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WO2008150868A1 - Procédés pour induire des lymphocytes t thérapeutiques pour des maladies immunitaires - Google Patents

Procédés pour induire des lymphocytes t thérapeutiques pour des maladies immunitaires Download PDF

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WO2008150868A1
WO2008150868A1 PCT/US2008/065085 US2008065085W WO2008150868A1 WO 2008150868 A1 WO2008150868 A1 WO 2008150868A1 US 2008065085 W US2008065085 W US 2008065085W WO 2008150868 A1 WO2008150868 A1 WO 2008150868A1
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disease
antigen
cells
kit
specific antigen
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Guoxing Zheng
Aoshuang Chen
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University of Illinois at Urbana Champaign
University of Illinois System
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University of Illinois System
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/10—Cellular immunotherapy characterised by the cell type used
    • A61K40/11—T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/30—Cellular immunotherapy characterised by the recombinant expression of specific molecules in the cells of the immune system
    • A61K40/32—T-cell receptors [TCR]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
    • A61K40/41—Vertebrate antigens
    • A61K40/42—Cancer antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterized by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the dose, timing or administration schedule

Definitions

  • This invention is related to the area of pathological immune responses. In particular, it relates to treatment to reduce the pathology of such responses.
  • DCs are the most potent antigen-presenting cells (APCs). It is generally recognized that the context in which an antigen is presented, but not the antigen per se, determines whether the encounter between the antigen and its cognate T cell leads to immunity or tolerance.
  • Tolerogenic DCs are marked by a semi-mature phenotype and the ability to produce tolerogenic cytokines such as IL-IO while downregulating pro-inflammatory cytokines such as IL-12 ( Lutz, M. B., and G. Schuler. 2002. Immature, semi-mature and fully mature dendritic cells: which signals induce tolerance or immunity? Trends Immunol 23:445-449; Wakkach, A., N. Fournier, V. Brun, J. P. Breittmayer, F. Cottrez, and H. Groux.
  • Regulatory T cells and tolerogenic dendritic cells from basic biology to clinical applications. Immunol Lett 94:11-26; Morelli, A. E., and A. W. Thomson. 2007. Tolerogenic dendritic cells and the quest for transplant tolerance. Nat Rev Immunol 7:610-621), which is immunosuppressive and plays a pivotal role in immune tolerance. Tolerogenic DCs can be induced by the use of anti- inflammatory cytokines or immunosuppressants ( Morelli, A. E., and A. W. Thomson. 2007. Tolerogenic dendritic cells and the quest for transplant tolerance. Nat Rev Immunol 7:610-621; Adorini, L., N. Giarratana, and G. Penna. 2004.
  • Glucocorticoids severely impair differentiation and antigen presenting function of dendritic cells despite upregulation of Toll-like receptors. Clin Immunol 120:260-271); DEX decreases the expression of MHC and costimulatory molecules and the production of IL-12, while stimulating the production of IL-10 ( Piemonti, L., P. Monti, P. Allavena, M. Sironi, L. Soldini, B. E. Leone, C. Socci, and V. Di Carlo. 1999. Glucocorticoids affect human dendritic cell differentiation and maturation. J Immunol 162:6473-6481; Rea, D., C. van Kooten, K. E. van Meijgaarden, T. H.
  • DC-based therapy is limited by the requirement for isolation and ex vivo manipulation of autologous DCs ⁇ i.e., DCs from the very patient to be treated); this necessitates individualized DC preparation, which may be too costly and complex for routine clinical application.
  • the second approach is to isolate autologous, antigen-specific regulatory T cells from a patient, expand them ex vivo and, subsequently, adoptively transfer them into the same patient ( June, C. H., and B. R. Blazar. 2006. Clinical application of expanded CD4+25+ cells.
  • regulatory T cells-based adoptive therapy while proven effective in animal models, is difficult to be translated into clinical trials due to the technical, regulatory, and economic concerns (Bluestone, J. A., A. W. Thomson, E. M. Shevach, and H. L. Weiner. 2007. What does the future hold for cell- based tolerogenic therapy? Nat Rev Immunol 7:650-654; Verbsky, J. W. 2007. Therapeutic use of T regulatory cells. Curr Opin Rheumatol 19:252-258).
  • the third approach involves inducing antigen-specific desensitization via cell-free immunization using an antigen or peptide fragments encompassing a relevant epitope ( Larche, M., and D. C. Wraith. 2005. Peptide-based therapeutic vaccines for allergic and autoimmune diseases. Nat Med 11 :S69-76).
  • peptide immunization works by allowing in vivo presentation of the antigen in the context of nonprofessional APCs or steady-state (quiescent) DCs, both of which have been shown to favor tolerance induction (Steinman, R. M., D. Hawiger, and M. C. Nussenzweig. 2003. Tolerogenic dendritic cells.
  • peptide immunization alone lacks the active control of the context in which the antigen is presented, which critically affects the efficacy in tolerance induction. For instance, while low doses of antigens are found to cause favorable responses, high doses often promote antigen presentation in an inflammatory context, leading to adverse immune responses (Larche, M. 2007. Update on the current status of peptide immunotherapy. J Allergy Clin Immunol 119:906-909). Especially, inevitable exposure of humans to environmental antigens in uncontrolled doses and inflammatory milieu renders antigen-based therapy unreliable for clinical applications.
  • a method for treating a patient with an allo-immune or auto-immune disease.
  • a disease-specific antigen is administered to the patient.
  • a tolerogenic adjuvant is administered to the patient.
  • the tolerogenic adjuvant is selected from the group consisting of glucocorticoids, vitamin D3, and vitamin D3 analogues. Symptoms of the disease are thereby reduced, delayed, or eliminated.
  • kits for treating a patient comprises a disease- specific antigen or a nucleic acid encoding a disease-specific antigen; and a tolerogenic adjuvant selected from the group consisting of glucocorticoids, vitamin D3, and vitamin D3 analogues.
  • a further aspect of the invention is a method of treating a patient with a chronic inflammatory disorder.
  • a disease-specific antigen is administered to the patient.
  • a tolerogenic adjuvant is administered to the patient.
  • the tolerogenic adjuvant is selected from the group consisting of glucocorticoids, vitamin D3, and vitamin D3 analogues. Symptoms of the disease are thereby reduced, delayed, or eliminated.
  • An additional aspect of the invention is a population of CDl Ic + dendritic cells (DC) in which the percentage of IL-IO producing DC is at least two-fold greater than in a control population of DC in blood of a human who has not been immunized with an antigen or treated with an immunosuppressant.
  • DC CDl Ic + dendritic cells
  • Yet another aspect of the invention is a population of CDl Ic + dendritic cells (DC) in which the percentage of IL-IO producing DC is at least two-fold greater than in a control population of DC in blood of a human that has been immunized with an antigen or treated with an immunosuppressant.
  • DC CDl Ic + dendritic cells
  • a further aspect of the invention is a population of CD4 + CD25 + T cells in which the percentage of CD4 + CD25 + Foxp3 + Treg is at least twice that in a control population of CD4 + CD25 + T cells in blood of a human who has not been immunized with an antigen or treated with an immunosuppressant.
  • Another embodiment or the invention is a population of CD4 + CD25 + Foxp3 + Treg in which antigen-specific Treg comprise at least a two-fold greater proportion than in a population of CD4 + CD25 + Foxp3 + Treg in blood of a human that not been immunized with the antigen or treated with an immunosuppressant.
  • a further aspect of the invention is a population of memory CD4 + CD25 + Foxp3 + Treg that remain viable for at least 120 days after discontinuation of antigenic stimulation and that are capable of proliferation in response to recurring antigenic stimulation.
  • Fig. IA-ID Suppressed immunization induces immune tolerance against established DTH.
  • Fig. IA BALB/c mice with pre-established DTH were divided into four groups and each was treated with an indicated combination of DEX and OVA 323-33 C,. All groups were then retested for DTH at a footpad.
  • Fig. IB The test and negative control groups were tested again 4-5 months later.
  • Fig. 1 C Treg (CD4 + CD25 + Foxp3 + ) in blood samples, taken immediately before (open bar) and 48 h after (filled bar) the second DTH test, were quantified relatively to total CD4 + cells.
  • Fig. IA BALB/c mice with pre-established DTH were divided into four groups and each was treated with an indicated combination of DEX and OVA 323-33 C,. All groups were then retested for DTH at a footpad.
  • Fig. IB The test and negative control groups were tested again 4-5 months later.
  • Fig. 1 C Treg (
  • Fig. 2A-2E Suppressed immunization blocks DC maturation and preferentially expands antigen- specific Treg.
  • Fig. 2A DOl 1.10 mice were divided into four groups, each injected at a hind footpad with the indicated combination of DEX and OVA 323-33 C,. Three days later, draining LN (popliteal) were recovered and analyzed by flow cytometry, gating on CDl Ic + cells (total DC). Immature (CD83 " CD86 low ) and mature (CDSS + CDSo 111811 ) DC were quantified relatively to total DC.
  • Fig. 2B IL-10-producing (IL-IO + ) DCs were quantified relatively to total DC.
  • Activated effector T cells (Teff, CD4 + CD25 + Foxp3 " ) and Treg (CD4 + CD25 + Foxp3 + ) in same LN were quantified relatively to total CD4 + T cells.
  • Fig. ID CFSE-labeled DOl 1.10 CD4 + T cells were co- injected with OVA323-339 into BALB/c mice that had been either pretreated (indicated as "DEX + peptide") or non-pretreated ("peptide”) with DEX.
  • DEX + peptide indicated as "DEX + peptide”
  • the T cells were also injected without OVA 323 _ 339 into non-pretreated mice ("PBS").
  • Treg from DOl 1.10 mice treated with D ⁇ X and OVA 323-33 9 were co-cultured with Teff (CD4 + CD25 ⁇ ) from na ⁇ ve DOl 1.10 mice, along with syngeneic accessory cells and OVA 323-339 . Proliferation was assessed by 3 H-thymidine incorporation.
  • Treg 1 and Treg 2 denote Treg from immunized and nonimmunized DOl 1.10 mice, respectively. Bar, mean and SD from 2-4 independent experiments, each using at least 2 mice per group (n > 2); *, P ⁇ 0.05 between the indicated pair.
  • FIG. 3A-3C Suppressed immunization protects animals from predisposed autoimmune diseases.
  • CFS ⁇ dilution was analyzed 3 days later by flow cytometry, gating on CD4+CD25+ cells (Treg and activated Teff). Shown are quadrant plots separating Treg (Foxp3+), Teff (Foxp3-), antigen-specific (CFS ⁇ -low), or nonantigen-specific (CFS ⁇ -high) cells. The percentage of cells in each quadrant is indicated. Shown is 1 of 2 independent experiments with similar results.
  • Fig. 3 C Prediabetic NOD mice were treated with PBS (indicated as "Control") or D ⁇ X and B:9-23 (“Test”), as described in A. At the completion of the treatment, blood samples were taken from both groups.
  • White cells were labeled with CFSE and stimulated with B:9-23 in culture. As control for antigen specificity, an aliquot of white cells from the test mice were stimulated with OVA 323-339 ("Control antigen"). Cells were analyzed by flow cytometry as described in B. Antigen-specific cells were identified by CFSE dilution and quantified relatively to total CD4+CD25+ cells gated. Bar, mean and SD of 2 independent experiments employing 2-3 mice per group; *, P ⁇ 0.0016 between the indicated pair.
  • the inventors have developed methods for regulating undesired antigen-specific T cell responses.
  • the methods employ a combination of agents which can be packaged as a kit.
  • populations of cells are expanded within the body that have different compositions from those in untreated bodies.
  • the populations of cells can be extracted for analysis.
  • regulatory T cells are those which exert regulatory, immunosuppressive activities instead (Shevach, E. M. 2006. From vanilla to 28 flavors: multiple varieties of T regulatory cells. Immunity 25:195-201). Regulatory T cells play a pivotal role in governing peripheral tolerance (i.e., tolerance to self or auto antigens) by inhibiting overactive T cells, and by dampening B cell, DC, and natural killer cell activities (Raimondi, G., M. S. Turner, A. W. Thomson, and P. A. Morel. 2007. Naturally occurring regulatory T cells: recent insights in health and disease. Crit Rev Immunol 27:61-95).
  • Treg CD4 + CD25 + Foxp3 + cells
  • a unique therapeutic advantage of regulatory T cells in general over conventional immunosuppressive drugs is that the former are antigen-specific. That is because like any T cell, a regulatory T cell is able to recognize a specific antigen via T cell receptors (TCRs). Triggering of the TCRs leads to activation and clonal expansion of the regulatory T cell, the outcome of which is increased numbers of antigen-specific regulatory T cells capable of migrating to, and suppressing immune reactions at, the site inflammation without general immunosuppression. It is the last two properties, being antigen-specific and antigen-responsive, that makes these cells particularly well-suited for treating autoimmunity, transplantation rejection, and allergy, for example, where untoward immunity causes disease.
  • Suppressed immunization is a method for in vivo manipulation of regulatory T cells using a chemically-defined antigen and tolerogenic adjuvant combination. This method makes isolation and ex vivo expansion of regulatory T cells unnecessary. Instead, it enables direct sensitization and expansion of antigen-specific Treg in vivo via simple immunization. Thus, it is highly useful for human therapy.
  • the two agents, antigen and adjuvant can be administered together at the same time, or separated in time over a course of 1-10 minutes, 1-72 hours, or 1-14 days. If administered at the same time, they may be mixed together or administered in separate vehicles.
  • Suppressed immunization uses a pharmaceutical immunosuppressant as adjuvant that exerts three effects.
  • the immunosuppressant preferentially dampens the proliferation of conventional T cells (Fig. 2) and induces their apoptosis (programmed cell death) (Chen, X., T. Murakami, J. J. Oppenheim, and O. M. Howard. 2004. Differential response of murine CD4+CD25+ and CD4+CD25- T cells to dexamethasone-induced cell death. Eur J Immunol 34:859-869), while preserving the activity of Treg (Fig. T).
  • the immunosuppressant works to block ongoing pathogenic immune reactions by conventional T cells and prevent them from responding to the immunogen applied.
  • the immunosuppressant is anti-inflammatory and blocks inflammation- stimulated maturation of DC.
  • the immunosuppressant induces differentiation of IL- 10-producing, tolerogenic DC, which, in conjunction with an immunogen (antigen), can preferentially stimulate the proliferation and expansion of antigen-specific Treg (Fig. T).
  • the immunosuppressant serves as an adjuvant for active control of the antigen- presentation context, thereby ensuring that antigenic immunization forcefully drives the induction of Treg.
  • suppressed immunization also uses a disease-specific immunogen derived from a disease-specific antigen.
  • the disease-specific antigen can be either a disease-causing antigen, such as an autoimmune antigen (Fig. 3), or a disease-induced antigen, such as a tissue-specific antigen released to circulation due to autoimmune destruction of the tissue.
  • a disease-causing antigen such as an autoimmune antigen (Fig. 3)
  • a disease-induced antigen such as a tissue-specific antigen released to circulation due to autoimmune destruction of the tissue.
  • Fig. 3 Once induced, disease-specific Treg block pathogenic immunity and prevent it from causing overt disease (Fig. 3).
  • the induced Treg also develop into "memory-like" cells that persist over a long period of time and are capable of recall expansion in response to antigenic rechallenge (Figs. 1 and 3).
  • These memory-like cells are novel and may be unique to suppressed immunization. They are also particularly useful because most immune diseases are chronic or recurrent in nature, and, thus, there is compelling need for long-term protection against disease recurrence. As such recurrence is likely preceded or followed by the disease- specific antigen, the presence of memory-like Treg may provide a surveillance and suppression mechanism that blocks overt recurrence.
  • suppressed immunization works by selectively expanding disease-specific Treg that suppress ongoing pathogenic immunity as well as providing long-term surveillance against disease recurrence. Further, although our studies have thus far examined only Treg, suppressed immunization, in principle, may also be useful for in vivo expansion of other regulatory T cell types that respond similarly to the adjuvant and immunogen combination.
  • Autoimmune diseases include but are not limited to Acute disseminated encephalomyelitis (ADEM); Addison's disease; Ankylosing spondylitis; Antiphospholipid antibody syndrome (APS); Diabetes mellitus type 1 ; Guillain-Barre syndrome (GBS); Hashimoto's disease; Idiopathic thrombocytopenic purpura; Goodpasture's syndrome; Graves' disease; Lupus erythematosus; Multiple sclerosis; Myasthenia gravis; Rheumatoid arthritis; Pemphigus; Sjogren's syndrome; Temporal arteritis; Aplastic anemia; Autoimmune hepatitis; Autoimmune Oophoritis; Celiac disease; Crohn's disease; Gestational pemphigoid; Kawasaki's Disease; Mixed Connective Tissue Disease; Opsoclonus myoclonus syndrome (OMS); Ord's thyroiditis; Pernicious anaemia;
  • Allergic diseases include allergic rhinitis, allergic asthma, atopic dermatitis, allergic gastroentheropathy, anaphylaxis, urticaria and angioedema.
  • Allo-immune diseases include transplantation rejection and graft versus host disease, as well as fetus, neonates, and pregnant mothers.
  • Immune rejection of tissue transplants including lung, heart, liver, kidney, pancreas, bone marrow, and other organs and tissues, is mediated by immune responses in the transplant recipient directed against the transplanted organ.
  • Allogeneic transplanted organs contain proteins with variations in their amino acid sequences when compared to the amino acid sequences of the transplant recipient. Because the amino acid sequences of the transplanted organ differ from those of the transplant recipient they frequently elicit an immune response in the recipient against the transplanted organ.
  • Rejection of transplanted organs is a major complication and limitation of tissue transplant, and can cause failure of the transplanted organ in the recipient. The chronic inflammation that results from rejection frequently leads to dysfunction in the transplanted organ.
  • the antigen for an future or past transplant recipient may include one or more major histocompatibility antigens, e.g. HLA-A, HLA-B, HLA-C, HLA-DR, HLA-DQ, HLA- DP, etc., and may comprise a cocktail of such antigens, where the antigens will include those not matched between the recipient and the donor.
  • major histocompatibility antigens e.g. HLA-A, HLA-B, HLA-C, HLA-DR, HLA-DQ, HLA- DP, etc.
  • Antigens may be protein or nonprotein, including other biomolecules such as pyrophosphates and gangliosides. Protein antigens for treating allergic diseases may include proteins of Alternaria altemata (Alt a I), Artemisia vulgaris (Art v II), Aspergillus fumigatus (Asp f II), Dermatophagoides far. (Der fl), Dermatophagoides pteron. (Der p I, Der p III, Der p IV, Der p VI and Der p VIII).
  • antigens may include proteins from domestic and farm animals, fungal antigens including from Basidiomycetes such as Ustilago, Ganoderma, Alternaria, Cladosporium, Aspergillus, Sporobofomyces, Penicillium, Epicoccum, Fusarium, Phoma, Borrytis, Helminthosporium, Stemphylium and Cephalosporium; Phycomycetes such as Mucor and Rhizopus; and Ascomycetes such as Eurotium and Chaetomium.
  • Basidiomycetes such as Ustilago, Ganoderma, Alternaria, Cladosporium, Aspergillus, Sporobofomyces, Penicillium, Epicoccum, Fusarium, Phoma, Borrytis, Helminthosporium, Stemphylium and Cephalosporium
  • Phycomycetes such as Mucor and Rhizopus
  • Ascomycetes such as Eurotium and Chaetomium.
  • Plant antigens associated with allergies may be used as antigens including club mosses, ferns, conifers, flowering plants, grasses, sedges, palms, cattails, nettles, beeches, chenopods, sorrels, willows, poplars, maples, ashes, ragweeds (antigen E, antigen K and Ra3) and sages, or proteinaceous plant products such as those found in latex products.
  • Insect antigens with allergies include proteins from the honeybee, yellow jacket, hornet, wasp and fire ant.
  • Food allergens can be used as antigens, including those from crustaceans, mollusks, fish, legumes, seeds, nuts, berries, egg white, buckwheat, and milk.
  • any antigen associated with such diseases as described can be used, including acetylcholine receptor, oxidized LDL, heat shock protein, proteolipid protein (PLP), myelin basic protein (MBP), myelin oligodendrocyte protein (MOG), cyclic nucleotide phosphodiesterase (CNPase), myelin-associated glycoprotein (MAG), and myelin- associated oligodendrocytic basic protein (MBOP), alpha-B-crystalin (a heat shock protein), OSP (oligodendrocyte specific-protein), type II collagen, hnRNP, A2/RA33, Sa, filaggrin, keratin, citruUine, cartilage proteins including gp39, collagens type I, III, IV, V, IX, XI; HSP-65/60, IgM (rheumatoid factor), RNA polymerase, hnRNP-Bl, hnRNP-D, cardiolipin
  • Tolerogenic adjuvants which can be used in the methods described include but are not limited to glucocorticoids, vitamin D3, vitamin D3 analogues which are tolerogenic adjuvants, such as l ⁇ ,25(OH 2 )D3, short chain fatty acids, such as butyrate, rapamycin, sanglifehrin, 15-desoxyspergualin, and mycophenolate mofetil.
  • Glucocorticoids which may be used include Hydrocortisone (Cortisol), Cortisone acetate, Prednisone, Prednisolone, Methylprednisolone, Dexamethasone, Betamethasone, Triamcinolone, Beclometasone, Fludrocortisone acetate, Deoxycorticosterone acetate (DOCA), Aldosterone, and dexamethasone.
  • Hydrocortisone Cortisol
  • Cortisone acetate Prednisone
  • Prednisolone Prednisolone
  • Methylprednisolone Dexamethasone
  • Betamethasone Triamcinolone
  • Beclometasone Triamcinolone
  • Beclometasone Fludrocortisone acetate
  • Deoxycorticosterone acetate D3
  • Aldosterone Aldosterone
  • dexamethasone dexa
  • Kits for practicing the methods comprise both a disease-specific antigen as well as a tolerogenic adjuvant. These may be packaged together in a single or divided container. They may be in the same or different format, such as liquid, frozen, dried, tablet, etc. They may optionally require reconstitution prior to administration.
  • the kit may comprise instructions regarding dosages, side effects, scheduling, etc.
  • Populations of cells as are induced using the methods described above include those that are induced in the body and those that are later removed, for example for analysis.
  • the populations can be stored, saved, and used for re-infusion at a later time.
  • the method described above induces changes in populations of cells and their relative proportions of subsets of cells. Subsets can increase relative to larger sets or relative to control populations by at least 1.5 fold, at least 2 fold, at least 3 fold, at least 5 fold, or at least 10 fold.
  • OVA in incomplete Freund's adjuvant was injected subcutaneously into BALB/c mice (100 ⁇ g/mouse) twice in a two-week interval. The mice were also similarly sensitized for hen lysozyme. Delayed-type hypersensitity (DTH) to either sensitizing antigen was determined by rechallenge at a footpad (10 ⁇ g/injection) and measuring the net increase in footpad thickness (swelling) at 24 h. Suppressed immunization
  • mice were injected four times (on days 1, 4, 7, and 10) with DEX into the two hind footpads (8 ⁇ g/footpad).
  • OVA 323-339 (1 ⁇ g/footpad) was co- injected with DEX. This regimen was given twice in a two-week interval.
  • white cells were labeled with CFSE (Invitrogen) and stimulated in a 96-well plate with the immunizing peptide (10 ⁇ g/ml), or an irrelevant peptide as control, in the presence of syngeneic accessory cells (2.5 x 10 4 /well) and IL-2 (800 IU/ml). Three days later, cells were stained for CD4, CD25, and Foxp3 as described above, and analyzed for CFSE dilution by flow cytometry, gating on Treg.
  • CFSE Invitrogen
  • CFSE-labeled DOl 1.10 TCR-transgenic CD4 + T cells (2.5 ⁇ 5 x 10 5 /footpad) were co- injected with OVA 323 _ 339 (1 ⁇ g) into a footpad of BALB/c mice that had been pretreated with DEX on days -6, -3, and 0. Draining LN were recovered on day 4; total cellular content was immunostained with KJ 1-26, anti-CD25, and anti-Foxp3 mAbs and analyzed by flow cytometry.
  • mice Female NOD mice (6 weeks of age) were injected 4 times (on days 1, 4, 1, and 10) with DEX into the two hind footpads (8 ⁇ g/footpad). For the day-7 injection, B:9-23 (1 ⁇ g/footpad) was co-injected with DEX. This regimen was given twice in a two-week interval. Glycosuria was checked weekly using Diastix strips (Bayer Corp.). Mice tested positive (> 250 mg/dl) twice consecutively were deemed diabetic.
  • mice were rechallenged (day 0) at a footpad with the immunizing peptide emulsified in incomplete Freund's adjuvant (50 ⁇ g/footpad).
  • splenic CD4 + T cells were isolated, labeled with CFSE, and stimulated in a 96-well plate with the immunizing peptide (10 ⁇ g/ml) or an irrelevant peptide (as control), in the presence of na ⁇ ve syngeneic accessory cells (2.5 x 10 4 /well) and IL-2 (800 IU/ml).
  • cells were stained for CD4, CD25, and Foxp3 and analyzed for CFSE dilution by flow cytometry, gating on CD4 + CD25 + cells.
  • Treg CD4 + CD25 + Foxp3 + regulatory T cells
  • Fig. 1C At least part of the increased Treg count consisted of OVA 323 _ 339 -specific Treg, because they proliferated in culture in response to OVA 323-33 Q ( Figure ID), but not to an irrelevant peptide (data not shown). In comparison, no such Treg were detected in the blood of the non-treated control group (Fig. ID).
  • CD4 + T cells from DOl 1.10 mice, labeled them with carboxyfluorescein succinimidyl ester (CFSE) to allow tracking of cell division (11) and adoptively transferred the cells into syngeneic BALB/c mice, where they were stimulated with DEX and OVA 323-339 .
  • CFSE carboxyfluorescein succinimidyl ester
  • mice treated with either DEX or B:9-23 showed a delayed median incidence of 24.5 and 26 weeks, respectively (Fig. 3A).
  • most mice treated with both DEX and B:9-23 remained disease-free during the entire period of the experiment (35 weeks), indicating that suppressed immunization is effective for delaying or preventing the progression of autoimmune diabetes.
  • DEX can function as a tolerogenic adjuvant when applied in conjunction with a peptide immunogen.
  • the particular effect of DEX on Treg expansion is consistent with prior findings by Chen et al. that DEX alone could alter the ratio of CD4 + CD25 + Treg to CD4 + CD25 " conventional T cells in vivo in favor of the former (16) and that DEX could also amplify IL-2-dependent expansion of functional CD4 + CD25 + Foxp3 + Treg in vivo (17).
  • the novel finding from the present study is that when combined with antigenic immunization, the use of DEX can lead to preferential induction of Treg that are antigen-specific and long-term persistent.
  • DEX or glucocorticoids in general, may not be unique in its ability to serve as a tolerogenic adjuvant.
  • Other small- molecule immunosuppressive drugs such as vitamin D3 and analogues, cyclosporine A, FK506, and rapamycin, have been shown to have similar pharmacological effects on DC maturation and function (18) and might therefore also be useful for tolerogenic immunization.

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Abstract

L'invention concerne un traitement de combinaison d'un adjuvant immunosuppresseur et d'un antigène spécifique à une maladie qui fournit des bénéfices à court et long terme vis-à-vis de maladies associées à des réponses immunitaires hyperactives. De telles maladies comprennent des maladies immunitaires, le rejet de transplantation et des maladies allergiques. Le traitement peut employer des agents d'administration de protéine ou d'acide nucléique pour une immunisation spécifique à un antigène. L'adjuvant immunosuppresseur inhibe la différenciation de cellules dendritiques et stimule la propagation de cellules Treg, en particulier des cellules Treg spécifiques à un antigène.
PCT/US2008/065085 2007-05-29 2008-05-29 Procédés pour induire des lymphocytes t thérapeutiques pour des maladies immunitaires Ceased WO2008150868A1 (fr)

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EP2527428A1 (fr) * 2011-05-26 2012-11-28 Hospital Clínic de Barcelona Cellules dendritiques tolérogènes et leur utilisation dans la thérapie cellulaire
US8652487B2 (en) 2011-04-29 2014-02-18 Selecta Biosciences, Inc. Tolerogenic synthetic nanocarriers for inducing regulatory B cells
WO2014058915A3 (fr) * 2012-10-08 2014-05-30 St. Jude Children's Research Hospital Thérapies fondées sur la stabilité et la fonction des lymphocytes t régulateurs par l'intermédiaire d'un axe neuropiline-1:sémaphorine
US8846098B2 (en) 2009-07-10 2014-09-30 University Of Pittsburgh-Of The Commonwealth System Of Higher Education Artificial cell constructs for cellular manipulation
US10046064B2 (en) 2014-09-07 2018-08-14 Selecta Biosciences, Inc. Methods and compositions for attenuating exon skipping anti-viral transfer vector immune responses
US10335395B2 (en) 2013-05-03 2019-07-02 Selecta Biosciences, Inc. Methods of administering immunosuppressants having a specified pharmacodynamic effective life and therapeutic macromolecules for the induction of immune tolerance
US11090363B2 (en) 2009-07-10 2021-08-17 University of Pittsburgh—of the Commonwealth System of Higher Education Vasoactive intestinal peptide release from microparticles
US11426451B2 (en) 2017-03-11 2022-08-30 Selecta Biosciences, Inc. Methods and compositions related to combined treatment with antiinflammatories and synthetic nanocarriers comprising an immunosuppressant
US12553041B2 (en) 2019-06-04 2026-02-17 Cartesian Therapeutics Inc. Formulations and doses of pegylated uricase

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US9757339B2 (en) 2009-07-10 2017-09-12 University of Pittsburgh—of the Commonwealth System of Higher Education Artificial cell constructs for cellular manipulation
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US11090363B2 (en) 2009-07-10 2021-08-17 University of Pittsburgh—of the Commonwealth System of Higher Education Vasoactive intestinal peptide release from microparticles
US9289477B2 (en) 2011-04-29 2016-03-22 Selecta Biosciences, Inc. Tolerogenic synthetic nanocarriers to reduce cytotoxic T lymphocyte responses
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US10420835B2 (en) 2011-04-29 2019-09-24 Selecta Biosciences, Inc. Tolerogenic synthetic nanocarriers for antigen-specific deletion of T effector cells
EP2527428A1 (fr) * 2011-05-26 2012-11-28 Hospital Clínic de Barcelona Cellules dendritiques tolérogènes et leur utilisation dans la thérapie cellulaire
WO2014058915A3 (fr) * 2012-10-08 2014-05-30 St. Jude Children's Research Hospital Thérapies fondées sur la stabilité et la fonction des lymphocytes t régulateurs par l'intermédiaire d'un axe neuropiline-1:sémaphorine
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US10046064B2 (en) 2014-09-07 2018-08-14 Selecta Biosciences, Inc. Methods and compositions for attenuating exon skipping anti-viral transfer vector immune responses
US11633422B2 (en) 2014-09-07 2023-04-25 Selecta Biosciences, Inc. Methods and compositions for attenuating anti-viral transfer vector immune responses
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