Antigen-specific tolerance strategies for the prevention and treatment of autoimmune disease

Nature Reviews Immunology

Volumn 7, Issue 9, 2007, Pages 665-677

  Miller, Stephen D ^a   Turley, Danielle M ^a   Podojil, Joseph R ^a  

^a NORTHWESTERN UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIDIABETIC AGENT; ANTIGEN; COLLAGEN TYPE 2; DIAPEP 277; DNA VACCINE; GLATIRAMER; INSULIN; MBP 85-96 PEPTIDE; MYELIN OLIGODENDROCYTE GLYCOPROTEIN; NEUROVAX; PEPTIDE DERIVATIVE; PLACEBO; PROTEOLIPID PROTEIN; UNCLASSIFIED DRUG;

ANTIGEN SPECIFICITY; AUTOIMMUNE DISEASE; CELLULAR IMMUNITY; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; HUMAN; IMMUNOLOGICAL TOLERANCE; IMMUNOTHERAPY; INSULIN DEPENDENT DIABETES MELLITUS; MULTIPLE SCLEROSIS; NONHUMAN; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; REVIEW; RHEUMATOID ARTHRITIS;

ANIMALS; AUTOANTIGENS; AUTOIMMUNE DISEASES; CLINICAL TRIALS; DISEASE MODELS, ANIMAL; HUMANS; IMMUNE TOLERANCE; IMMUNOTHERAPY; MICE; PEPTIDES;

EID: 34548204279     PISSN: 14741733     EISSN: None     Source Type: Journal    
DOI: 10.1038/nri2153     Document Type: Review

References (119)

1. Nikolich-Žugich, J., Slifka, M. K. & Messaoudi, I. The many important facets of T-cell repertoire diversity. Nature Rev. Immunol. 4, 123-132 (2004).
2. Hafler, D. A. et al. Multiple sclerosis. Immunol. Rev. 204, 208-231 (2005).
3. Burstein, H. J., Shea, C. M. & Abbas, A. K. Aqueous antigens induce in vivo tolerance selectively in IL-2- and IFN-γ-producing (Th1) cells. J. Immunol. 148, 3687-3691 (1992).
4. Critchfield, J. M. et al. T cell deletion in high antigen dose therapy of autoimmune encephalomyelitis. Science 263, 1139-1143 (1994). This study shows that high-dose peptide-induced tolerance leads to clonal deletion.
5. Gaur, A., Wiers, B., Liu, A., Rothbard, J. & Fathman, C. G. Amelioration of autoimmune encephalomyelitis by myelin basic protein synthetic peptide-induced anergy. Science 258, 1491-1494 (1992). This study shows that high-dose peptide tolerance induces anergy in EAE.
6. Racke, M. K. et al. Intravenous antigen administration as a therapy for autoimmune demyelinating disease. Ann. Neurol. 39, 46-56 (1996).
7. Pipeleers, D. et al. A view on β cell transplantation in diabetes. Ann. NY Acad. Sci. 958, 69-76 (2002).
8. Judkowski, V. et al. Peptide specific amelioration of T cell mediated pathogenesis in murine type 1 diabetes. Clin. Immunol. 113, 29-37 (2004).
9. + T cells in autoimmune diabetes. Proc. Natl Acad. Sci. USA 100, 8384-8388 (2003).
10. + regulatory T cells generated in response to insulin B:9-23 peptide prevent adoptive transfer of diabetes by diabetogenic T cells. J. Autoimmun. 21, 221-237 (2003).
11. Coon, B., An, L. L., Whitton, J. L. & von Herrath, M. G. DNA immunization to prevent autoimmune diabetes. J. Clin. Invest. 104, 189-194 (1999). This paper reports the inhibition of type 1 diabetes by vaccination with insulin-encoding DNA.
12. Weaver, D. J. Jr, Liu, B. & Tisch, R. Plasmid DNAs encoding insulin and glutamic acid decarboxylase 65 have distinct effects on the progression of autoimmune diabetes in nonobese diabetic mice. J. Immunol. 167, 586-592 (2001).
13. Chang, Y. et al. DNA vaccination with an insulin construct and a chimeric protein binding to both CTLA4 and CD40 ameliorates type 1 diabetes in NOD mice. Gene Ther. 12, 1679-1685 (2005).
14. Smith, C. E., Eagar, T. N., Strominger, J. L. & Miller, S. D. Differential induction of IgE-mediated anaphylaxis after soluble vs. cell-bound tolerogenic peptide therapy of autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 102, 9595-9600 (2005). This paper shows that high-dose intravenous peptide-induced tolerance can induce fatal anaphylaxis in various EAE models.
15. Genain, C. P. et al. Late complications of immune deviation therapy in a nonhuman primate. Science 274, 2054-2057 (1996).
16. Katz, D. H., Bargatze, R. F., Bogowitz, C. A. & Katz, L. R. Regulation of IgE antibody production by serum molecules. IV. Complete Freund's adjuvant induces both enhancing and suppressive activities detectable in the serum of low and high responder mice. J. Immunol. 122, 2184-2190 (1979).
17. Warren, K. G., Catz, I. & Wucherpfennig, K. W. Tolerance induction to myelin basic protein by intravenous synthetic peptides containing epitope P85 VVHFFKNIVTP96 in chronic progressive multiple sclerosis. J. Neurol. Sci. 152, 31-38 (1997).
18. Pedotti, R. et al. An unexpected version of horror autotoxicus: anaphylactic shock to a self-peptide. Nature Immunol. 2, 216-222 (2001).
19. Mayer, L. & Shao, L. Therapeutic potential of oral tolerance. Nature Rev. Immunol. 4, 407-419 (2004).
20. Mowat, A. M., Strobel, S., Drummond, H. E. & Ferguson, A. Immunological responses to fed protein antigens in mice. I. Reversal of oral tolerance to ovalbumin by cyclophosphamide. Immunology 45, 105-113 (1982).
21. Faria, A. M. & Weiner, H. L. Oral tolerance: mechanisms and therapeutic applications. Adv. Immunol. 73, 153-264 (1999).
22. Friedman, A. & Weiner, H. L. Induction of anergy or active suppression following oral tolerance is determined by antigen dosage. Proc. Natl Acad. Sci. USA 91, 6688-6692 (1994).
23. Bitar, D. M. & Whitacre, C. C. Suppression of experimental autoimmune encephalomyelitis by the oral administration of myelin basic protein. Cell. Immunol. 112, 364-370 (1988). This paper provides the first demonstration of oral tolerance for the prevention of EAE.
24. Whitacre, C. C., Gienapp, I. E., Orosz, C. G. & Bitar, D. M. Oral tolerance in experimental autoimmune encephalomyelitis: III. Evidence for clonal anergy. J. Immunol. 147, 2155-2163 (1991).
25. Khoury, S. J., Hancock, W. W. & Weiner, H. L. Oral tolerance to myelin basic protein and natural recovery from experimental autoimmune encephalomyelitis are associated with down-regulation of inflammatory cytokines and differential upregulation of transforming growth factor beta, interleukin 4, and prostaglandin E expression in the brain. J. Exp. Med. 176, 1355-1364 (1992).
26. H3 cells.
27. Miller, A., Lider, O., Roberts, A. B., Sporn, M. B. & Weiner, H. L. Suppressor T cells generated by oral tolerization to myelin basic protein suppress both in vitro and in vivo immune responses by the release of transforming growth factor β after antigen-specific triggering. Proc. Natl Acad. Sci. USA 89, 421-425 (1992).
28. Mowat, A. M., Parker, L. A., Beacock-Sharp, H., Millington, O. R. & Chirdo, F. Oral tolerance: overview and historical perspectives. Ann. NY Acad. Sci. 1029, 1-8 (2004).
29. Weiner, H. L. Current issues in the treatment of human diseases by mucosal tolerance. Ann. NY Acad. Sci. 1029, 211-224 (2004).
30. Meyer, A. L., Benson, J. M., Gienapp, I. E., Cox, K. L. & Whitacre, C. C. Suppression of murine chronic relapsing experimental autoimmune encephalomyelitis by the oral administration of myelin basic protein. J. Immunol. 157, 4230-4238 (1996).
31. Benson, J. M. et al. Oral administration of myelin basic protein is superior to myelin in suppressing established relapsing experimental autoimmune encephalomyelitis. J. Immunol. 162, 6247-6254 (1999).
32. Bai, X. F. et al. Complexities of applying nasal tolerance induction as a therapy for ongoing relapsing experimental autoimmune encephalomyelitis (EAE) in DA rats. Clin. Exp. Immunol. 111, 205-210 (1998).
33. Kennedy, K. J., Smith, W. S., Miller, S. D. & Karpus, W. J. Induction of antigen-specific tolerance for the treatment of ongoing, relapsing autoimmune encephalomyelitis: a comparison between oral and peripheral tolerance. J. Immunol. 159, 1036-1044 (1997).
34. 139-151 molecule. J. Neurosci. Res. 45, 410-423 (1996).
35. Bai, X. F. et al. Nasal administration of myelin basic protein prevents relapsing experimental autoimmune encephalomyelitis in DA rats by activating regulatory cells expressing IL-4 and TGF-β mRNA. J. Neuroimmunol. 80, 65-75 (1997).
36. Slavin, A. J., Maron, R. & Weiner, H. L. Mucosal administration of IL-10 enhances oral tolerance in autoimmune encephalomyelitis and diabetes. Int. Immunol. 13, 825-833 (2001).
37. Maron, R., Slavin, A. J., Hoffmann, E., Komagata, Y. & Weiner, H. L. Oral tolerance to copolymer 1 in myelin basic protein (MBP) TCR transgenic mice: cross-reactivity with MBP-specific TCR and differential induction of anti-inflammatory cytokines. Int. Immunol. 14, 131-138 (2002).
38. Metzler, B. & Wraith, D. C. Inhibition of experimental autoimmune encephalomyelitis by inhalation but not oral administration of the encephalitogenic peptide: influence of MHC binding affinity. Int. Immunol. 5, 1159-1165 (1993). This is a comparison of oral and nasal routes of peptide administration for the prevention of EAE.
39. Weiner, H. L. et al. Double-blind pilot trial of oral tolerization with myelin antigens in multiple sclerosis. Science 259, 1321-1324 (1993). This paper provides a description of the initial clinical trial that used orally administered myelin in patients with MS.
40. Miller, S. D., Wetzig, R. P. & Claman, H. N. The induction of cell-mediated immunity and tolerance with protein antigens coupled to syngeneic lymphoid cells. J. Exp. Med. 149, 758-773 (1979). This is the initial demonstration that antigen-pulsed, ECDI-fixed splenic APCs induce T-cell tolerance.
41. Sriram, S., Schwartz, G. & Steinman, L. Administration of myelin basic protein-coupled spleen cells prevents experimental allergic encephalitis. Cell. Immunol. 75, 378-382 (1983).
42. Miller, S. D. et al. Evolution of the T cell repertoire during the course of experimental autoimmune encephalomyelitis. Immunol. Rev. 144, 225-244 (1995).
43. h2 cells to induction of anergy and apoptosis by ECDI/antigen-coupled antigen-presenting cells. Int. Immunol. 12, 57-66 (2000). This paper shows that peptide-pulsed, ECDI-fixed PBLs induce anergy in MBP-specific human T-cell lines.
44. Lehmann, P. V., Forsthuber, T., Miller, A. & Sercarz, E. E. Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature 358, 155-157 (1992). This is the initial description of epitope spreading in autoimmunity.
45. Vanderlugt, C. L. et al. Pathologic role and temporal appearance of newly emerging autoepitopes in relapsing experimental autoimmune encephalomyelitis. J. Immunol. 164, 670-678 (2000). This reference demonstrates that tolerance to spread epitopes is required to inhibit progression of established relapsing EAE.
46. Smith, C. E. & Miller, S. D. Multi-peptide coupled-cell tolerance ameliorates ongoing relapsing EAE associated with multiple pathogenic autoreactivities. J. Autoimmunity 27, 218-231 (2006).
47. Kennedy, M. K., Tan, L. J., Dal Canto, M. C. & Miller, S. D. Regulation of the effector stages of experimental autoimmune encephalomyelitis via neuroantigen-specific tolerance induction. J. Immunol. 145, 117-126 (1990).
48. Kennedy, M. K. et al. Inhibition of murine relapsing experimental autoimmune encephalomyelitis by immune tolerance to proteolipid protein and its encephalitogenic peptides. J. Immunol. 144, 909-915 (1990). This is the initial demonstration that myelinpeptide-coupled cells can inhibit EAE induction.
49. Vandenbark, A. A., Vainiene, M., Ariail, K., Miller, S. D. & Offner, H. Prevention and treatment of relapsing autoimmune encephalomyelitis with myelin peptide-coupled splenocytes. J. Neurosci. Res. 45, 430-438 (1996).
50. Su, X. M. & Sriram, S. Treatment of chronic relapsing experimental allergic encephalomyelitis with the intravenous administration of splenocytes coupled to encephalitogenic peptide 91-103 of myelin basic protein. J. Neuroimmunol. 34, 181-190 (1991).
51. Tan, L. J., Kennedy, M. K. & Miller, S. D. Regulation of the effector stages of experimental autoimmune encephalomyelitis via neuroantigen-specific tolerance induction. II. Fine specificity of effector T cell inhibition. J. Immunol. 148, 2748-2755 (1992).
52. Miller, S. D., Tan, L. J., Pope, L., McRae, B. L. & Karpus, W. J. Antigen-specific tolerance as a therapy for experimental autoimmune encephalomyelitis. Int. Rev. Immunol. 9, 203-222 (1992).
53. Miller, S. D. & Karpus, W. J. The immunopathogenesis and regulation of T-cell mediated demyelinating diseases. Immunol. Today 15, 356-361 (1994).
54. McRae, B. L., Vanderlugt, C. L., Dal Canto, M. C. & Miller, S. D. Functional evidence for epitope spreading in the relapsing pathology of experimental autoimmune encephalomyelitis. J. Exp. Med. 182, 75-85 (1995). This study provides the initial description of the functional pathological significance of epitope spreading to disease progression in relapsing EAE.
55. Miller, S. D. et al. Blockade of CD28/B7-1 interaction prevents epitope spreading and clinical relapses of murine EAE. Immunity 3, 739-745 (1995).
56. Tan, L. J., Kennedy, M. K., Dal Canto, M. C. & Miller, S. D. Successful treatment of paralytic relapses in adoptive experimental autoimmune encephalomyelitis via neuroantigen-specific tolerance. J. Immunol. 147, 1797-1802 (1991).
57. Vanderlugt, C. L. & Miller, S. D. Epitope spreading. Curr. Opin. Immunol. 8, 831-836 (1996).
58. McMahon, E. J., Bailey, S. L., Castenada, C. V., Waldner, H. & Miller, S. D. Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis. Nature Med. 11, 335-339 (2005). This reference shows that epitope spreading initiates in the CNS.
59. H-17 cells in relapsing EAE. Nature Immunol. 8, 172-180 (2007). This study shows that epitope spreading in the CNS is driven primarily by peripherally derived myeloid APCs presenting endogenous myelin antigens.
60. Braley-Mullen, H., Tompson, J. G., Sharp, G. C. & Kyriakos, M. Suppression of experimental autoimmune thyroiditis in guinea pigs by pretreatment with thyroglobulin-coupled spleen cells. Cell. Immunol. 51, 408-413 (1980).
61. Dua, H. S., Gregerson, D. S. & Donoso, L. A. Inhibition of experimental autoimmune uveitis by retinal photoreceptor antigens coupled to spleen cells. Cell. Immunol. 139, 292-305 (1992).
62. Gregorian, S. K., Clark, L., Heber-Katz, E., Amento, E. P. & Rostami, A. Induction of peripheral tolerance with peptide-specific anergy in experimental autoimmune neuritis. Cell. Immunol. 150, 298-310 (1993).
63. Fife, B. T. et al. Insulin-induced remission in new-onset NOD mice is maintained by the PD-1-PD-L1 pathway. J. Exp. Med. 203, 2737-2747 (2006).
64. Jenkins, M. K. & Schwartz, R. H. Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J. Exp. Med. 165, 302-319 (1987).
65. Eagar, T. N., Karandikar, N. J., Bluestone, J. & Miller, S. D. The role of CTLA-4 in induction and maintenance of peripheral T cell tolerance. Eur. J. Immunol. 32, 972-981 (2002).
66. Turley, D. M. & Miller, S. D. Peripheral tolerance Induction using ethylenecarbodiimide-fixed APCs uses both direct and indirect mechanisms of antigen presentation for prevention of experimental autoimmune encephalomyelitis. J. Immunol. 178, 2212-2220 (2007). This study shows that ECDI-fixed-cell-induced tolerance works primarily by an indirect pathway of antigen re-presentation by host APCs.
67. Pope, L., Paterson, P. Y. & Miller, S. D. Antigen-specific inhibition of the adoptive transfer of experimental autoimmune encephalomyelitis in Lewis rats. J. Neuroimmunol. 37, 177-190 (1992).
68. Bilsborough, J., George, T. C., Norment, A. & Viney, J. L. Mucosal CD8alpha+ DC, with a plasmacytoid phenotype, induce differentiation and support function of T cells with regulatory properties. Immunology 108, 481-492 (2003).
69. + dendritic cells endowed with type 1 interferon production capacity and tolerogenic potential. Blood 100, 383-390 (2002).
70. Young, D. A. et al. IL-4, IL-10, IL-13, and TGF-β from an altered peptide ligand-specific Th2 cell clone down-regulate adoptive transfer of experimental autoimmune encephalomyelitis. J. Immunol. 164, 3563-3572 (2000).
71. Nicholson, L. B., Murtaza, A., Hafler, B. P., Sette, A. & Kuchroo, V. K. A T cell receptor antagonist peptide induces T cells that mediate bystander suppression and prevent autoimmune encephalomyelitis induced with multiple myelin antigens. Proc. Natl Acad. Sci. USA 94, 9279-9284 (1997).
72. Samson, M. F. & Smilek, D. E. Reversal of acute experimental autoimmune encephalomyelitis and prevention of relapses by treatment with a myelin basic protein peptide analogue modified to form long-lived peptide-MHC complexes. J. Immunol. 155, 2737-2746 (1995).
73. Wraith, D. C., Smilek, D. E., Mitchell, D. J., Steinman, L. & McDevitt, H. O. Antigen recognition in autoimmune encephalomyelitis and the potential for peptide-mediated immunotherapy. Cell 59, 247-255 (1989).
74. Nicholson, L. B. & Kuchroo, V. K. T cell recognition of self and altered self antigens. Crit. Rev. Immunol. 17, 449-462 (1997).
75. Karin, N., Mitchell, D. J., Brocke, S., Ling, N. & Steinman, L. Reversal of experimental autoimmune encephalomyelitis by a soluble peptide variant of a myelin basic protein epitope: T cell receptor antagonism and reduction of interferon γ and tumor necrosis factor α production. J. Exp. Med. 180, 2227-2237 (1994).
76. Nicholson, L. B., Greer, J. M., Sobel, R. A., Lees, M. B. & Kuchroo, V. K. An altered peptide ligand mediates immune deviation and prevents autoimmune encephalomyelitis. Immunity 3, 397-405 (1995). This study shows that APL therapy induces immune deviation in prevention of EAE.
77. Aharoni, R., Teitelbaum, D., Arnon, R. & Sela, M. Copolymer 1 acts against the immunodominant epitope 82-100 of myelin basic protein by T cell receptor antagonism in addition to major histocompatibility complex blocking. Proc. Natl Acad. Sci. USA 96, 634-639 (1999).
78. Ruiz, P. J. et al. Immunomodulation of experimental autoimmune encephalomyelitis with ordered peptides based on MHC-TCR binding motifs. J. Immunol. 167, 2688-2693 (2001).
79. Illes, Z. et al. Modified amino acid copolymers suppress myelin basic protein 85-99-induced encephalomyelitis in humanized mice through different effects on T cells. Proc. Natl Acad. Sci. USA 101, 11749-11754 (2004).
80. Stern, J. N. et al. Peptide 15-mers of defined sequence that substitute for random amino acid copolymers in amelioration of experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 102, 1620-1625 (2005).
81. Skyler, J. S. et al. Effects of oral insulin in relatives of patients with type 1 diabetes: the diabetes prevention trial - type 1. Diabetes Care 28, 1068-1076 (2005).
82. Chaillous, L. et al. Oral insulin administration and residual β-cell function in recent-onset type 1 diabetes: a multicentre randomised controlled trial. Diabete Insuline Orale group. Lancet 356, 545-549 (2000).
83. Ergun-Longmire, B. et al. Oral insulin therapy to prevent progression of immune-mediated (type 1) diabetes. Ann. NY Acad. Sci. 1029, 260-277 (2004).
84. Monetini, L. et al. Cytokine profile and insulin antibody IgG subclasses in patients with recent onset type 1 diabetes treated with oral insulin. Diabetologia 47, 1795-1802 (2004).
85. Staeva-Vieira, T., Peakman, M. & von Herrath, M. Translational mini-review series on type 1 diabetes: Immune-based therapeutic approaches for type 1 diabetes. Clin. Exp. Immunol. 148, 17-31 (2007).
86. Faria, A. M. & Weiner, H. L. Oral tolerance: therapeutic implications for autoimmune diseases. Clin. Dev. Immunol. 13, 143-157 (2006).
87. Barnett, M. L. et al. Treatment of rheumatoid arthritis with oral type II collagen. Results of a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum. 41, 290-297 (1998).
88. Prakken, B. J. et al. Epitope-specific immunotherapy induces immune deviation of proinflammatory T cells in rheumatoid arthritis. Proc. Natl Acad. Sci. USA 101, 4228-4233 (2004).
89. Bielekova, B. et al. Encephalitogenic potential of the myelin basic protein peptide (amino acids 83-99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand. Nature Med. 6, 1167-1175 (2000). This paper demonstrates that an MBP APL leads to exacerbated clinical MS.
90. Kappos, L. et al. Induction of a non-encephalitogenic type 2 T helper-cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo-controlled, randomized phase II trial. The Altered Peptide Ligand in Relapsing MS Study Group. Nature Med. 6, 1176-1182 (2000).
91. Johnson, K. P. et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology 45, 1268-1276 (1995).
92. Cohen, J. A. et al. Randomized, double-blind, dose-comparison study of glatiramer acetate in relapsing-remitting MS. Neurology 68, 939-944 (2007).
93. Alleva, D. G. et al. Immunomodulation in type 1 diabetes by NBI-6024, an altered peptide ligand of the insulin B epitope. Scand. J. Immunol. 63, 59-69 (2006).
94. + T cells in multiple sclerosis. J. Immunol. 172, 3893-3904 (2004).
95. Chatenoud, L., Thervet, E., Primo, J. & Bach, J. F. Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Proc. Natl Acad. Sci. USA 91, 123-127 (1994).
96. Chatenoud, L. CD3-specific antibody-induced active tolerance: from bench to bedside. Nature Rev. Immunol. 3, 123-132 (2003).
97. + T cell unresponsiveness and functional reversal of established experimental autoimmune encephalomyelitis. J. Immunol. 174, 4525-4534 (2005).
98. Herold, K. C. et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N. Engl. J. Med. 346, 1692-1698 (2002).
99. Pozzilli, P. et al. No effect of oral insulin on residual β-cell function in recent-onset type I diabetes (the IMDIAB VII). IMDIAB Group. Diabetologia 43, 1000-1004 (2000).
100. Keymeulen, B. et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N. Engl. J. Med. 352, 2598-2608 (2005).
101. Utset, T. O. et al. Modified anti-CD3 therapy in psoriatic arthritis: a phase I/II clinical trial. J. Rheumatol. 29, 1907-1913 (2002).
102. Herold, K. C. et al. Activation of human T cells by FcR nonbinding anti-CD3 mAb, hOKT3γ1(Ala-Ala). J. Clin. Invest. 111, 409-418 (2003).
103. Belghith, M. et al. TGF-β-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes. Nature Med. 9, 1202-1208 (2003).
104. 1 integrin. Nature 356, 63-66 (1992).
105. Miller, D. H. et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 348, 15-23 (2003).
106. Karpus, W. J. et al. An important role for the chemokine macrophage inflammatory protein-1 α in the pathogenesis of the T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis. J. Immunol. 155, 5003-5010 (1995).
107. Ruddle, N. H. et al. An antibody to lymphotoxin and tumor necrosis factor prevents transfer of experimental allergic encephalomyelitis. J. Exp. Med. 172, 1193-1200 (1990).
108. Khalili, K., White, M. K., Lublin, F., Ferrante, P. & Berger, J. R. Reactivation of JC virus and development of PML in patients with multiple sclerosis. Neurology 68, 985-990 (2007).
109. Macián, F., Lopéz-Rodríguez, C. & Rao, A. Partners in transcription: NFAT and AP-1. Oncogene 20, 2476-2489 (2001).
110. Heissmeyer, V. & Rao, A. E3 ligases in T cell anergy - turning immune responses into tolerance. Sci. STKE 2004, pe29 (2004).
111. Wu, Y. et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 126, 375-387 (2006).
112. Jeon, M. S. et al. Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction. Immunity. 21, 167-177 (2004).
113. Seroogy, C. M. et al. The gene related to anergy in lymphocytes, an E3 ubiquitin ligase, is necessary for anergy induction in CD4 T cells. J. Immunol. 173, 79-85 (2004).
114. + T cells. Immunity. 18, 535-547 (2003).
115. Naramura, M., Kole, H. K., Hu, R. J. & Gu, H. Altered thymic positive selection and intracellular signals in Cbl-deficient mice. Proc. Natl Acad. Sci. USA 95, 15547-15552 (1998).
116. Ohashi, P. S. T-cell signalling and autoimmunity: molecular mechanisms of disease. Nature Rev. Immunol. 2, 427-438 (2002).
117. Raz, I. et al. β-cell function in new-onset type 1 diabetes and immunomodulation with a heat-shock protein peptide (DiaPep277): a randomised, double-blind, phase II trial. Lancet 358, 1749-1753 (2001).
118. Raz, I. et al. Treatment of new-onset type 1 diabetes with peptide DiaPep277 is safe and associated with preserved β-cell function: extension of a randomized, double-blind, phase II trial. Diabetes. Metab. Res. Rev. 23, 292-298 (2007).
119. Bourdette, D. N. et al. A highly immunogenic trivalent T cell receptor peptide vaccine for multiple sclerosis. Mult. Scler. 11, 552-561 (2005).