Current and future immunomodulation strategies to restore tolerance in autoimmune diseases

Cold Spring Harbor Perspectives in Biology

Volumn 4, Issue 11, 2012, Pages

  Bluestone, Jeffrey A ^a   Bour Jordan, Hélène ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANIMAL; ARTICLE; AUTOIMMUNE DISEASE; HUMAN; IMMUNOLOGICAL TOLERANCE; IMMUNOLOGY; IMMUNOTHERAPY; METHODOLOGY; PATHOPHYSIOLOGY; T LYMPHOCYTE;

ANIMALS; AUTOIMMUNE DISEASES; HUMANS; IMMUNE TOLERANCE; IMMUNOTHERAPY; PERIPHERAL TOLERANCE; T-LYMPHOCYTES;

ANIMALIA;

EID: 84868596823     PISSN: None     EISSN: 19430264     Source Type: Journal    
DOI: 10.1101/cshperspect.a007542     Document Type: Article

References (196)

1. Abrams JR, Lebwohl MG, Guzzo CA, Jegasothy BV, Goldfarb MT, Goffe BS, Menter A, Lowe NJ, Krueger G, Brown MJ, et al. 1999. CTLA4Ig-mediated blockade of Tcell costimulation in patients with psoriasis vulgaris. J Clin Invest 103: 1243.
2. Alexander T, Thiel A, Rosen O, Massenkeil G, Sattler A, Kohler S, Mei H, Radtke H, Gromnica-Ihle E, Burmeste GR, et al. 2009. Depletion of autoreactive immunologic memory followed by autologous hematopoietic stem cell transplantation in patients with refractory SLE induces long-term remission through de novo generation of a juvenile and tolerant immune system. Blood 113: 214-223.
3. Alyanakian MA, Grela F, Aumeunier A, Chiavaroli C, Gouarin C, Bardel E, Normier G, Chatenoud L, Thieblemon N, Bach JF. 2006. Transforming growth factor-β and natural killer T-cells are involved in the protective effect of a bacterial extract on type 1 diabetes. Diabetes 55: 179-185.
4. Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, von Boehmer H, Bronson R, Dierich A, Benoist C, et al. 2002. Projection of an immunological self shadow within the thymus by the aire protein. Science 298: 1395-1401.
5. Anderton SM. 2004. Post-translational modifications of self antigens: Implications for autoimmunity. Curr Opin Immunol 16: 753-758.
6. Arnson Y, Shoenfeld Y, Amital H. 2009. Intravenous immunoglobulin therapy for autoimmune diseases. Autoimmunity 42: 553-560.
7. Bagdanoff JT, Donoviel MS, Nouraldeen A, Carlsen M, Jessop TC, Tarver J, Aleem S, Dong L, Zhang H, Boteju L, et al. 2010. Inhibition of sphingosine 1-phosphate lyase for the treatment of rheumatoid arthritis: Discovery of (E)-1-(4-(1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone oxime (LX2931) and (1R,2S,3R)-1-(2-(isoxazol-3-yl)-1H-imidazol-4-yl)butane-1,2,3,4-tetraol (LX2932). J Med Chem 53: 8650-8662.
8. Bai XF, Li HL, Shi FD, Liu JQ, Xiao BG, Van der Meide PH, Link H. 1998. 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.
9. Bai Y, Liu J, Wang Y, Honig S, Qin L, Boros P, Bromberg JS. 2002. L-Selectin-dependent lymphoid occupancy is required to induce alloantigen-specific tolerance. J Immunol 168: 1579-1589.
10. Bar-Or A, Vollmer T, Antel J, Arnold DL, Bodner CA, Campagnolo D, Gianettoni J, Jalili F, Kachuck N, Lapierre Y, et al. 2007. Induction of antigen-specific tolerance in multiple sclerosis after immunization with DNA encoding myelin basic protein in a randomized, placebo-controlled phase 1/2 trial. Arch Neurol 64: 1407-1415.
11. +regulatory T cells. Blood 105: 4743-4748.
12. Bayry J, Lacroix-Desmazes S, Carbonneil C, Misra N, Donkova V, Pashov A, Chevailler A, Mouthon L, Weill B, Bruneval P, et al. 2003. Inhibition of maturation and function of dendritic cells by intravenous immunoglobulin. Blood 101: 758-765.
13. Belghith M, Bluestone JA, Barriot S, Megret J, Bach JF, Chatenoud L. 2003. TGF-β-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes. Nat Med 9: 1202-1208.
14. Bielekova B, Goodwin B, Richert N, Cortese I, Kondo T, Afshar G, Gran B, Eaton J, Antel J, Frank JA, et al. 2000. 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. Nat Med 6: 1167-1175.
15. Bielekova B, Howard T, Packer AN, Richert N, Blevins G, Ohayon J, Waldmann TA, McFarland HF, Martin R. 2009. Effect of anti-CD25 antibody daclizumab in the inhibition of inflammation and stabilization of disease progression in multiple sclerosis. Arch Neurol 66: 483-489.
16. Bluestone JA, St ClairEW, Turka LA. 2006. CTLA4Ig: Bridging the basic immunology with clinical application. Immunity 24: 233-238.
17. Bluestone JA, Liu W, Yabu JM, Laszik ZG, Putnam A, Belingheri M, Gross DM, Townsend RM, Vincenti F. 2008. The effect of costimulatory and interleukin 2 receptor blockade on regulatory T cells in renal transplantation. Am J Transplant 8: 2086-2096.
18. Bluestone JA, Herold K, Eisenbarth G. 2010. Genetics, pathogenesis and clinical interventions in type 1 diabetes. Aug 17 464: 1293-1300.
19. +T cell tolerance. J Exp Med 196: 1627-1638.
20. Bour-Jordan H, Bluestone JA. 2009. Regulating the regulators: Costimulatory signals control the homeostasis and function of regulatory T cells. Immunol Rev 229: 41-66.
21. Bour-Jordan H, Salomon BL, Thompson HL, Szot GL, Bernhard MR, Bluestone JA. 2004. Costimulation controls diabetes by altering the balance of pathogenic and regulatory T cells. J Clin Invest 114: 979-987.
22. Bour-Jordan H, Esensten JH, Martinez-Llordella M, Penaranda C, Stumpf M, Bluestone JA. 2011. Intrinsic and extrinsic control of peripheral T-cell tolerance by costimulatory molecules of the CD28/ B7 family. Immunol Rev 241: 180-205.
23. Boyman O, Kovar M, Rubinstein MP, Surh CD, Sprent J. 2006. Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science 311: 1924-1927.
24. Brunstein CG, Miller JS, Cao Q, McKenna DH, Hippen KL, Curtsinger J, Defor T, Levine BL, June CH, Rubinstein P, et al. 2011. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: Safety profile and detection kinetics. Blood 117: 1061-1070.
25. Brusko TM, Putnam AL, Bluestone JA. 2008. Human regulatory T cells: Role in autoimmune disease and therapeutic opportunities. Immunol Rev 223: 371-390.
26. Brusko TM, Koya RC, Zhu S, Lee MR, Putnam AL, Mc-Clymont SA, Nishimura MI, Han S, Chang LJ, Atkinso MA, et al. 2010. Human antigen-specific regulatory T cells generated by T cell receptor gene transfer. PloS ONE 5: e11726.
27. Burli RW, Haughan AF, Hodges AJ. 2010. Development of small-molecule therapies for autoimmune diseases. Autoimmunity 43: 526-538.
28. Burt RK, Testori A, Craig R, Cohen B, Suffit R, Barr W. 2008. Hematopoietic stem cell transplantation for autoimmune diseases: What have we learned? J Autoimmun 30: 116-120.
29. +regulatory T cells. J Immunol 180: 858-869.
30. Chaillous L. 2000. 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.
31. Chatenoud L, Primo J, Bach JF. 1997. CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice. J Immunol 158: 2947-2954.
32. Cheng G, Yu A, Malek TR. 2011. T-cell tolerance and the multi-functional role of IL-2R signaling in T-regulatory cells. Immunol Rev 241: 63-76.
33. Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, Pelletier J, Capra R, Gallo P, Izquierdo G, et al. 2010. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 362: 402-415.
34. Coombs JH, Bloom BJ, Breedveld FC, Fletcher MP, Gruben D, Kremer JM, Burgos-Vargas R, Wilkinson B, Zerbini CA, Zwillich SH. 2010. Improved pain, physical functioning and health status in patients with rheumatoid arthritis treated with CP-690,550, an orally active Janus kinase (JAK) inhibitor: Results from a randomised, double-blind, placebo-controlled trial. Ann Rheum Dis 69: 413-416.
35. Coon B, An LL, Whitton JL, von Herrath MG. 1999. DNA immunization to prevent autoimmune diabetes. J Clin Invest 104: 189-194.
36. Corper AL, Stratmann T, Apostolopoulos V, Scott CA, Garcia KC, Kang AS, Wilson IA, Teyton L. 2000. A structural framework for deciphering the link between I-Ag7 and autoimmune diabetes. Science 288: 505-511.
37. Couri CE, Oliveira MC, Stracieri AB, Moraes DA, Pieroni F, Barros GM, Madeira MI, Malmegrim KC, Foss-Freitas MC, Simoes BP, et al. 2009. C-peptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA 301: 1573-1579.
38. Craig RM, Traynor A, Oyama Y, Burt RK. 2003. Hematopoietic stem cell transplantation for severe Crohn's disease. Bone Marrow Transplant 32: S57-S59.
39. +T cells in type 1 diabetes in the nonobese diabetic (NOD) mouse. Proc Natl Acad Sci 108: 16729-16734.
40. +regulatory T cells. J Immunol 178: 2458-2468.
41. De Groot AS, Moise L, McMurry JA, Wambre E, Van Overtvelt L, Moingeon P, Scott DW, Martin W. 2008. Activation of natural regulatory T cells by IgG Fc-derived peptide "Tregitopes. " Blood 112: 3303-3311.
42. Delgoffe GM, Kole TP, Zheng Y, Zarek PE, Matthews KL, Xiao B, Worley PF, Kozma SC, Powell JD. 2009. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30: 832-844.
43. Delgoffe GM, Pollizzi KN, Waickman AT, Heikamp E, Meyers DJ, Horton MR, Xiao B, Worley PF, Powell JD. 2011. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol 12: 295-303.
44. +regulatory T cells in human autoimmune disease. Nat Med 17: 673-675.
45. DPT-1-Diabetes-Study-Group. 2002. Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med 346: 1685-1691.
46. Dubertret L, Sterry W, Bos JD, Chimenti S, Shumack S, Larsen CG, Shear NH, Papp KA, Group CMS. 2006. Clinical experience acquired with the efalizumab (Raptiva) (CLEAR) trial in patients with moderate-to-severe plaque psoriasis: Results from a phase III international randomized, placebo-controlled trial. Br J Dermatol 155: 170-181.
47. Eagar TN, Karandikar NJ, Bluestone J, Miller SD. 2002. The role of CTLA-4 in induction and maintenance of peripheral T cell tolerance. Eur J Immunol 32: 972-981.
48. Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, Stevens RM, Shaw T. 2004. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 350: 2572-2581.
49. Ehrenstein MR, Evans JG, Singh A, Moore S, Warnes G, Isenberg DA, Mauri C. 2004. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFa therapy. J Exp Med 200: 277-285.
50. Elias D, Cohen IR. 1996. The hsp60 peptide p277 arrests the autoimmune diabetes induced by the toxin streptozotocin. Diabetes 45: 1168-1172.
51. Elinav E, Adam N, Waks T, Eshhar Z. 2009. Amelioration of colitis by genetically engineered murine regulatory T cells redirected by antigen-specific chimeric receptor. Gastroenterology 136: 1721-1731.
52. +regulatory T cells by intravenous immunoglobulin: Acritical factor in controlling experimental autoimmune encephalomyelitis. Blood 111: 715-722.
53. Farge D, Henegar C, Carmagnat M, Daneshpouy M, Marjanovic Z, Rabian C, Ilie D, Douay C, Mounier N, Clave E, et al. 2005. Analysis of immune reconstitution after autologous bone marrow transplantation in systemic sclerosis. Arthritis Rheum 52: 1555-1563.
54. +regulatory T cells in vitro. Blood 111: 3675-3683.
55. Fife BT, Bluestone JA. 2008. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev 224: 166-182.
56. Fife BT, Guleria I, Gubbels Bupp M, Eagar TN, Tang Q, Bour-Jordan H, Yagita H, Azuma M, Sayegh MH, Bluestone JA. 2006. Insulin-induced remission in newonsetNODmice is maintained by the PD-1-PD-L1 pathway. J Exp Med 203: 2737-2747.
57. Fife BT, Pauken KE, Eagar TN, Obu T, Wu J, Tang Q, Azuma M, Krummel MF, Bluestone JA. 2009. Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nat Immunol 10: 1185-1192.
58. Fleming JO, Isaak A, Lee JE, Luzzio CC, Carrithers MD, Cook TD, Field AS, Boland J, Fabry Z. 2011. Probiotic helminth administration in relapsing-remitting multiple sclerosis: A phase 1 study. Multiple Sclerosis (Houndmills, Basingstoke, England) 17: 743-754.
59. +regulatory T cells. Nat Immunol 4: 330-336.
60. Ford C, Goodman AD, Johnson K, Kachuck N, Lindsey JW, Lisak R, Luzzio C, Myers L, Panitch H, Preiningerova J, et al. 2010. Continuous long-term immunomodulatory therapy in relapsing multiple sclerosis: Results from the 15-year analysis of the US prospective open-label study of glatiramer acetate. Multiple Sclerosis (Houndmills, Basingstoke, England) 16: 342-350.
61. Freedman MS, Bar-Or A, Oger J, Traboulsee A, Patry D, Young C, Olsson T, Li D, Hartung HP, Krantz M, et al. 2011. A phase III study evaluating the efficacy and safety of MBP8298 in secondary progressive MS. Neurology 77: 1551-1560.
62. Fridman JS, Scherle PA, Collins R, Burn TC, Li Y, Li J, Covington MB, Thomas B, Collier P, Favata MF, et al. 2010. Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: Preclinical characterization of INCB028050. J Immunol 184: 5298-5307.
63. Garren H, Robinson WH, Krasulova E, Havrdova E, Nadj C, Selmaj K, Losy J, Nadj I, Radue EW, Kidd BA, et al. 2008. Phase 2 trial of a DNA vaccine encoding myelin basic protein for multiple sclerosis. Ann Neurol 63: 611-620.
64. Genovese MC, Becker JC, Schiff M, Luggen M, Sherrer Y, Kremer J, Birbara C, Box J, Natarajan K, Nuamah I, et al. 2005. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor a inhibition. N Engl J Med 353: 1114.
65. Goodnow CC, Sprent J, Fazekas de St Groth B, Vinuesa CG. 2005. Cellular and genetic mechanisms of self tolerance and autoimmunity. Nature 435: 590-597.
66. Goverman JM. 2011. Immune tolerance in multiple sclerosis. Immunol Rev 241: 228-240.
67. Govers C, Sebestyen Z, Coccoris M, Willemsen RA, Debets R. 2010. T cell receptor gene therapy: Strategies for optimizing transgenic TCR pairing. Trend Mol Med 16: 77-87.
68. Grewal IS, Flavell RA. 1996. The role of CD40 ligand in costimulation and T-cell activation. Immunol Rev 153: 85-106.
69. Guillot-Delost M, Cherai M, Hamel Y, Rosenzwajg M, Baillou C, Simonin G, Leclercq V, Mariotti-Ferrandiz ME, Six A, Bon-Durand V, et al. 2008. Clinical-grade preparation of human natural regulatory T-cells encoding the thymidine kinase suicide gene as a safety gene. J Gene Med 10: 834-846.
70. Hanidziar D, Koulmanda M. 2010. Inflammation and the balance of Treg and Th17 cells in transplant rejection and tolerance. Curr Opin Organ Transplant 15: 411-415.
71. Harry RA, Anderson AE, Isaacs JD, Hilkens CM. 2010. Generation and characterisation of therapeutic tolerogenic dendritic cells for rheumatoid arthritis. Ann Rheum Dis 69: 2042-2050.
72. Hartung HP. 2009. New cases of progressive multifocal leukoencephalopathy after treatment with natalizumab. Lancet Neurol 8: 28-31.
73. Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, Bar-Or A, Panzara M, Sarkar N, Agarwal S, et al. 2008. Bcell depletionwith rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 358: 676-688.
74. He XL, Radu C, Sidney J, Sette A, Ward ES, Garcia KC. 2002. Structural snapshot of aberrant antigen presentation linked to autoimmunity: The immunodominant epitope of MBP complexed with I-Au. Immunity 17: 83-94.
75. Herold KC, Hagopian W, Auger JA, Poumian-Ruiz E, Taylor L, Donaldson D, Gitelman SE, Harlan DM, Xu D, Zivin RA, et al. 2002. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 346: 1692-1698.
76. Herold KC, Burton JB, Francois F, Poumian-Ruiz E, Glandt M, Bluestone JA. 2003. Activation of human T cells by FcR nonbinding anti-CD3 mAb, hOKT3γ1(Ala-Ala). J Clin Invest 111: 409-418.
77. Herold KC, Gitelman S, Greenbaum C, Puck J, Hagopian W, Gottlieb P, Sayre P, Bianchine P, Wong E, Seyfert-Margolis V, et al. 2009. Treatment of patients with new onset Type 1 diabetes with a single course of anti-CD3 mAb Teplizumab preserves insulin production for up to 5 years. Clin Immunol 132: 166-173.
78. Hilkens CM, Isaacs JD, Thomson AW. 2010. Development of dendritic cell-based immunotherapy for autoimmunity. Int Rev Immunol 29: 156-183.
79. Hu CY, Rodriguez-Pinto D, Du W, Ahuja A, Henegariu O, Wong FS, Shlomchik MJ, Wen L. 2007. Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice. J Clin Invest 117: 3857-3867.
80. +cells after anti-CD20 treatment in type 1 diabetes in nonobese diabetic mice. J Immunol 188: 294-301.
81. Illei GG, Cervera R, Burt RK, Doria A, Hiepe F, Jayne D, Pavletic S, Martin T, Marmont A, Saccardi R, et al. 2011. Current state and future directions of autologous hematopoietic stem cell transplantation in systemic lupus erythematosus. Ann Rheum Dis 70: 2071-2074.
82. Jacobson DL, Gange SJ, Rose NR, Graham NM. 1997. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol 84: 223-243.
83. Kappos L, Comi G, Panitch H, Oger J, Antel J, Conlon P, Steinman L. 2000. 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. Nat Med 6: 1176-1182.
84. Kappos L, Radue EW, O'Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, et al. 2010. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 362: 387-401.
85. Karpus WJ, Kennedy KJ, Smith WS, Miller SD. 1996. Inhibition of relapsing experimental autoimmune encephalomyelitis in SJL mice by feeding the immunodominant PLP139-151 molecule. J Neurosci Res 45: 410-423.
86. Karussis DM, Vourka-Karussis U, Lehmann D, Ovadia H, Mizrachi-Koll R, Ben-Nun A, Abramsky O, Slavin S. 1993. Prevention and reversal of adoptively transferred, chronic relapsing experimental autoimmune encephalomyelitis with a single high dose cytoreductive treatment followed by syngeneic bone marrow transplantation. J Clin Invest 92: 765-772.
87. Kennedy KJ, Smith WS, Miller SD, Karpus WJ. 1997. 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.
88. Kessel A, Ammuri H, Peri R, Pavlotzky ER, Blank M, Shoenfeld Y, Toubi E. 2007. Intravenous immunoglobulin therapy affects T regulatory cells by increasing their suppressive function. J Immunol 179: 5571-5575.
89. Keymeulen B, Vandemeulebroucke E, Ziegler AG, Mathieu C, Kaufman L, Hale G, Gorus F, Goldman M, Walter M, Candon S, et al. 2005. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med 352: 2598-2608.
90. Kode JA, Mukherjee S, Joglekar MV, Hardikar AA. 2009. Mesenchymal stem cells: Immunobiology and role in immunomodulation and tissue regeneration. Cytotherapy 11: 377-391.
91. +regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. J Immunol 169: 4712-4716.
92. +T cell unresponsiveness and functional reversal of established experimental autoimmune encephalomyelitis. J Immunol 174: 4525-4534.
93. Koulmanda M, Strom TB. 2010. T-cell-directed treatment strategies for Type 1 diabetes and the confounding role of inflammation. Immunotherapy 2: 431-436.
94. Latek RR, Suri A, Petzold SJ, Nelson CA, Kanagawa O, Unanue ER, Fremont DH. 2000. Structural basis of peptide binding and presentation by the type I diabetes-associated MHC class II molecule of NOD mice. Immunity 12: 699-710.
95. +T cells in autoimmune diabetes after pancreas transplantation. Clin Immunol 128: 23-30.
96. Law CL, Grewal IS. 2009. Therapeutic interventions targeting CD40L (CD154) and CD40: The opportunities and challenges. Adv Exp Med Biol 647: 8-36.
97. Lazar L, Ofan R, Weintrob N, Avron A, Tamir M, Elias D, Phillip M, Josefsberg Z. 2007. Heat-shock protein peptide DiaPep277 treatment in children with newly diagnosed type 1 diabetes: A randomised, double-blind phase II study. Diabetes Metab Res Rev 23: 286-291.
98. Levisetti MG, Suri A, Petzold SJ, Unanue ER. 2007. The insulin-specific T cells of nonobese diabetic mice recognize a weak MHC-binding segment in more than one form. J Immunol 178: 6051-6057.
99. Li Y, Huang Y, Lue J, Quandt JA, Martin R, Mariuzza RA. 2005. Structure of a human autoimmune TCRbound to a myelin basic protein self-peptide and a multiple sclerosisassociate MHC class II molecule. EMBO J 24: 2968-2979.
100. +T reg cells. J Exp Med 203: 1701-1711.
101. +regulatory T-cells of type 1 diabetic subjects. Diabetes 59: 407-415.
102. Long SA, Rieck M, Sanda S, Bollyky JB, Samuels PL, Goland R, Ahman A, Rabinovitch A, Aggarwal S, Phippard D, et al. 2012. Rapamycin/IL-2 combination therapy in paitients with Type 1 diabetics augments Treg yet transiently impairs β cell function. Diabetes 61: 2340-2348.
103. +regulatory T cells. J Am Soc Nephrol 17: 2844-2853.
104. Loschko J, Heink S, Hackl D, Dudziak D, Reindl W, Korn T, Krug AB. 2011. Antigen targeting to plasmacytoid dendritic cells via Siglec-H inhibits Th cell-dependent autoimmunity. J Immunol 187: 6346-6356.
105. Louvet C, Szot GL, Lang J, Lee MR, Martinier N, Bollag G, Zhu S, Weiss A, Bluestone JA. 2008. Tyrosine kinase inhibitors reverse type 1 diabetes in nonobese diabetic mice. Proc Natl Acad Sci 105: 18895-18900.
106. Ludvigsson J, Krisky D, Casas R, Battelino T, Castano L, Greening J, Kordonouri O, Otonkoski T, Pozzilli P, Robert JJ, et al. 2012. GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus. N Engl J Med 366: 433-442.
107. Machen J, Harnaha J, Lakomy R, Styche A, Trucco M, Giannoukakis N. 2004. Antisense oligonucleotides downregulating costimulation confer diabetes-preventive properties to nonobese diabetic mouse dendritic cells. J Immunol 173: 4331-4341.
108. MacMillan HF, Lee T, Issekutz AC. 2009. Intravenous immunoglobulin G-mediated inhibition of T-cell proliferation reflects an endogenous mechanism by which IgG modulates T-cell activation. Clin Immunol 132: 222-233.
109. Maier LM, Hafler DA. 2009. Autoimmunity risk alleles in costimulation pathways. Immunol Rev 229: 322-336.
110. Maki T, Gottschalk R, Ogawa N, Monaco AP. 2005. Prevention and cure of autoimmune diabetes in nonobese diabetic mice by continuous administration of FTY720. Transplantation 79: 1051-1055.
111. Malek TR, Yu A, Vincek V, Scibelli P, Kong L. 2002. CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rb-deficient mice. Implications for the nonredundant function of IL-2. Immunity 17: 167-178.
112. Mandala S, Hajdu R, Bergstrom J, Quackenbush E, Xie J, Milligan J, Thornton R, Shei GJ, Card D, Keohane C, et al. 2002. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296: 346-349.
113. Maron R, Slavin AJ, Hoffmann E, Komagata Y, Weiner HL. 2002. 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.
114. +regulatory T cells from nonobese diabetic mice. J Immunol 175: 3053-3059.
115. Matloubian M, Lo CG, Cinamon G, Lesneski MJ, Xu Y, Brinkmann V, Allende ML, Proia RL, Cyster JG. 2004. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427: 355-360.
116. McClymont SA, Putnam AL, Lee MR, Esensten JH, Liu W, HulmeMA, Hoffmuller U, Baron U, Olek S, Bluestone JA, et al. 2011. Plasticity ofhumanregulatoryTcells in healthy subjects and patientswith type 1 diabetes. J Immunol 186: 3918-3926.
117. McFarland HF, Martin R. 2007. Multiple sclerosis: A complicated picture of autoimmunity. Nat Immunol 8: 913-919.
118. Merrill JT, Burgos-Vargas R, Westhovens R, Chalmers A, D'Cruz D, Wallace DJ, Bae SC, Sigal L, Becker JC, Kelly S, et al. 2010. The efficacy and safety of abatacept in patients with non-life-threatening manifestations of systemic lupus erythematosus: Results of a twelve-month, multicenter, exploratory, phase IIb, randomized, doubleblind, placebo-controlled trial. Arthritis Rheum 62: 3077.
119. Mohan JF, Levisetti MG, Calderon B, Herzog JW, Petzold SJ, Unanue ER. 2010. Unique autoreactive T cells recognize insulin peptides generatedwithin the islets of Langerhans in autoimmune diabetes. Nat Immunol 11: 350-354.
120. Mohan JF, Petzold SJ, Unanue ER. 2011. Register shifting of an insulin peptide-MHC complex allows diabetogenic T cells to escape thymic deletion. J Exp Med 208: 2375-2383.
121. Monson NL, Cravens P, Hussain R, Harp CT, Cummings M, de Pilar Martin M, Ben LH, Do J, Lyons JA, Lovette-Racke A, et al. 2011. Rituximab therapy reduces organ-specific T cell responses and ameliorates experimental autoimmune encephalomyelitis. PloS ONE 6: e17103.
122. +regulatory T-cells. Diabetes 57: 2341-2347.
123. +regulatory T cells. J Immunol 170: 3939-3943.
124. Muraro PA, Douek DC, Packer A, Chung K, Guenaga FJ, Cassiani-Ingoni R, Campbell C, Memon S, Nagle JW, Hakim FT, et al. 2005. Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients. J Exp Med 201: 805-816.
125. Nadkarni S, Mauri C, Ehrenstein MR. 2007. Anti-TNF-α therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-β. J Exp Med 204: 33-39.
126. Nanto-Salonen K, Kupila A, Simell S, Siljander H, Salonsaari T, Hekkala A, Korhonen S, Erkkola R, Sipila JI, Haavist L, et al. 2008. Nasal insulin to prevent type 1 diabetes in children with HLA genotypes and autoantibodies conferring increased risk of disease: A double-blind, randomised controlled trial. Lancet 372: 1746-1755.
127. Nicholson LB, Kuchroo VK. 1997. T cell recognition of self and altered self antigens. Crit Rev Immunol 17: 449-462.
128. Nicholson LB, Greer JM, Sobel RA, Lees MB, Kuchroo VK. 1995. An altered peptide ligand mediates immune deviation and prevents autoimmune encephalomyelitis. Immunity 3: 397-405.
129. Nicolls MR, Gill RG. 2006. LFA-1 (CD11a) as a therapeutic target. Am J Transplant 6: 27-36.
130. Niens M, Grier AE, Marron M, Kay TW, Greiner DL, Serreze DV. 2011. Prevention of "Humanized" diabetogenic CD8 T-cell responses in HLA-transgenic NOD mice by a multipeptide coupled-cell approach. Diabetes 60: 1229-1236.
131. Nimmerjahn F, Ravetch JV. 2008. Anti-inflammatory actions of intravenous immunoglobulin. Annu Rev Immunol 26: 513-533.
132. +regulatory T cells. J Immunol 174: 6993-7005.
133. +T cells. Nov 12: 627-635.
134. Oh U, Blevins G, Griffith C, Richert N, Maric D, Lee CR, McFarland H, Jacobson S. 2009. Regulatory T cells are reduced during anti-CD25 antibody treatment of multiple sclerosis. Arch Neurol 66: 471-479.
135. Orban T, Bundy B, Becker DJ, DiMeglio LA, Gitelman SE, Goland R, Gottlieb PA, Greenbaum CJ, Marks JB, Monzavi R, et al. 2011. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: A randomised, double-blind, placebo-controlled trial. Lancet 378: 412-419.
136. Oyama Y, Barr WG, Statkute L, Corbridge T, Gonda EA, Jovanovic B, Testori A, Burt RK. 2007. Autologous nonmyeloablative hematopoietic stem cell transplantation in patients with systemic sclerosis. Bone Marrow Transplant 40: 549-555.
137. Penaranda C, Tang Q, Ruddle NH, Bluestone JA. 2010. Prevention of diabetes by FTY720-mediated stabilization of peri-islet tertiary lymphoid organs. Diabetes 59: 1461-1468.
138. Penaranda C, Tang Q, Bluestone JA. 2011. Anti-CD3 therapy promotes tolerance by selectively depleting pathogenic cells while preserving regulatory T cells. J Immunol 187: 2015-2022.
139. Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H, Becker DJ, Gitelman SE, Goland R, Gottlieb PA, Marks JB, McGee PF, Moran AM, et al. 2009. Rituximab, B-lymphocyte depletion, and preservation of β-cell function. N Engl J Med 361: 2143-2152.
140. +T cells into regulatory T cells and promotes immunotolerance in NOD mice. Rev Diabet Stud 7: 47-61.
141. Punwani N, Scherle P, Flores R, Shi J, Liang J, Yeleswaram S, Levy R, Williams W, Gottlieb A. 2012. Preliminary clinical activity of a topical JAK1/2 inhibitor in the treatment of psoriasis. J Am Acad Dermatol doi: org/10.1016/ j.jaad.2011.12.018.
142. Putnam AL, Brusko TM, Lee MR, Liu W, Szot GL, Ghosh T, Atkinson MA, Bluestone JA. 2009. Expansion of human regulatory T-cells from patients with type 1 diabetes. Diabetes 58: 652-662.
143. Rabinovitch A, Suarez-Pinzon WL, Shapiro AM, Rajotte RV, Power R. 2002. Combination therapy with sirolimus and interleukin-2 prevents spontaneous and recurrent autoimmune diabetes in NOD mice. Diabetes 51: 638-645.
144. Ransohoff RM. 2007. Natalizumab for multiple sclerosis. N Engl J Med 356: 2622-2629.
145. Raz I, Avron A, Tamir M, Metzger M, Symer L, Eldor R, Cohen IR, Elias D. 2007. 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.
146. Rigby RJ, Vinuesa CG. 2008. SiLEncing SLE: The power and promise of small noncodingRNAs. Curr Opin Rheumatol 20: 526-531.
147. +regulator T cells. Blood 111: 5233-5241.
148. Salomon B, Bluestone JA. 2001. Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annu Rev Immunol 19: 225-252.
149. +immunoregulatory T cells that control autoimmune diabetes. Immunity 12: 431-440.
150. Saudek F, Havrdova T, Boucek P, Karasova L, Novota P, Skibova J. 2004. Polyclonal anti-T-cell therapy for type 1 diabetes mellitus of recent onset. Rev Diabet Stud 1: 80-88.
151. +T-regulatory cells and enhances their functional activity. J Immunol 175: 7973-7980.
152. Scalapino KJ, Daikh DI. 2008. CTLA-4: A key regulatory point in the control of autoimmune disease. Immunol Rev 223: 143-155.
153. Scalapino KJ, Tang Q, Bluestone JA, Bonyhadi ML, Daikh DI. 2006. Suppression of disease in New Zealand Black/New ZealandWhite lupus-prone mice by adoptive transfer of ex vivo expanded regulatory T cells. J Immunol 177: 1451-1459.
154. Schloot NC, Meierhoff G, Lengyel C, Vandorfi G, Takacs J, Panczel P, Barkai L, Madacsy L, Oroszlan T, Kovacs P, et al. 2007. Effect of heat shock protein peptide DiaPep277 on β-cell function in paediatric and adult patients with recent-onset diabetes mellitus type 1: Two prospective, randomized, double-blind phase II trials. Diabetes Metab Res Rev 23: 276-285.
155. Sfikakis PP. 2010. The first decade of biologic TNF antagonists in clinical practice: Lessons learned, unresolved issues and future directions. Curr Direct Autoimmun 11: 180-210.
156. Simon G, Parker M, Ramiya V, Wasserfall C, Huang Y, Bresson D, Schwartz RF, Campbell-Thompson M, Tenace L, Brusko T, et al. 2008. Murine antithymocyte globulin therapy alters disease progression in NOD mice by a time-dependent induction of immunoregulation. Diabetes 57: 405-414.
157. Smith CE, Eagar TN, Strominger JL, Miller SD. 2005. Differential induction of IgE-mediated anaphylaxis after soluble vs. cell-bound tolerogenic peptide therapy of autoimmune encephalomyelitis. Proc Natl Acad Sci 102: 9595-9600.
158. Stadinski B, Kappler J, Eisenbarth GS. 2010a. Molecular targeting of islet autoantigens. Immunity 32: 446-456.
159. Stadinski BD, Delong T, Reisdorph N, Reisdorph R, Powell RL, Armstrong M, Piganelli JD, Barbour G, Bradle B, Crawford F, et al. 2010b. Chromogranin A is an autoantigen in type 1 diabetes. Nat Immunol 11: 225-231.
160. Stadinski BD, Zhang L, Crawford F, Marrack P, Eisenbart GS, Kappler JW. 2010c. Diabetogenic T cells recognize insulin bound to IAg7 in an unexpected, weakly binding register. Proc Natl Acad Sci 107: 10978-10983.
161. Steinman RM, Hawiger D, Nussenzweig MC. 2003. Tolerogenic dendritic cells. Annu Rev Immunol 21: 685-711.
162. Sugiyama H, McCormick TS, Cooper KD, Korman NJ. 2008. Alefacept in the treatment of psoriasis. Clin Dermatol 26: 503-508.
163. Tak PP, Rigby WF, Rubbert-Roth A, Peterfy CG, van Vollenhoven RF, Stohl W, Hessey E, Chen A, Tyrrell H, Shaw TM, et al. 2011. Inhibition of joint damage and improved clinical outcomes with rituximab plus methotrexate in early active rheumatoid arthritis: The IMAGE trial. Ann Rheum Dis 70: 39-46.
164. +regulatory T cell: A jack of all trades, master of regulation. Nat Immunol 9: 239-244.
165. Tang Q, Henriksen KJ, Bi M, Finger EB, Szot G, Ye J, Masteller EL, McDevitt H, Bonyhadi M, Bluestone JA. 2004. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med 199: 1455-1465.
166. Tang Q, Adams JY, Penaranda C, Melli K, Piaggio E, Sgouroudis E, Piccirillo CA, Salomon BL, Bluestone JA. 2008. Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity 28: 687.
167. Tao R, de Zoeten EF, Ozkaynak E, Chen C, Wang L, Porrett PM, Li B, Turka LA, Olson EN, Greene MI, et al. 2007. Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat Med 13: 1299-1307.
168. +T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. J Exp Med 199: 1467-1477.
169. Targan SR, Feagan BG, Fedorak RN, Lashner BA, Panaccione R, Present DH, Spehlmann ME, Rutgeerts PJ, Tulassay Z, Volfova M, et al. 2007. Natalizumab for the treatment of active Crohn's disease: Results of the ENCORE Trial. Gastroenterology 132: 1672-1683.
170. +T cells. Transplantation 89: 1446-1455.
171. +T cells in patients with active rheumatoid arthritis is reduced by infliximab. Ann NYAcad Sci 1051: 506-514.
172. Tsai S, Shameli A, Yamanouchi J, Clemente-Casares X, Wang J, Serra P, Yang Y, Medarova Z, Moore A, Santamari P. 2010. Reversal of autoimmunity by boosting memory-like autoregulatory T cells. Immunity 32: 568-580.
173. Tyndall A. 2011. Successes and failures of stem cell transplantation in autoimmune diseases. Hematology 2011: 280-284.
174. Tyndall A, Uccelli A. 2009. Multipotent mesenchymal stromal cells for autoimmune diseases: Teaching new dogs old tricks. Bone Marrow Transplant 43: 821-828.
175. van de Linde P, Tysma OM, Medema JP, Hale G, Waldman H, Roelen DL, Roep BO. 2006. Mechanisms of antibody immunotherapy on clonal islet reactive T cells. Human Immunol 67: 264-273.
176. Vandenbark AA, Vainiene M, Ariail K, Miller SD, Offner H. 1996. Prevention and treatment of relapsing autoimmune encephalomyelitis with myelin peptide-coupled splenocytes. J Neurosci Res 45: 430-438.
177. Vendrame F, Pileggi A, Laughlin E, Allende G, Martin-Pagola A, Molano RD, Diamantopoulos S, Standifer N, Geubtner K, Falk BA, et al. 2010. Recurrence of type 1 diabetes after simultaneous pancreas-kidney transplantation, despite immunosuppression, is associated with autoantibodies and pathogenic autoreactive CD4 T-cells. Diabetes 59: 947-957.
178. Verburg RJ, Flierman R, Sont JK, Ponchel F, van Dreunen L, Levarht EW, Welling MM, Toes RE, Isaacs JD, van Laar JM. 2005. Outcome of intensive immunosuppression and autologous stem cell transplantation in patients with severe rheumatoid arthritis is associated with the composition of synovial T cell infiltration. Ann Rheu Dis 64: 1397-1405.
179. Waldron-Lynch F, Henegariu O, Deng S, Preston-Hurlburt P, Tooley J, Flavell R, Herold KC. 2012. Teplizumab induces human gut-tropic regulatory cells in humanized mice and patients. Sci Trans Med 4: 118ra112.
180. Walter M, Philotheou A, Bonnici F, Ziegler AG, Jimenez R. 2009. No effect of the altered peptide ligand NBI-6024 on β-cell residual function and insulin needs in new-onset type 1 diabetes. Diabetes Care 32: 2036-2040.
181. Weaver DJ Jr, Liu B, Tisch R. 2001. 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.
182. Webb M, Tham CS, Lin FF, Lariosa-Willingham K, Yu N, Hale J, Mandala S, Chun J, Rao TS. 2004. Sphingosine 1-phosphate receptor agonists attenuate relapsing-remitting experimental autoimmune encephalitis in SJL mice. J Neuroimmunol 153: 108-121.
183. Wellcome Trust Case Control C. 2007. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447: 661-678.
184. Wen Y, Ouyang J, Yang R, Chen J, Liu Y, Zhou X, Burt RK. 2008. Reversal of new-onset type 1 diabetes in mice by syngeneic bone marrow transplantation. Biochem Biophys Res Comm 374: 282-287.
185. Wherrett DK, Bundy B, Becker DJ, DiMeglio LA, Gitelman SE, Goland R, Gottlieb PA, Greenbaum CJ, Herold KC, Marks JB, et al. 2011. Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: A randomised double-blind trial. Lancet 378: 319-327.
186. Wicker LS, Todd JA, Peterson LB. 1995. Genetic control of autoimmune diabetes in the NOD mouse. Annu Rev Immunol 13: 179-200.
187. Wing K, Sakaguchi S. 2010. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol 11: 7-13.
188. Wolinsky JS, Narayana PA, O'Connor P, Coyle PK, Ford C, Johnson K, Miller A, Pardo L, Kadosh S, Ladkani D, et al. 2007. Glatiramer acetate in primary progressive multiple sclerosis: Results of a multinational, multicenter, double-blind, placebo-controlled trial. Ann Neurol 61: 14-24.
189. Woodle ES, Xu D, Zivin RA, Auger J, Charette J, O'Laughlin R, Peace D, Jollife LK, Haverty T, Bluestone JA, et al. 1999. Phase I trial of a humanized, Fc receptor nonbinding OKT3 antibody, huOKT3γ1(Ala-Ala) in the treatment of acute renal allograft rejection. Transplantation 68: 608-616.
190. Wright GP, Notley CA, Xue SA, Bendle GM, Holler A, Schumacher TN, Ehrenstein MR, Stauss HJ. 2009. Adoptive therapy with redirected primary regulatory T cells results in antigen-specific suppression of arthritis. Pro Natl Acad Sci 106: 19078-19083.
191. Wynn D, Kaufman M, Montalban X, Vollmer T, Simon J, Elkins J, O'Neill G, Neyer L, Sheridan J, Wang C, et al. 2010. Daclizumab in active relapsing multiple sclerosis (CHOICE study): A phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon β. Lancet Neurol 9: 381-390.
192. Yopp AC, Krieger NR, Ochando JC, Bromberg JS. 2004. Therapeutic manipulation of T cell chemotaxis in transplantation. Curr Opin Immunol 16: 571-577.
193. Yoshida Y, Tsuji T, Fujita T, Kohno T. 2011. Relapse of experimental autoimmune encephalomyelitis after discontinuation of FTY720 (Fingolimod) treatment, but not after combination of FTY720 and pathogenic autoantigen. Biol Pharm Bull 34: 933-936.
194. Zand MS, Vo T, Huggins J, Felgar R, Liesveld J, Pellegrin T, Bozorgzadeh A, Sanz I, Briggs BJ. 2005. Polyclonal rabbit antithymocyte globulin triggers B-cell and plasma cell apoptosis by multiple pathways. Transplantation 79: 1507-1515.
195. Zhang L, Nakayama M, Eisenbarth GS. 2008. Insulin as an autoantigen inNOD/human diabetes. Curr Opin Immunol 20: 111-118.
196. Zhou X, Bailey-Bucktrout SL, Jeker LT, Penaranda C, Martinez-Llordella M, Ashby M, Nakayama M, Rosenthal W, Bluestone JA. 2009. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol 10: 1000-1007.