SK10092001A3 - Modulation of immune response by ribavirin - Google Patents

Abstract

The response of an immune system to a challenge is modified by presenting the system with a nucleoside in a concentration selected to have an effect on a B7 marker that is inverse from the effect of the challenge. Contemplated challenges include allergens, neoplasm, virus, bacteria, infestation, and autoimmune reaction. Molecular markers of particular interest are B7-1 and B7-2. Preferred nucleosides are Ribavirin and Ribavirin analogs, especially provided within a concentration range between about 0.2 :M and about 5 :M, respectively, in a fluid containing cells expressing the B7 marker.

Description

Technical field

The invention relates to the field of immunology, more particularly to the use of a nucleoside as a medicament for the treatment of the immune system's response to exposure.

BACKGROUND OF THE INVENTION

In addition to commonly used physiological and phenotypic diagnostic parameters, diseases can sometimes be compared to each other based on molecular markers such as polids, mutations of specific genes, expression of certain cell surface markers, etc. A number of such markers act as a predictor or indicator of disease and can thus be used as a diagnostic tool for a clear definition of physiological conditions.

A complex of diseases such as autoimmunity, asthma, malignancy, etc. is currently being compared. with specific molecular markers. Several studies have shown that there is a direct or indirect effect of costimulatory molecules B7-1 and B7-2 on immune system modulation in diseases. However, although such studies have given a detailed view of the different expression levels of B7-1 and B7-2 in different diseases, they did not produce an overall and uniform image (Hepatology 25, No. 5, 1997, p. 1108-1114: Expression of costimulatory molecules B7-1 and B7-2 and human hepatocellular carcinoma, J. Cancer Res Clin Oncol 124, No. 7, 1998, pp. 383-388, Expression of costimulatory molecules B7-1 and B7-2 on human gastric carcinoma, J. Neuroimmunol., 84, No. 2, 1998, pp. 179-187: Costimulatory CD80 (C7-1) and CD86 (B7-2) on Cerebrospinal Fluid Cells in Multiple Sclerosis, J Neuroimmunol 91, No. 1-2, 1998, pp. 198-203: B7-1 (CD80), B7-2 (CD-86), interleukin-13 and transforming growth factor-beta mRNA expression in CSF and peripheral blood. mononuclear cells from multiple sclerosis patients).

In many cases, an apparent non-uniform relationship between B7-1, B7-2, and a specific disease can be observed, as shown in FIG. For example, in some types of malignancy, B7-1 is present in a relatively high amount and B7-2 is present in a relatively small amount. In other types of malignancies, B7-1 and B7-2 are in a completely opposite relationship (J. Cancer Res. Clin. Oncol. 124, No. 7, 1998, pp. 383-388: Expression of costimulatory molecules B7 -1 and B7-2 on human gastric carcinoma, Br. J. Haematol., 102, No. 5, 1998, pp. 1257-1262: The expression of costimulatory molecules and their relationship to the prognosis of human acute myeloid leukemia: poor prognosis B7 -2-positive leukemia, Int J Mol Med 2, No. 2, 1998, pp 167-171: Lack B7-1 and B7-2 on head and neck cancer cells and possible significance for gene therapy).

Expression of B7-1 and B7-2 also shows non-uniform correlation with known cytokine models, as shown in FIG. 2. For example, overexpression of B7-1 is associated with positive and negative regulation of the type 1 response and expression of B7-2 is also related to positive and negative regulation of the type 1 response. The same can be said for the relationship B7-1 and B7-2 with type 2 response, as shown in FIG. 1 (described in Am. J. Respir. Cell. Mol. Biol. 17, No. 2, 1997, pp. 235-242: Differential Regulation of Human, Type 1 and Type 2 Responses by B-7 Homologues CD80 and CD86, J. Immunmol. 156, No. 8, 1996, pp. 2387-2391: Costimulation of IL-4 production by murine B7-1 and B7-2 molecules).

It is still unclear which drugs or even which category of drugs will be effective in modulating B7-1 or B72 activity, and even if such drugs would be identified, it is not clear how to advantageously use these costimulatory molecules to modulate the immune system. When all the unknowns are put together, there is still a need to provide methods and means suitable for modulating one or more B7 markers, in particular a method of affecting the immune system's response to a given exposure.

SUMMARY OF THE INVENTION

The invention relates to the use of a nucleoside as a medicament for the treatment of an immune system response to exposure to an effect on marker B7, wherein the nucleoside is present in an amount effective to reverse modulate the effect on marker B7.

The invention describes methods and means by which the immune system response to exposure is modified. Generally, the response is modified so that the system comes into contact with the nucleoside at a concentration selected to have an effect on the marker B7, which acts in reverse to the effect of immunization. In one preferred embodiment of the invention, the immunization means is selected from the group consisting of allergens, neoplasm, virus, bacteria, infestation and autoimmune response. Particularly interesting molecular markers are B7-1 and B7-2. In another preferred embodiment, the nucleoside is a ribavirin analog and in a particularly preferred embodiment the nucleoside is ribavirin. In another preferred embodiment of the invention, sufficient nucleoside must be provided to achieve a concentration range in the liquid containing cells expressing marker B7 of about 0.2 M to 5 M.

In preferred embodiments of the invention, the immunization is associated with an enhanced Type 2 response and the administration of the nucleoside is related to an attenuation of the Type 2 response.

The invention discloses that there is a surprising connection between certain nucleosides, particularly ribavirin and its analogs, and the expression of one or more B7 markers. Further investigation revealed another unexpected link that the application of such nucleosides can positively affect disease termination or other change. In particular, a method has been investigated to modulate the immune system's response to exposure, comprising (a) exposure correlating with effect on marker B7, (b) administering a nucleoside in a concentration range correlating with modulation of a molecular marker B7 counteracting immunization; a nucleoside system in a given concentration range.

The term nucleoside means a compound that contains any pentose or modified pentose moiety trapped at a specific position of the heterocycle or at the natural position of the purine (position 9) or pyrimidine (position 1) or an equivalent position on an analogue which mainly includes the D- and L-form bicyclic and monocyclic heterocycles. The term D-nucleosides means nucleoside compounds having a sugar portion of D-ribose (e.g., adenosine). The term Lnucleosides means nucleoside compounds having the sugar component of L-ribose. The term nucleotide refers to nucleosides in which phosphoric acid esters have substituted the 5 'position of the nucleoside.

The term "pharmaceutically acceptable salt" means any salt obtained from inorganic or organic acids or bases.

The term neoplasm refers to any kind of autonomous tissue disease growth, which may or may not become malignant, including all types of tumors and malignancies.

The term "treating and treating a disease" means practicing a protocol, which may include administering one or more kinds of drugs to a patient to alleviate the signs or symptoms of the disease. Such treatment or treatment does not require complete relief of symptoms or symptoms, does not require cure, and specifically includes protocols that have minimal effect on the patient (such as a placebo effect).

The term immune system refers to any collection of immunocompetent cells that collectively identify and attack foreign elements and that dynamically respond to new pathogens or other exposures. Examples of immune systems are the human or other mammalian immune system, which includes spleen, thymus B cells, T cells and antibodies. The immune system as defined herein must have cellular components but may or may not have humoral components. Where the immune system comprises a humoral component, it may include soluble molecules secreted from immunocompetent cells that contain antibodies or interleukins. Examples of soluble molecules are IgG, IgM, IgE or IL-2, IL-4, IL-10.

According to this definition, the immune system is also considered to include whole blood, fibrinogen-depleted blood, platelets and erythrocytes because it contains immunocompetent cells that are capable of dynamically responding to new pathogens. Other immune systems are cell culture media that contain immunocompetent cells. By contrast, buffered antibody solutions are not considered to be the immune system because they contain a large number of immunocompetent cells. In another preferred embodiment of the invention, the human or other animal comprises immune systems as defined herein.

Exposure means any component or phenomenon that elicits an immune system response. Exposures can be divided into three categories: own exposure, own and modified own exposure. Self-exposure includes cells or molecules where the immune system and the components of the exposure are from the same organism, self-proteins or autologous proteins, or fragments thereof. Examples include human blood cells, undifferentiated cells, antibodies or coagulation factors that originate from the same human. The improper type of exposure includes cells, viruses or molecules where the immune system and the components of the exposure originate from different organisms or the exposure is xenogeneous. Examples include organs or cells from a non-identical donor, bacterium, virus, or any type of molecule that are typical of other species and include endotoxins, enzymes, or structural proteins. Altered intrinsic exposures include cells or molecules wherein the immune system and the component of exposure originate from the same organism, but wherein the component of exposure is subject to modification, degradation or neoplastic changes. Examples of such modifications include modification of the B7 marker profile to antigen-expressing cells. Examples of degradation changes include cells intended for apoptosis or necrotic tissue. Examples of neoplastic changes indicate malignancy.

The terms immune response and immune response mean any response of the immune system to exposure.

Of interest are immune responses that include modulation of the B7 marker. Such modulation may include any combination of enhancement or attenuation of B7-1 and B7-2 expression. Thus, all responses shown in the tables of FIG. 1 and 2 are examples of contemplated immune system responses.

Other predicted immune system responses include the association of cellular components in cell-specific interactions or changes in genetic activity. The cell-specific interactions may be a cell-cell interaction or a cell-component of exposure. Examples of cell-cell interactions are T cells that are in contact with T-helper cells or T-helper cells are in contact with macrophages. Examples of cell-exposure component interactions are antigen-presenting cells that contain an exposure component, process the exposure component, and express the processed cell-surface exposure component or B-cells expressing the antibody-specific component on their surface and bind the exposure components to the antibodies. Changes in genetic activity may result from a refolding of genomic DNA or by selective activation of genes. Examples of refolding of genomic DNA are splicing that results in affinity maturation of antibodies against exposure or splicing that results in switching classes between individual classes of antibodies. Examples of selective gene activation are enhancement or attenuation of the transcription or translation of genes that code for interleukins or B7-1 or B7-2.

Production of the effect of B7, which acts opposite to the exposure-associated model, means that the effect of B7 produced by the nucleoside itself acts at least partially in the opposite direction to that of the exposure alone. Thus, when exposure is associated with reduced expression of B7-1, then the effect of B7 is that when B7-1 can be at least partially evaluated. Similarly, if exposure is associated with enhanced expression of B7-2, the opposite effect of B7 is that in which B7-2 is at least partially reduced.

The term immune system is in contact with the nucleoside means that the nucleoside is sufficiently in contact with any component of the immune system to produce an immune system response. In preferred embodiments, this involves introducing the nucleoside into the body. In other embodiments, this involves introducing a nucleoside into a vein or other site of the immune system.

The term immune system in contact with the nucleoside is broad enough to include any combination of in vivo, in vitro, or ex-vivo contact. In vivo contact may include injection, ingestion, transdermal delivery or inhalation. Examples of different types of injections are into muscle, intravenous or subcutaneous. Examples of various forms suitable for ingestion are tablets, syrups or powders. Occlusion dressings, ointments or electrophoretic methods by which trandermal delivery can be performed. Inhalation may include methods of evaporation and spraying.

In vitro contact can be accomplished either by introducing a solution containing the nucleoside into the immune system in a suitable composition, or by dissolving the nucleoside in a solution that may be in or part of the immune system. Examples of delivery include automatic or manual pipetting, dropping or injection of solutions. Alternatively, the nucleoside may also be dissolved in the liquid by pouring ribavirin into the liquid and mixing. This solution may contain the immune system or there may be a carrier solution that includes a buffer, isotonic solutions, blood. These carriers are then introduced into the immune system.

Obtained by removing parts of the immune immune parts

Ex vivo contact can be achieved in several steps (1) recovering parts of the immune system from the source, (2) applying the nucleoside to the immune system, and (3) at least partially returning the immune system to the source.

The system may be performed from a system in vivo and in vitro. Examples of in vivo sources of vertebrate animals that include humans and others that are not vertebrate animals. Return to the system may be by venipuncture, eye drip or puncture. Examples of in vitro sources are cell cultures found in the cellular system, conditioned or stored blood. Return to the system can be accomplished by any liquid transfer method, for example, by automatic or manual pipetting, aspiration, dripping, etc. The return of the immune system to the source can be accomplished by any liquid transfer method. This can occur in the case of an in vitro source by automatic or manual pipetting, aspiration, dripping, or in the case of an in vivo source by intravenous injection.

The nucleosides to be considered are ribavirin (1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) and analogues thereof. Ribavirin analogs are any ribavirin derivatives wherein (1) one or more hydroxyl groups are replaced with a non-hydroxyl moiety having less than 25 atoms. It includes a hydrogen atom, lower alkyl, lower aryl, lower aralkyl, lower alkylalkenyl, halogen, and the like. and independently one or more hydrogen atoms substituted with a non-hydrogen moiety containing less than 25 atoms including OH, lower alkyl, lower aryl, lower aralkyl, lower alkylalkenyl, halogen, and the like.

The ribavirin, ribavirin analog or other nucleoside is preferably prepared in a buffered aqueous solution. However, in other embodiments of the invention, the nucleoside may be prepared in a variety of other liquids or solid forms. Liquid forms may be solutions that contain only a solvent including water, DMSO, or ethanol. Liquid forms may also contain solutions which contain solvent mixtures or dissolved solids including water-ethanol mixtures, water-DMSO mixtures, buffers. Further, the liquid forms of the nucleosides may be mixed, for example, with a substance which modifies the consistency to form a gel, cream or ointment. Examples are amphiphilic molecules, waxes or gelatin. Solid forms may contain solids which may or may not be the active ingredients. Examples of active ingredients are buffers, ion exchange resins, including MOPS, phosphates or citrates. Examples of inactive ingredients include starch, cellulose or silica. Further, solid forms may be included in various formulations such as tablets, capsules, powder, etc.

In a preferred embodiment of the invention, a sufficient nucleoside is prepared to achieve a concentration range of 0.2 M to 5 M in a liquid containing cells expressing marker B7. Less preferred embodiments of the invention contemplate other concentrations in the range of 0.1 μΜ to 20 μΜ.

In preferred embodiments of the invention, the exposure correlates with an enhancement of the type 2 response and the administration of the nucleoside correlates with a decrease in the type 2 response. The type 2 response is as follows.

Mammalian immune systems contain two major classes of lymphocytes: B lymphocytes (B cells) derived from bone marrow and T lymphocytes (T cells) derived from the thymus. B cells are responsible for humoral immunity (i.e., antibody production), while T cells are responsible for cell-mediated immunity. T cells are considered to belong to two subclasses. They are helper T cells and cytotoxic T cells. Helper T cells activate other lymphocytes including B cells and cytotoxic T cells and macrophages by releasing soluble protein mediators called cytokines, which are involved in cell-mediated immunity. Lymphokines are a subset of cytokines.

corresponding elimination and

T helper cells are generally considered to fall into two subclasses. It is type 1 and type 2. Cells of type 1 (also known as Th1 cells) produce interleukin 2 (IL-2), tumor necrosis factor (ΤηΓβ) and interferon gamma (IFNγ) and are primarily responsible for cell-mediated immunity such as delayed type of hypersensitivity and antiviral immunity. Conversely, type 2 cells (also known as Th2 cells) produce IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13 interleukins and are primarily involved in assisting a humoral immune response, such as allergens such as IgE and IgG4 antibody rearrangements (Mosmann, 1989, Annu Rev Immunol, 7: 145-173).

The terms of type 1 and type 2 responses encompass the full range of effects resulting from the induction of type 1 and type 2 lymphocytes. Among others, such responses include variations in cytokine production through transcription, translation, probably other mechanisms, enhanced proliferation of corresponding lymphocytes increased production of cytokines that include effects on motility.

Type 1 and 2 responses may be selectively suppressed while others are either induced or remain unaffected, and / or type 1 or 2 responses may be selectively induced, while other responses are suppressed or remain relatively unaffected.

Certain nucleosides, such as ribavirin, are effective in selectively modulating the type 1 and 2 responses. Determining which nucleosides are effective in reducing the type 2 response can be readily accomplished by experiment.

It is contemplated that the methods described herein can be used in the treatment of various diseases and, in fact, can be any of the diseases that respond well to said treatment. Among other things, it is contemplated that such combinations may be used to treat allergies, malignancies, viral infections, bacterial infections, or autoimmune diseases.

The nucleoside-treatable infections of the invention may be caused by respiratory syncytial virus (RSV), hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex virus types 1 and 2, herpes genitalis, herpes keratitis, herpes encephalitis, herpes zoster, herpes zoster, , influenza A virus, hanntan virus (hemorrhagic fever), human papillomavirus (HPV), measles virus and fungi. In particular, it is contemplated that the combinations described herein may be used in the treatment of chronic viral and bacterial infections, including HIV, tuberculosis, leprosy, and the like.

Infestations that can be treated with the nucleosides of the invention include intracellular protozoa infestations such as helminth and other parasite infestations. Again, it is contemplated that the combinations described herein may be used in the treatment of chronic attack.

Tumors that can be treated are caused by viruses, and the effect may include inhibiting the transformation of cells infected with the virus to a neoplastic stage, inhibiting the spread of the virus from the transformed cells to normal cells, and / or arresting the growth of the cells transformed with the virus.

Allergies believed to be treatable include all IgE and IgG allergies, hyper IgE syndrome, and skin conditions such as atopic dermatitis. It is also contemplated that the methods can be used to treat graft rejection (graft versus host) and graft response.

An autoimmune disease may be classified as an organ-specific disease and a non-organ-specific disease. Non-organ autoimmune disease includes rheumatoid arthritis, gout and gouty arthritis, systemic lupus erythematosus (SLE), Sjorgenon syndrome, scleroderma, polymyositis and dermomyositis, ankylosing spondylitis and rheumatoid arthritis. Organ-specific autoimmune disease is known to each organ and includes diabetes, thyroid disease (Grav's disease and Hashimoto's thyroiditis), Addison's disease and some kidney and lung diseases including allergy and asthma, multiple sclerosis, myasthenia gravis, uveitis, psoriasis, a form of hepatitis and cirrhosis, abdominal diseases, inflammatory bowel diseases and some types of female and male infertility. Autoimmune processes may also be stimulated by viral infections, which include HIV, may be the result of transplanted transplantation, and may accompany certain tumors, or may be due to the action of certain chemicals.

synthesis

The synthesis of ribavirin is well known and the synthesis of ribavirin analogs is contemplated.

Application

It is contemplated that the nucleosides of the invention may be administered in any suitable pharmaceutical composition and according to any suitable protocol. Preferred doses and protocols were compiled based on the results of experiments in certain patients. Such experiments need not be extensive, and nucleosides are expected to be administered to humans at a dose of 100 mg / day and about 5000 mg / day. In humans and other systems, ribavirin or other nucleoside is believed to meet parameters such as the nucleoside concentration in a liquid containing cells expressing B7 of about 2 M to 5 M.

Of course, one skilled in the art will recognize that in treating a disease, the therapeutically effective amount varies according to infection, the condition of the disease being treated, its severity, the treatment regimen, the kinetics of the pharmaceutical compositions and the patient (whether animal or human) being treated. Effective doses may range from 1 mg / kg or less to 25 mg / kg body weight or more. Generally, the therapeutically effective amount of the second pharmaceutical composition ranges from a little less than 1 mg / kg to 25 mg / kg of the patient's body weight, depending on the nucleoside used, the condition and the infection being treated and the mode of administration. This dose range generally produces an effective concentration of active nucleosides in the blood that is in the range of 0.04 to 100 pg / cc of the patient's blood. However, it is believed that it is possible to develop treatment regimens suitable for the patient when a small amount is applied and then the amount is increased until the side effect becomes undesirable and / or the desired effect is achieved.

The administration of the nucleoside of the invention may take place orally, parenterally (by subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion), spray inhalation or rectally, topically and so on. The dosage unit contains conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.

It is contemplated that the nucleosides of the invention may be prepared in admixture with a pharmaceutically acceptable carrier. For example, the nucleosides of the invention may be administered orally as pharmaceutically acceptable salts. Since the nucleosides of the invention are mostly water soluble, they can be administered intravenously in saline (e.g., pH adjusted to 7.2-7.5). Conventional buffers such as phosphates, carbonates or citrates may be used for this purpose. Of course, one of skill in the art can modify the compositions to provide a variety of compositions for certain modes of administration without the components of the invention becoming unstable or losing their therapeutic activity. In particular, modifications of nucleosides to become more soluble in water or other carrier can be readily accomplished by a small treatment (salt formation, esterification, etc.), which is well known in the art. regimen of certain nucleosides in order to optimize the kinetics of the pharmaceutical composition of the putative nucleosides in order to achieve the maximum effect that is beneficial to the patient.

In certain pharmaceutical dosage forms, the prodrug form of the nucleoside administered primarily includes acylated (acetylated or other) derivatives, with pyridine esters and various nucleoside salt forms being preferred. One of ordinary skill in the art will recognize that it is necessary to adapt the prodrug forms to allow delivery of active nucleosides to a target site in a host organism or patient. One of ordinary skill in the art can also utilize the preferred pharmacokinetic parameters of the prodrug forms when administering nucleosides to the target site of the host organism or patient to achieve maximum effect.

In addition, the putative nucleosides may be administered separately or together and separately administered in any desired manner. The amount of active ingredient and pharmaceutical active ingredient, and the relative timing of administration, are selected to achieve the desired therapeutic effect.

Methods of administering the putative nucleosides range from continuous administration (intravenous infusion) to daily oral administration (e.g. QID) and may include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (including penetration enhancer) administration, mucosal administration and suppository application.

Description of the drawings

In FIG. 1 is a table showing specific diseases and their correlation with B7-1 and B7-2 expression.

FIG. 2 is a table showing various types of diseases and their correlation with type 1, type 2, B7-1 and B7-2 expression.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

In the method of treatment of the invention, a therapeutically effective amount of the nucleoside is preferably admixed with a pharmaceutically acceptable carrier based on conventional pharmaceutical techniques to produce a suitable dose. The carrier may take various forms depending on the form of preparation desired for administration, for example oral or parenteral administration. A conventional pharmaceutical medium may be used to prepare the pharmaceutical compounds for oral pharmaceutical form. In the case of liquid oral forms such as suspensions, elixirs and solutions, suitable carriers, additives, including water, glycols, oils, alcohols, preservatives, coloring agents and the like can be used. Suitable carriers and additives, including starches, sugar carriers such as dextrose, mannitol, lactose and related carriers, diluents, granulating agents, lubricants, may be used in the preparation of solid forms for oral administration such as powder, tablets, capsules and suppositories. , binders, disintegrating agents and the like. If necessary, tablets and capsules can be coated to form enteric tablets and sustained release is ensured.

In the case of parenteral compositions, the carrier will usually comprise sterile water or aqueous sodium chloride solution and other ingredients which may, for example, form a dispersion. Of course, when sterile water is used and kept sterile, the individual additional ingredients and carriers are also sterilized. Suspensions are also prepared which can be injected, where appropriate liquid carriers, suspending agents and the like can be used.

It is preferred that the active nucleosides of the invention be used to be relatively less toxic to host cells for which they are not intended, and to have a relatively greater effect on their targets. In this case, it may also be advantageous that the Lnucleosides may exhibit higher stability compared to the Dnucleosides, which lead to better pharmacokinetics. This can be achieved by the fact that L-nucleosides do not recognize enzymes and therefore have a longer half-life.

Then, this method demonstrates that the use of ribavirin and other nucleosides advantageously modifies the molecular marker B7.

Fig. 1

Correlation of specific disease with expression of B7-1 and B7-2

type of malignancy B7-1 B7-2 hepatcytic carcinoma attenuates attenuates primary gastric cancer intensifies intensifies gastric cancer metastasis attenuates attenuates head and neck (primary) attenuates attenuates acute myeloid leukemia attenuates intensifies autoimmune disease multiple sclerosis intensifies intensifies asthma neutral intensifies inflammation of the abdominal cavity intensifies intensifies

Fig. 2

Correlation of different disease types with type 1, type 2 response and B7-1 and B7-2 expression.

Type / Response type 1 type 2 B7-1 B7-2 autoimmune disease amplifies (specific to AIDS) intensifies (system AIDS) intensifies amplifies / attenuates malignant exuberance attenuates intensifies amplifies / attenuates amplifies / attenuates bacterial infection intensifies intensifies intensifies intensifies viral infection intensifies intensifies intensifies intensifies

Claims (1)

PATENT CLAIMS Use of a nucleoside as a medicament for the treatment of an immune system response to exposure to an effect on marker B7, wherein the nucleoside is present in an amount effective to reverse modulate the effect on marker B7. Second The use exposure nucleoside is an allergen. by claim 1, v which component Third The use exposure nucleoside is a neoplasm by • claim 1 / v which component 4th The use exposure nucleoside is a virus. by claim 1 / v which component 5th The use exposure nucleoside is a bacterium by claim 1, v which component 6th The use nucleoside by claim 1, v whose exposure involves assault. Use of a nucleoside according to claim 1, wherein the exposure comprises an autoimmune reaction. Use of a nucleoside according to any one of claims 1 to 8, wherein the molecular marker is B7-1. Use of a nucleoside according to any one of claims 1 to 8, wherein the molecular marker is B7-2. Use of a nucleoside according to any one of claims 1 to 8, wherein the nucleoside is ribavirin. Use of a nucleoside according to any one of claims 1 to 8, wherein the nucleoside is a ribavirin analog. Use of a nucleoside according to claim 1, wherein the exposure component is selected from the group consisting of an allergen, a microorganism, a neoplasm, an attack and an autoimmune response, wherein the molecular marker is B7-1 and the nucleoside is ribavirin. Use of a nucleoside according to claim 1, wherein the exposure component is selected from the group consisting of an allergen, a microorganism, a neoplasm, an attack and an autoimmune response, wherein the molecular marker is B7-2 and the nucleoside is ribavirin. Use of a nucleoside according to claim 1, wherein the exposure component is selected from the group consisting of an allergen, a microorganism, a neoplasm, an attack and an autoimmune response, wherein the molecular marker is B7-1 and the nucleoside is not ribavirin. Use of a nucleoside according to any one of claims 12 to 14, wherein the concentration range in the liquid containing the cells expressing marker B7 is about 0.2 M to 5 M. The use of a nucleoside according to any one of claims 1 to 8, wherein the exposure is correlated with a Type 2 enhancement response and the nucleoside application is correlated with a Type 2 response fading.