Antigen-specific tolerance strategies for the prevention and treatment of autoimmune disease (original) (raw)

• Nikolich-Žugich, J., Slifka, M. K. & Messaoudi, I. The many important facets of T-cell repertoire diversity. Nature Rev. Immunol. 4, 123–132 (2004).
  Article CAS Google Scholar
• Hafler, D. A. et al. Multiple sclerosis. Immunol. Rev. 204, 208–231 (2005).
  Article CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• Racke, M. K. et al. Intravenous antigen administration as a therapy for autoimmune demyelinating disease. Ann. Neurol. 39, 46–56 (1996).
  Article CAS PubMed Google Scholar
• Pipeleers, D. et al. A view on β cell transplantation in diabetes. Ann. NY Acad. Sci. 958, 69–76 (2002).
  Article PubMed Google Scholar
• Judkowski, V. et al. Peptide specific amelioration of T cell mediated pathogenesis in murine type 1 diabetes. Clin. Immunol. 113, 29–37 (2004).
  Article CAS PubMed Google Scholar
• Lieberman, S. M. et al. Identification of the β cell antigen targeted by a prevalent population of pathogenic CD8+ T cells in autoimmune diabetes. Proc. Natl Acad. Sci. USA 100, 8384–8388 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Mukherjee, R., Chaturvedi, P., Qin, H. Y. & Singh, B. CD4+CD25+ 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).
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed PubMed Central Google Scholar
• Genain, C. P. et al. Late complications of immune deviation therapy in a nonhuman primate. Science 274, 2054–2057 (1996).
  Article CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Pedotti, R. et al. An unexpected version of horror autotoxicus: anaphylactic shock to a self-peptide. Nature Immunol. 2, 216–222 (2001).
  Article CAS Google Scholar
• Mayer, L. & Shao, L. Therapeutic potential of oral tolerance. Nature Rev. Immunol. 4, 407–419 (2004).
  Article CAS Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Faria, A. M. & Weiner, H. L. Oral tolerance: mechanisms and therapeutic applications. Adv. Immunol. 73, 153–264 (1999).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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 downregulation 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).
  Article CAS PubMed Google Scholar
• Chen, Y., Kuchroo, V. K., Inobe, J., Hafler, D. A. & Weiner, H. L. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 265, 1237–1240 (1994). This study reports that oral tolerance induces TGFβ-producing T H 3 cells.
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Weiner, H. L. Current issues in the treatment of human diseases by mucosal tolerance. Ann. NY Acad. Sci. 1029, 211–224 (2004).
  Article CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed Google Scholar
• Karpus, W. J., Kennedy, K. J., Smith, W. S. & Miller, S. D. Inhibition of relapsing experimental autoimmune encephalomyelitis in SJL mice by feeding the immunodominant PLP139–151 molecule. J. Neurosci. Res. 45, 410–423 (1996).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• Sriram, S., Schwartz, G. & Steinman, L. Administration of myelin basic protein-coupled spleen cells prevents experimental allergic encephalitis. Cell. Immunol. 75, 378–382 (1983).
  Article CAS PubMed Google Scholar
• Miller, S. D. et al. Evolution of the T cell repertoire during the course of experimental autoimmune encephalomyelitis. Immunol. Rev. 144, 225–244 (1995).
  Article CAS PubMed Google Scholar
• Vandenbark, A. A. et al. Differential susceptibility of human Th1 versus Th2 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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).
  Article CAS Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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 myelin-peptide-coupled cells can inhibit EAE induction.
  CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Miller, S. D. & Karpus, W. J. The immunopathogenesis and regulation of T-cell mediated demyelinating diseases. Immunol. Today 15, 356–361 (1994).
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Vanderlugt, C. L. & Miller, S. D. Epitope spreading. Curr. Opin. Immunol. 8, 831–836 (1996).
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• Bailey, S. L., Schreiner, B., McMahon, E. J. & Miller, S. D. CNS myeloid DCs presenting endogenous myelin peptides 'preferentially' polarize CD4+ TH-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.
  Article CAS Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Martin, P. et al. Characterization of a new subpopulation of mouse CD8α+B220+ dendritic cells endowed with type 1 interferon production capacity and tolerogenic potential. Blood 100, 383–390 (2002).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Nicholson, L. B. & Kuchroo, V. K. T cell recognition of self and altered self antigens. Crit. Rev. Immunol. 17, 449–462 (1997).
  CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Faria, A. M. & Weiner, H. L. Oral tolerance: therapeutic implications for autoimmune diseases. Clin. Dev. Immunol. 13, 143–157 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• 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.
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Cohen, J. A. et al. Randomized, double-blind, dose-comparison study of glatiramer acetate in relapsing-remitting MS. Neurology 68, 939–944 (2007).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Bielekova, B. et al. Expansion and functional relevance of high-avidity myelin-specific CD4+ T cells in multiple sclerosis. J. Immunol. 172, 3893–3904 (2004).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Chatenoud, L. CD3-specific antibody-induced active tolerance: from bench to bedside. Nature Rev. Immunol. 3, 123–132 (2003).
  Article CAS Google Scholar
• Kohm, A. P. et al. Treatment with nonmitogenic anti-CD3 monoclonal antibody induces CD4+ T cell unresponsiveness and functional reversal of established experimental autoimmune encephalomyelitis. J. Immunol. 174, 4525–4534 (2005).
  Article CAS PubMed Google Scholar
• Herold, K. C. et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N. Engl. J. Med. 346, 1692–1698 (2002).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Keymeulen, B. et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N. Engl. J. Med. 352, 2598–2608 (2005).
  Article CAS PubMed Google Scholar
• Utset, T. O. et al. Modified anti-CD3 therapy in psoriatic arthritis: a phase I/II clinical trial. J. Rheumatol. 29, 1907–1913 (2002).
  CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Yednock, T. A. et al. Prevention of experimental autoimmune encephalomyelitis by antibodies against α4β1 integrin. Nature 356, 63–66 (1992).
  Article CAS PubMed Google Scholar
• Miller, D. H. et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 348, 15–23 (2003).
  Article CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Macián, F., Lopéz-Rodríguez, C. & Rao, A. Partners in transcription: NFAT and AP-1. Oncogene 20, 2476–2489 (2001).
  Article PubMed Google Scholar
• Heissmeyer, V. & Rao, A. E3 ligases in T cell anergy—turning immune responses into tolerance. Sci. STKE 2004, pe29 (2004).
  PubMed Google Scholar
• Wu, Y. et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 126, 375–387 (2006).
  Article CAS PubMed Google Scholar
• Jeon, M. S. et al. Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction. Immunity. 21, 167–177 (2004).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Anandasabapathy, N. et al. GRAIL: an E3 ubiquitin ligase that inhibits cytokine gene transcription is expressed in anergic CD4+ T cells. Immunity. 18, 535–547 (2003).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Ohashi, P. S. T-cell signalling and autoimmunity: molecular mechanisms of disease. Nature Rev. Immunol. 2, 427–438 (2002).
  Article CAS Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Bourdette, D. N. et al. A highly immunogenic trivalent T cell receptor peptide vaccine for multiple sclerosis. Mult. Scler. 11, 552–561 (2005).
  Article CAS PubMed Google Scholar