resistance, increasing giuconeogenesis.

Glucagon rises to five times normal, producing giuconeogenesis.

Catecholamines remain at high level,

Growth hormone declines.

Mix continues insulin resistance. Peripheral tissues continue loss of nutrients.

Mi continues suppression of lymphocytes not antigen-selected and cytokine stimulated.

Selected lymphocytes present 6,000 insulin receptors, receive last essential stimulus, begin attack on pathogens.

High levels of insulin , IL-2 and IL-10, secreted by Th-1 lymphocytes, cause IL-17 to decrease, suppress innate system [Kaminski],

High levels of IL-2 stimulate production of T-regs.

IL-15, produced by non-iymphoid cells, supports parallel attack by NK cells,

IL-10, produced in rising amounts by T-regs, inhibits synthesis of SL-1, !F QTNF GM-CSF further decreasing innate attack.

Monocytes become macrophages, are stimulated by insulin to aggressively phagocytose pathogens. Remaining PfvlNs die,

Cytotoxic T lymphocytes {CTLs} destroy cells infected with pathogens.

Antibodies released by plasma ceils bind to humoral pathogens, facilitate destruction by macrophages.

Th-17 cells transform into T-regs, secrete IL-10.

Reduction of IL-17 decreases CTL activity,

CTLs, Th-1, Th-2 lymphocytes become apoptotic,

Supported by IL-15, some armed lymphocytes become memory cells,

CD4 T-regs and CDS T-regs expand, provoke apoptosis among armed lymphocytes. .. Fever, C-reactive protein (C P), erythrocyte sedimentation rate ^ES ) fail

insulin receptors disappear from lymphocytes,

iGF-1 receptors reappear.

TABLE 3, SUMMARY OF NORMAL CASCADE PHASE Hi, HEALING PHASE Endocrine mix changes:

insulin recedes to low norma! levels.

Growth Hormone rises, stimulating repletion of damaged tissues.

iGF-1 ieve!s rise, synergize with Growth Hormone.

Glucagon, Cortisol, remain high, continuing insulin resistance, stimulating gSuconeogenesis, Systemic TGFP rises, further suppressing immunity, supporting repletion of tissues, Mixture is profoundly immunosuppressive and catabolic of periphera! tissues. Effect is to cannibalize peripheral tissues for use in replacing damaged ceils.

Th-17s transform into iT-regs, produce IL-10.

nT-regs appear in increasing numbers, produce TGFp.

iGF-1 binds to, inactivates T cells, 8 cells, NK cells.

T regs inhibit CD-4, CD-S, T and B lymphocytes, and T cells, dendritic cells (DCs), macrophages.

Macrophages debride damaged tissues, release angiogenic factors, assist repair of tissues, Damaged tissues access nutrients, proliferate, begin recovery.

Supported by IL-15, remaining lymphocytes become memory cells.

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Claims

1. A method of stimulating adaptive immune cascade activity in a patient in need thereof, said method comprising administering insuiin to said patient via continuous intravenous infusion in amounts sufficient to maintain the patient's b!ood insuiin SeveS at about 15 to about 25 pU/mi above the patient's normal pre-treatrnent blood insuiin ievei for a period of time sufficient to stimulate adaptive immune cascade activity in said patient.

2. The method of claim 1 wherein said patient in need of stimulation of immune cascade activity has an initial CD4iCD8 ratio and the method results in a finai CD4:CDS ratio in said patient that is higher than normal and higher than said initial CD4:CDS ratio,

3. The method of claim 2 wherein said initial CD4:CD8 ratio is tower than normal and said finai CD4:CD8 ratio is higher than normal

4. The method of claim 2 wherein said initial CD4:CD8 ratio is normal or higher,

5. The method of claim 2 wherein said final CD4:CD8 ratio is greater than or equal to about 3:1,

6. The method of claim 2 wherein said patient in need of stimulation of adaptive immune cascade activity has an initial blood insulin SeveS of less than about 25 U/mi.

7. The method of claim 1 wherein said method is performed for at least a period of time sufficient to produce a fever in said patient,

8. The method of claim 12 wherein said method is performed for at least a period of time sufficient for said fever to return to normal for said patient,

9. The method of claim 1 wherein insuiin is administered for a period of time at least about 48 hours,

10. The method of claim 1 also comprising interrupting the administration of said insulin if the patient's temperature rises above a level likely to do permanent damage to the patient if maintained, and restarting said administration of insuiin when the patient's temperature drops to normal.

11. The method of claim IS wherein the total period of time during which insulin is administered is between about 4S and about 96 hours,

12. The method of claim 1 wherein said insulin is administered to said patient at a rate between about 0,10 U/kg/hr and about 0.15 U/kg/hr,

13. The method of claim 1 wherein the patient's insuiin blood levels are monitored at least about ever/ three to four hours, and the rate of insuiin administration adjusted as required to maintain the patient's blood insuiin SeveS at about 15 to about 25 μΙΙ/mi above the patient's normal pre-treatment blood insuiin level.

14. The method of claim 1 also comprising periodically monitoring the patient's blood levels of at feast one of glucose and potassium, and taking appropriate action comprising at least one of administering food or glucose in amounts sufficient to maintain said patient's blood glucose within normal levels and administering potassium as necessary to maintain said patient's potassium ieveis at s!ightiy hyperkalemic levels,

15. The method of c!aim 1 also comprising measuring the patient's CD :CD8 ratio prior to administration of insuiin.

16. The method of claim 1 wherein said patient suffers from a condition seiected from the group consisting of metabolic syndrome; chronic inflammation; chronic infection; a solid tumor; autoimmune disease; both a healing wound an infection.

17. A method of stimulating immune cascade activity in a patient in need thereof, said method comprising:

a. determining that said patient's initial blood insulin level is less than about 25 pU/ml; b. determining said patient's initial CD4;CD8 ratio;

c. administering insulin to said patient via continuous intravenous infusion at a rate of about 0.10 to about 0.15 U/kg/hr, in amounts sufficient to maintain a desired blood insulin level in said patient of about 15 to about 25 μϋ/mf above the patient^'s norma! pre-treatment blood insuiin level for at least about 48-96 hours to stimulate adaptive immune cascade activity in said patient;

d. periodically monitoring said patient's blood insulin, glucose and potassium;

e. adjusting said rate of insulin administration to maintain said desired blood

insulin level;

f. administering glucose in amounts sufficient to maintain said patient's blood glucose levels within normal range;

g. administering potassium to maintain mild hyperkalemia in said patient as shown by potassium biood ieveis between about 5,1 and about 6.0 mEq/L;

h. interrupting said insulin administration in the event said patient develops a dangerously high fever and resuming said insulin administration when said patient's temperature drops to a non- dangerous level;

i. continuing administration of said insulin for at ieast about four to about eight hours after said patient's fever returns to normal; and

j. measuring the patient's final CD4:CDS ratio after administration of said insulin, wherein the patient's final CD4:CDS ratio is both greater than the patient's initial CD4:CDS ratio and greater than or equal to about 3:1.

18. A system for carrying out a method for stimulating adaptive immune cascade activity in a patient in need thereof, said system comprising:

a, insulin in a suitable pharmaceutical carrier for intravenous infusion an amount sufficient to stimulate adaptive immune cascade activity in said patient when administered to said patient by intravenous infusion over a period of at least about 48 hours; and b. instructions for administering the insulin for the purpose of stimulating adaptive immune cascade activity in a patient in need thereof; and

19. The system of claim IS also comprising:

a. at least one blood insulin test apparatus;

b. apparatus for administration of said insulin via continuous intravenous infusion;

c. potassium in an amount between about 120 and about 2000 mEq sufficient to maintain the patient's blood potassium at normal to mildly hyperkaiemic ieveis during administration of said insulin over a period of at least about 48 hours; and

d. at !east one CD4:CDS ratio test apparatus,

20, The system of claim 19 also comprising one or more of the following components:

a. at least one blood glucose test apparatus;

b. glucose suitable for enteral or parenteral administration in an amount between about 150 and about 6000 mg sufficient to maintain the patient's blood g!ucose at normal ieveis during administration of said insulin over a period of at least about 48 hours; and

c. apparatus for administration of said glucose.