Role of Regulatory T Cells for the Treatment of Type 1 Diabetes Mellitus

Abstract

Beta-cell specific autoreactive T cells can be found in patients with type I diabetes (T1D) and in healthy controls. They are usually controlled by a network of regulatory mechanisms including CD4+CD25+Foxp3+ regulatory T cells (Tregs). It was suspected that defects in Treg number and activity are causally related to the development of T1D. Although there are hints that this concept might be true, it is neither proven in animal models nor in patients with T1D. However, increasing the number of Tregs by adoptive transfer can be used to prevent and treat even established T1D. It was demonstrated that Tregs recognizing beta-cell antigens are far more efficient in treating the disease than polyspecific Tregs. The use of beta-cell specific Tregs is also leading to a tissue specific immunotolerance without perturbing the general immunocompetence. Two sources for beta-cell specific Tregs are currently employed: First natural Tregs specific for beta-cells are expanded in vitro and reinfused into diabetic animals. Second nave or activated T cells specific for beta-cell antigens are in vitro converted to Tregs by genetic manipulation or by specific cytokine combinations. Both approaches were successful in treating even established diabetes in animal models. Before such therapies can be used in patients safety measures regarding the fate and the effects of the transferred Tregs have to be studied. Besides this ethical considerations are important in regard to what risks we should take to treat a disease in young patients which can otherwise be treated medically. In the meantime the concept of Tregs for therapy of T1D is supported by successful clinical attempts to induce these cells in vivo by administration of monoclonal antibodies against CD3. If subsequent studies show that Tregs represent a safe and efficient source for therapy, they could become an important weapon in the fight against immune mediated pathology.

Key words

tolerance - regulatory T cell - diabetes - adoptive transfer - Foxp3 - NOD

References

• 1 Cooke A, Zaccone P, Raine T, Phillips JM, Dunne DW. Infection and autoimmunity: are we winning the war, only to lose the peace?.  Trends Parasitol. 2004;  20 316-321
• 2 Kyewski B, Klein L. A central role for central tolerance.  Annu Rev Immunol. 2006;  24 571-606
• 3 Derbinski J, Schulte A, Kyewski B, Klein L. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self.  Nat Immunol. 2001;  2 1032-1039
• 4 Mathis D, Benoist C. A decade of AIRE.  Nat Rev Immunol. 2007;  7 645-650
• 5 Boitard C, Yasunami R, Dardenne M, Bach JF. T cell-mediated inhibition of the transfer of autoimmune diabetes in NOD mice.  J Exp Med. 1989;  169 1669-1680
• 6 Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.  J Immunol. 1995;  155 1151-1164
• 7 Asano M, Toda M, Sakaguchi N, Sakaguchi S. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation.  J Exp Med. 1996;  184 387-396
• 8 Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses.  Annu Rev Immunol. 2004;  22 531-562
• 9 Thornton AM, Shevach EM. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production.  J Exp Med. 1998;  188 287-296
• 10 Klein L, Khazaie K, Boehmer H von. In vivo dynamics of antigen-specific regulatory T cells not predicted from behavior in vitro.  Proc Natl Acad Sci USA. 2003;  100 8886-8891
• 11 Khattri R, Cox T, Yasayko SA, Ramsdell F. An essential role for Scurfin in CD4+CD25+ T regulatory cells.  Nat Immunol. 2003;  4 337-342
• 12 Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3.  Science. 2003;  299 1057-1061
• 13 Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells.  Nat Immunol. 2003;  4 330-336
• 14 Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly TE, Saulsbury FT, Chance PF, Ochs HD. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3.  Nat Genet. 2001;  27 20-21
• 15 Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA, Wilkinson JE, Galas D, Ziegler SF, Ramsdell F. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse.  Nat Genet. 2001;  27 68-73
• 16 Jaeckel E, Boehmer H von, Manns MP. Antigen-specific FoxP3-transduced T-cells can control established type 1 diabetes.  Diabetes. 2005;  54 306-310
• 17 Lahl K, Loddenkemper C, Drouin C, Freyer J, Arnason J, Eberl G, Hamann A, Wagner H, Huehn J, Sparwasser T. Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease.  J Exp Med. 2007;  204 57-63
• 18 Wan YY, Flavell RA. Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter.  Proc Natl Acad Sci USA. 2005;  102 5126-5131
• 19 Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY. Regulatory T cell lineage specification by the forkhead transcription factor foxp3.  Immunity. 2005;  22 329-341
• 20 Seddiki N, Santner-Nanan B, Martinson J, Zaunders J, Sasson S, Landay A, Solomon M, Selby W, Alexander SI, Nanan R, Kelleher A, Fazekas de St Groth B. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells.  J Exp Med. 2006;  203 1693-1700
• 21 Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, Gottlieb PA, Kapranov P, Gingeras TR, Fazekas de St Groth B, Clayberger C, Soper DM, Ziegler SF, Bluestone JA. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells.  J Exp Med. 2006;  203 1701-1711
• 22 Ziegler SF. FOXP3: of mice and men.  Annu Rev Immunol. 2006;  24 209-226
• 23 Walker MR, Kasprowicz DJ, Gersuk VH, Benard A, Landeghen M Van, Buckner JH, Ziegler SF. Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25- T cells.  J Clin Invest. 2003;  112 1437-1443
• 24 Morgan ME, Bilsen JH van, Bakker AM, Heemskerk B, Schilham MW, Hartgers FC, Elferink BG, Zanden L van der, Vries RR de, Huizinga TW, Ottenhoff TH, Toes RE. Expression of FOXP3 mRNA is not confined to CD4+CD25+ T regulatory cells in humans.  Hum Immunol. 2005;  66 13-20
• 25 Yagi H, Nomura T, Nakamura K, Yamazaki S, Kitawaki T, Hori S, Maeda M, Onodera M, Uchiyama T, Fujii S, Sakaguchi S. Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells.  Int Immunol. 2004;  16 1643-1656
• 26 Allan SE, Passerini L, Bacchetta R, Crellin N, Dai M, Orban PC, Ziegler SF, Roncarolo MG, Levings MK. The role of 2 FOXP3 isoforms in the generation of human CD4+ Tregs.  J Clin Invest. 2005;  115 3276-3284
• 27 Allan SE, Alstad AN, Merindol N, Crellin NK, Amendola M, Bacchetta R, Naldini L, Roncarolo MG, Soudeyns H, Levings MK. Generation of potent and stable human CD4(+) T regulatory cells by activation-independent expression of FOXP3.  Mol Ther. 2008;  16 194-202
• 28 Floess S, Freyer J, Siewert C, Baron U, Olek S, Polansky J, Schlawe K, Chang HD, Bopp T, Schmitt E, Klein-Hessling S, Serfling E, Hamann A, Huehn J. Epigenetic control of the foxp3 locus in regulatory T cells.  PLoS Biol. 2007;  5 e38
• 29 Baron U, Floess S, Wieczorek G, Baumann K, Grutzkau A, Dong J, Thiel A, Boeld TJ, Hoffmann P, Edinger M, Turbachova I, Hamann A, Olek S, Huehn J. DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3(+) conventional T cells.  Eur J Immunol. 2007;  37 2378-2389
• 30 Jaeckel E, Kretschmer K, Apostolou I, Boehmer H von. Instruction of Treg commitment in peripheral T cells is suited to reverse autoimmunity.  Semin Immunol. 2006;  18 89-92
• 31 Apostolou I, Boehmer H von. In vivo instruction of suppressor commitment in naive T cells.  J Exp Med. 2004;  199 1401-1408
• 32 Kretschmer K, Apostolou I, Hawiger D, Khazaie K, Nussenzweig MC, Boehmer H von. Inducing and expanding regulatory T cell populations by foreign antigen.  Nat Immunol. 2005;  6 1219-1227
• 33 Chatenoud L, Bluestone JA. CD3-specific antibodies: a portal to the treatment of autoimmunity.  Nat Rev Immunol. 2007;  7 622-632
• 34 Chatenoud L, Thervet E, Primo J, Bach JF. Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice.  Proc Natl Acad Sci USA. 1994;  91 123-127
• 35 Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, MacGrady G, Wahl SM. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3.  J Exp Med. 2003;  198 1875-1886
• 36 Yamagiwa S, Gray JD, Hashimoto S, Horwitz DA. A role for TGF-beta in the generation and expansion of CD4+CD25+ regulatory T cells from human peripheral blood.  J Immunol. 2001;  166 7282-7289
• 37 Roncarolo MG, Battaglia M. Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans.  Nat Rev Immunol. 2007;  7 585-598
• 38 Vieira PL, Christensen JR, Minaee S, O’Neill EJ, Barrat FJ, Boonstra A, Barthlott T, Stockinger B, Wraith DC, O’Garra A. IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells.  J Immunol. 2004;  172 5986-5993
• 39 Levings MK, Sangregorio R, Galbiati F, Squadrone S, Waal Malefyt R de, Roncarolo MG. IFN-alpha and IL-10 induce the differentiation of human type 1 T regulatory cells.  J Immunol. 2001;  166 5530-5539
• 40 Levings MK, Gregori S, Tresoldi E, Cazzaniga S, Bonini C, Roncarolo MG. Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25+CD4+ Tr cells.  Blood. 2005;  105 1162-1169
• 41 You S, Chen C, Lee WH, Brusko T, Atkinson M, Liu CP. Presence of diabetes-inhibiting, glutamic acid decarboxylase-specific, IL-10-dependent, regulatory T cells in naive nonobese diabetic mice.  J Immunol. 2004;  173 6777-6785
• 42 Melamed D, Friedman A. Direct evidence for anergy in T lymphocytes tolerized by oral administration of ovalbumin.  Eur J Immunol. 1993;  23 935-942
• 43 Whitacre CC, Gienapp IE, Orosz CG, Bitar DM. Oral tolerance in experimental autoimmune encephalomyelitis III. Evidence for clonal anergy.  J Immunol. 1991;  147 2155-2163
• 44 Miller A, Lider O, Roberts AB, Sporn MB, Weiner HL. 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 beta after antigen-specific triggering.  Proc Natl Acad Sci USA. 1992;  89 421-425
• 45 Weiner HL. Oral tolerance: immune mechanisms and the generation of Th3-type TGF-beta-secreting regulatory cells.  Microbes Infect. 2001;  3 947-954
• 46 Skyler JS, Krischer JP, Wolfsdorf J, Cowie C, Palmer JP, Greenbaum C, Cuthbertson D, Rafkin-Mervis LE, Chase HP, Leschek E. Effects of oral insulin in relatives of patients with type 1 diabetes: The Diabetes Prevention Trial-Type 1.  Diabetes Care. 2005;  28 1068-1076
• 47 Diabetes Prevention Trial - Type 1 Diabetes Study Group: . Effects of insulin in relatives of patients with type 1 diabetes mellitus.  N Engl J Med. 2002;  346 1685-1691
• 48 Hong S, Wilson MT, Serizawa I, Wu L, Singh N, Naidenko OV, Miura T, Haba T, Scherer DC, Wei J, Kronenberg M, Koezuka Y, Kaer L Van. The natural killer T-cell ligand alpha-galactosylceramide prevents autoimmune diabetes in non-obese diabetic mice.  Nat Med. 2001;  7 1052-1056
• 49 Sharif S, Arreaza GA, Zucker P, Mi QS, Sondhi J, Naidenko OV, Kronenberg M, Koezuka Y, Delovitch TL, Gombert JM, Leite-De-Moraes M, Gouarin C, Zhu R, Hameg A, Nakayama T, Taniguchi M, Lepault F, Lehuen A, Bach JF, Herbelin A. Activation of natural killer T cells by alpha-galactosylceramide treatment prevents the onset and recurrence of autoimmune Type 1 diabetes.  Nat Med. 2001;  7 1057-1062
• 50 Naumov YN, Bahjat KS, Gausling R, Abraham R, Exley MA, Koezuka Y, Balk SB, Strominger JL, Clare-Salzer M, Wilson SB. Activation of CD1d-restricted T cells protects NOD mice from developing diabetes by regulating dendritic cell subsets.  Proc Natl Acad Sci USA. 2001;  98 13838-13843
• 51 Ly D, Mi QS, Hussain S, Delovitch TL. Protection from type 1 diabetes by invariant NK T cells requires the activity of CD4+CD25+ regulatory T cells.  J Immunol. 2006;  177 3695-3704
• 52 Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe A, Bluestone JA. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes.  Immunity. 2000;  12 431-440
• 53 Salomon B, Bluestone JA. Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation.  Annu Rev Immunol. 2001;  19 225-252
• 54 Wu AJ, Hua H, Munson SH, MacDevitt HO. Tumor necrosis factor-alpha regulation of CD4+CD25+ T cell levels in NOD mice.  Proc Natl Acad Sci USA. 2002;  99 12287-12292
• 55 Green EA, Choi Y, Flavell RA. Pancreatic lymph node-derived CD4(+)CD25(+) Treg cells: highly potent regulators of diabetes that require TRANCE-RANK signals.  Immunity. 2002;  16 183-191
• 56 Pop SM, Wong CP, Culton DA, Clarke SH, Tisch R. Single cell analysis shows decreasing FoxP3 and TGFbeta1 coexpressing CD4+CD25+ regulatory T cells during autoimmune diabetes.  J Exp Med. 2005;  201 1333-1346
• 57 Berzins SP, Venanzi ES, Benoist C, Mathis D. T-cell compartments of prediabetic NOD mice.  Diabetes. 2003;  52 327-334
• 58 Green EA, Gorelik L, MacGregor CM, Tran EH, Flavell RA. CD4+CD25+ T regulatory cells control anti-islet CD8+ T cells through TGF-beta-TGF-beta receptor interactions in type 1 diabetes.  Proc Natl Acad Sci USA. 2003;  100 10878-10883
• 59 Herman AE, Freeman GJ, Mathis D, Benoist C. CD4+CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion.  J Exp Med. 2004;  199 1479-1489
• 60 Tritt M, Sgouroudis E, d’Hennezel E, Albanese A, Piccirillo CA. Functional waning of naturally occurring CD4+ regulatory T-cells contributes to the onset of autoimmune diabetes.  Diabetes. 2008;  57 113-123
• 61 Gregori S, Giarratana N, Smiroldo S, Adorini L. Dynamics of pathogenic and suppressor T cells in autoimmune diabetes development.  J Immunol. 2003;  171 4040-4047
• 62 Mellanby RJ, Thomas D, Phillips JM, Cooke A. Diabetes in non-obese diabetic mice is not associated with quantitative changes in CD4+ CD25+ Foxp3+ regulatory T cells.  Immunology. 2007;  121 15-28
• 63 You S, Belghith M, Cobbold S, Alyanakian MA, Gouarin C, Barriot S, Garcia C, Waldmann H, Bach JF, Chatenoud L. Autoimmune diabetes onset results from qualitative rather than quantitative age-dependent changes in pathogenic T-cells.  Diabetes. 2005;  54 1415-1422
• 64 Kukreja A, Cost G, Marker J, Zhang C, Sun Z, Lin-Su K, Ten S, Sanz M, Exley M, Wilson B, Porcelli S, Maclaren N. Multiple immuno-regulatory defects in type-1 diabetes.  J Clin Invest. 2002;  109 131-140
• 65 Brusko TM, Wasserfall CH, Clare-Salzler MJ, Schatz DA, Atkinson MA. Functional defects and the influence of age on the frequency of CD4+ CD25+ T-cells in type 1 diabetes.  Diabetes. 2005;  54 1407-1414
• 66 Putnam AL, Vendrame F, Dotta F, Gottlieb PA. CD4+CD25high regulatory T cells in human autoimmune diabetes.  J Autoimmun. 2005;  24 55-62
• 67 Lindley S, Dayan CM, Bishop A, Roep BO, Peakman M, Tree TI. Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes.  Diabetes. 2005;  54 92-99
• 68 Baecher-Allan C, Viglietta V, Hafler DA. Inhibition of human CD4(+)CD25(+high) regulatory T cell function.  J Immunol. 2002;  169 6210-6217
• 69 Tree TI, Roep BO, Peakman M. A mini meta-analysis of studies on CD4+CD25+ T cells in human type 1 diabetes: report of the Immunology of Diabetes Society T Cell Workshop.  Ann N Y Acad Sci. 2006;  1079 9-18
• 70 Jaeckel E, Klein L, Martin-Orozco N, Boehmer H von. Normal incidence of diabetes in NOD mice tolerant to glutamic acid decarboxylase.  J Exp Med. 2003;  197 1635-1644
• 71 Elfving M, Lindberg B, Lynch K, Ivarsson SA, Lernmark A, Hampe CS. Epitope analysis of GAD65 binding in both cord blood and at the time of clinical diagnosis of childhood type 1 diabetes.  Horm Metab Res. 2007;  39 790-796
• 72 Nakayama M, Abiru N, Moriyama H, Babaya N, Liu E, Miao D, Yu L, Wegmann DR, Hutton JC, Elliott JF, Eisenbarth GS. Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice.  Nature. 2005;  435 220-223
• 73 Jaeckel E, Lipes MA, Boehmer H von. Recessive tolerance to preproinsulin 2 reduces but does not abolish type 1 diabetes.  Nat Immunol. 2004;  5 1028-1035
• 74 Shevach EM. CD4+ CD25+ suppressor T cells: more questions than answers.  Nat Rev Immunol. 2002;  2 389-400
• 75 Bopp T, Becker C, Klein M, Klein-Hessling S, Palmetshofer A, Serfling E, Heib V, Becker M, Kubach J, Schmitt S, Stoll S, Schild H, Staege MS, Stassen M, Jonuleit H, Schmitt E. Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression.  J Exp Med. 2007;  204 1303-1310
• 76 Tang Q, Adams JY, Tooley AJ, Bi M, Fife BT, Serra P, Santamaria P, Locksley RM, Krummel MF, Bluestone JA. Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice.  Nat Immunol. 2006;  7 83-92
• 77 Walker LS, Chodos A, Eggena M, Dooms H, Abbas AK. Antigen-dependent proliferation of CD4+ CD25+ regulatory T cells in vivo.  J Exp Med. 2003;  198 249-258
• 78 Zheng SG, Wang JH, Gray JD, Soucier H, Horwitz DA. Natural and induced CD4+CD25+ cells educate CD4+CD25- cells to develop suppressive activity: the role of IL-2, TGF-beta, and IL-10.  J Immunol. 2004;  172 5213-5221
• 79 Jonuleit H, Schmitt E, Kakirman H, Stassen M, Knop J, Enk AH. Infectious tolerance: human CD25(+) regulatory T cells convey suppressor activity to conventional CD4(+) T helper cells.  J Exp Med. 2002;  196 255-260
• 80 Furtado GC, Olivares-Villagomez D, Curotto de Lafaille MA, Wensky AK, Latkowski JA, Lafaille JJ. Regulatory T cells in spontaneous autoimmune encephalomyelitis.  Immunol Rev. 2001;  182 122-134
• 81 Mottet C, Uhlig HH, Powrie F. Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells.  J Immunol. 2003;  170 3939-3943
• 82 Liu H, Hu B Xu D, Liew FY. CD4+CD25+ regulatory T cells cure murine colitis: the role of IL-10, TGF-beta, and CTLA4.  J Immunol. 2003;  171 5012-5017
• 83 Morgan ME, Flierman R, Duivenvoorde LM van, Witteveen HJ, Ewijk W van, Laar JM van, Vries RR de, Toes RE. Effective treatment of collagen-induced arthritis by adoptive transfer of CD25+ regulatory T cells.  Arthritis Rheum. 2005;  52 2212-2221
• 84 Wood KJ, Sakaguchi S. Regulatory T cells in transplantation tolerance.  Nat Rev Immunol. 2003;  3 199-210
• 85 Taylor PA, Lees CJ, Blazar BR. The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality.  Blood. 2002;  99 3493-3499
• 86 Edinger M, Hoffmann P, Ermann J, Drago K, Fathman CG, Strober S, Negrin RS. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation.  Nat Med. 2003;  9 1144-1150
• 87 Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S. Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation.  J Exp Med. 2002;  196 389-399
• 88 Earle KE, Tang Q, Zhou X, Liu W, Zhu S, Bonyhadi ML, Bluestone JA. In vitro expanded human CD4+CD25+ regulatory T cells suppress effector T cell proliferation.  Clin Immunol. 2005;  115 3-9
• 89 Hoffmann P, Eder R, Kunz-Schughart LA, Andreesen R, Edinger M. Large-scale in vitro expansion of polyclonal human CD4(+)CD25high regulatory T cells.  Blood. 2004;  104 895-903
• 90 Hoffmann P, Eder R, Boeld TJ, Doser K, Piseshka B, Andreesen R, Edinger M. Only the CD45RA+ subpopulation of CD4+CD25high T cells gives rise to homogeneous regulatory T-cell lines upon in vitro expansion.  Blood. 2006;  108 4260-4267
• 91 Herbelin A, Gombert JM, Lepault F, Bach JF, Chatenoud L. Mature mainstream TCR alpha beta+CD4+ thymocytes expressing L-selectin mediate “active tolerance” in the nonobese diabetic mouse.  J Immunol. 1998;  161 2620-2628
• 92 Bougneres PF, Carel JC, Castano L, Boitard C, Gardin JP, Landais P, Hors J, Mihatsch MJ, Paillard M, Chaussain JL. et al . Factors associated with early remission of type 1 diabetes in children treated with cyclosporine.  N Engl J Med. 1988;  318 663-670
• 93 Mathisen PM, Yu M, Johnson JM, Drazba JA, Tuohy VK. Treatment of experimental autoimmune encephalomyelitis with genetically modified memory T cells.  J Exp Med. 1997;  186 159-164
• 94 Tang Q, Henriksen KJ, Bi M, Finger EB, Szot G, Ye J, Masteller EL, MacDevitt H, Bonyhadi M, Bluestone JA. In Vitro-expanded Antigen-specific Regulatory T Cells Suppress Autoimmune Diabetes.  J Exp Med. 2004;  199 1455-1465
• 95 Tarbell KV, Yamazaki S, Olson K, Toy P, Steinman RM. CD25+ CD4+ T Cells, Expanded with Dendritic Cells Presenting a Single Autoantigenic Peptide, Suppress Autoimmune Diabetes.  J Exp Med. 2004;  199 1467-1477
• 96 Keymeulen B, Vandemeulebroucke E, Ziegler AG, Mathieu C, Kaufman L, Hale G, Gorus F, Goldman M, Walter M, Candon S, Schandene L, Crenier L, Block C De, Seigneurin JM, Pauw P De, Pierard D, Weets I, Rebello P, Bird P, Berrie E, Frewin M, Waldmann H, Bach JF, Pipeleers D, Chatenoud L. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes.  N Engl J Med. 2005;  352 2598-2608
• 97 Herold KC, Hagopian W, Auger JA, Poumian-Ruiz E, Taylor L, Donaldson D, Gitelman SE, Harlan DM, Xu D, Zivin RA, Bluestone JA. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus.  N Engl J Med. 2002;  346 1692-1698
• 98 Almeida AR, Legrand N, Papiernik M, Freitas AA. Homeostasis of peripheral CD4+ T cells: IL-2R alpha and IL-2 shape a population of regulatory cells that controls CD4+ T cell numbers.  J Immunol. 2002;  169 4850-4860
• 99 Masteller EL, Warner MR, Tang Q, Tarbell KV, MacDevitt H, Bluestone JA. Expansion of functional endogenous antigen-specific CD4+CD25+ regulatory T cells from nonobese diabetic mice.  J Immunol. 2005;  175 3053-3059
• 100 Hacein-Bey-Abina S, Kalle C von, Schmidt M, Le Deist F, Wulffraat N, MacIntyre E, Radford I, Villeval JL, Fraser CC, Cavazzana-Calvo M, Fischer A. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency.  N Engl J Med. 2003;  348 255-256
• 101 Weber SE, Harbertson J, Godebu E, Mros GA, Padrick RC, Carson BD, Ziegler SF, Bradley LM. Adaptive islet-specific regulatory CD4 T cells control autoimmune diabetes and mediate the disappearance of pathogenic Th1 cells in vivo.  J Immunol. 2006;  176 4730-4739
• 102 Luo X, Tarbell KV, Yang H, Pothoven K, Bailey SL, Ding R, Steinman RM, Suthanthiran M. Dendritic cells with TGF-beta1 differentiate naive CD4+CD25- T cells into islet-protective Foxp3+ regulatory T cells.  Proc Natl Acad Sci USA. 2007;  104 2821-2826
• 103 Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid.  Science. 2007;  317 256-260
• 104 Faria AM, Weiner HL. Oral tolerance.  Immunol Rev. 2005;  206 232-259
• 105 Kretschmer K, Apostolou I, Jaeckel E, Khazaie K, Boehmer H von. Making regulatory T cells with defined antigen specificity: role in autoimmunity and cancer.  Immunol Rev. 2006;  212 163-169
• 106 Mahnke K, Qian Y, Knop J, Enk AH. Induction of CD4+/CD25+ regulatory T cells by targeting of antigens to immature dendritic cells.  Blood. 2003;  101 4862-4869
• 107 Hawiger D, Inaba K, Dorsett Y, Guo M, Mahnke K, Rivera M, Ravetch JV, Steinman RM, Nussenzweig MC. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo.  J Exp Med. 2001;  194 769-779
• 108 Bonifaz L, Bonnyay D, Mahnke K, Rivera M, Nussenzweig MC, Steinman RM. Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ T cell tolerance.  J Exp Med. 2002;  196 1627-1638
• 109 You S, Leforban B, Garcia C, Bach JF, Bluestone JA, Chatenoud L. Adaptive TGF-beta-dependent regulatory T cells control autoimmune diabetes and are a privileged target of anti-CD3 antibody treatment.  Proc Natl Acad Sci USA. 2007;  104 6335-6340
• 110 Belghith M, Bluestone JA, Barriot S, Megret J, Bach JF, Chatenoud L. TGF-beta-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes.  Nat Med. 2003;  9 1202-1208
• 111 Bresson D, Togher L, Rodrigo E, Chen Y, Bluestone JA, Herold KC, Herrath M von. Anti-CD3 and nasal proinsulin combination therapy enhances remission from recent-onset autoimmune diabetes by inducing Tregs.  J Clin Invest. 2006;  116 1371-1381
• 112 Herold KC, Gitelman SE, Masharani U, Hagopian W, Bisikirska B, Donaldson D, Rother K, Diamond B, Harlan DM, Bluestone JA. A single course of anti-CD3 monoclonal antibody hOKT3gamma1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes.  Diabetes. 2005;  54 1763-1769
• 113 Shultz LD, Ishikawa F, Greiner DL. Humanized mice in translational biomedical research.  Nat Rev Immunol. 2007;  7 118-130
• 114 Fritzsching B, Oberle N, Pauly E, Geffers R, Buer J, Poschl J, Krammer P, Linderkamp O, Suri-Payer E. Naive regulatory T cells: a novel subpopulation defined by resistance toward CD95L-mediated cell death.  Blood. 2006;  108 3371-3378
• 115 Huehn J, Siegmund K, Hamann A. Migration rules: functional properties of naive and effector/memory-like regulatory T cell subsets.  Curr Top Microbiol Immunol. 2005;  293 89-114
• 116 Siewert C, Menning A, Dudda J, Siegmund K, Lauer U, Floess S, Campbell DJ, Hamann A, Huehn J. Induction of organ-selective CD4+ regulatory T cell homing.  Eur J Immunol. 2007;  37 978-989

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