IMMUNE NETWORK

  • 제8권4호
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  • Pages.107-123
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  • 2008
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  • 1598-2629(pISSN)
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  • 2092-6685(eISSN)
대한면역학회 (The Korean Association of Immunobiologists)
권호 표지

Regulatory T Cell Therapy for Autoimmune Disease

  • Ha, Tai-You (Department of Immunology, Chonbuk National University Medical School)
  • 발행 : 2008.12.30
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초록

It has now been well documented in a variety of models that T regulatory T cells (Treg cells) play a pivotal role in the maintenance of self-tolerance, T cell homeostasis, tumor, allergy, autoimmunity, allograft transplantation and control of microbial infection. Recently, Treg cell are isolated and can be expanded in vitro and in vivo, and their role is the subject of intensive investigation, particularly on the possible Treg cell therapy for various immune-mediated diseases. A growing body of evidence has demonstrated that Treg cells can prevent or even cure a wide range of diseases, including tumor, allergic and autoimmune diseases, transplant rejection, graft-versus-host disease. Currently, a large body of data in the literature has been emerging and provided evidence that clear understanding of Treg cell work will present definite opportunities for successful Treg cell immunotherapy for the treatment of a broad spectrum of diseases. In this Review, I briefly discuss the biology of Treg cells, and summarize efforts to exploit Treg cell therapy for autoimmune diseases. This article also explores recent observations on pharmaceutical agents that abrogate or enhance the function of Treg cells for manipulation of Treg cells for therapeutic purpose.

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참고문헌

  1. Gershon RK, Cohen P, Hencin,R, Liebhaber SA: Suppressor T cells. J Immunol 108;586-590, 1972
  2. Gershon RK, Kondo K: Infectious immunological tolerance. Immunology 21;903-914, 1971
  3. Ha TY, Waksman BH: Role of the thymus in tolerance .X. 'Suppressor' activity of antigen-stimulated rat thymocytes transferred to normal recipients. J Immunol 110;1290-1299, 1973
  4. Ha TY, Waksman BH, Treffers HP: Thymic suppressor cell. I. Separation of subpopulation with suppressor activity. J Exp Med 139;13-23, 1974 https://doi.org/10.1084/jem.139.1.13
  5. Ha TY, Waksman BH, Treffers HP: The thymic suppressor cell. II. Metabolic requirement of suppressor activity. Immunol Commun 3;351-359, 1974 https://doi.org/10.3109/08820137409061115
  6. Tada T, Taniguchi M, Takemori T: Properties of primed suppressor T cells and their products. Transplant Rev 26;106-129, 1975
  7. Gershon RK, Eardley DD, Durum S, Green R, Shen FW, Yamauci K, Cantor H, Murphy DB: Contrasuppression. A novel immunoregulatory activity. J Exp Med 153;1533-1546, 1981 https://doi.org/10.1084/jem.153.6.1533
  8. Gerber NL, Hardin JA, Chused TM, Steinberg AD: Loss with age in NZB/W mice of thymic suppressor cells in the graft-vs-host reaction. J Immunol 113;1618-1625, 1974
  9. Durkin HG, Waksman BH: Thymus and tolerance. Is regulation the major function of the thymus? Immunol Rev 182;33-57, 2001 https://doi.org/10.1034/j.1600-065X.2001.1820103.x
  10. Dorf ME, Benaceraf B: Suppressor cells and immunoregulation. Ann Rev Immunol 2;127-158, 1984 https://doi.org/10.1146/annurev.iy.02.040184.001015
  11. Mitrrucker HW, Kaufmann HE: Mini-review: regulatory T cells and infection: suppression revisited. Eur J Immunol 34;306-312, 2004 https://doi.org/10.1002/eji.200324578
  12. Baecher-Allan C, Hafler DA: Suppressor T cells in human diseases. J Exp Med 200;273-276, 2004 https://doi.org/10.1084/jem.20040812
  13. Waksman BH: Tolerance, the thymus, and suppressor T cells. Clin Exp Immunol 28;363-374, 1977
  14. Shevach EM: D4+: CD4+ CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 182;389-400, 2002
  15. Rouse BT, Sehrawat S: Regulatory T cells and infectious disease. Immune Network 7;167-172, 2007 https://doi.org/10.4110/in.2007.7.4.167
  16. Basten A, Fazekas de St Groth B: Special regulatory T-cell review: T cell dependent suppression revisited. Immunol 123;33-39, 2008 https://doi.org/10.1111/j.1365-2567.2007.02772.x
  17. Tang Q, Bluestone JA: The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nat Immunol 9; 239-244, 2008 https://doi.org/10.1038/ni1572
  18. Ha TY, Chung HT: Effect of cyclophosphamide on humoral and cellular immune response in mice. J Korean Med Ass 20;985-994, 1977
  19. Ha TY, Kim HI, Im SY: Effect of dexamethasone on different types of murine T suppressor cells. Korean J Immunol 9;1-15, 1987
  20. Ha TY, Park YM, Park YK, Lee HK, Park CW: Regulation of cellular immunity in cryptococosis. III. Induction of Cryptococcus neoformans-specific T cells and hybridoma. Korean J Immunol 14;15-23, 1992
  21. Moeller G (Ed): Suppressor T lymphocytes. Transplantation Rev 26;3-205, 1975
  22. 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 mechanisms of self-tolerance causes various autoimmune diseases. J Immunol 155;1151-1164, 1995
  23. Sakaguchi S: Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Ann Rev Immunol 22;531-562, 2004 https://doi.org/10.1146/annurev.immunol.21.120601.141122
  24. Mills KH: Regulatory T cells: friend or foe in immunity to infection? Nature Rev Immunol 4;841-855, 2004 https://doi.org/10.1038/nri1485
  25. Stein-Streilein J, Taylor AW: An eye's view of T regulatory cells. J Leukoc Biol 81;593-598, 2007 https://doi.org/10.1189/jlb.0606383
  26. Jiang S, Lechler RI: CD4+CD25+regulatory T-cell therapy for allergy, autoimmune and transplant rejection. Inflamm Allergy Drug Targets 5;239-242, 2006 https://doi.org/10.2174/187152806779010981
  27. Beyer M, Schultze JL: Regulatory T cells in cancer. Blood 1108;804-811, 2006
  28. Bluestone JA: Regulatory T-cell therapy: is it ready for the clinic? Nat Rev Immunol 5;343-349, 2005 https://doi.org/10.1038/nri1574
  29. Vignail DA, Collison LW, Workman CJ: How regulatory T cell work. Nat Rev Immunol 8;523-532, 2008 https://doi.org/10.1038/nri2343
  30. Bendelac A, Savage PB, Teyton L: The biology of NKT cells. Ann Rev Immunol 25;297-336, 2007 https://doi.org/10.1146/annurev.immunol.25.022106.141711
  31. Sakaguchi S, Powrie F: Emerging challenges in regulatory T cell function and biology. Science 317;627-629, 2007 https://doi.org/10.1126/science.1142331
  32. Kang SM, Tang Q. Bluestone JA: CD4+CD25+ regulatory T cells in transplantation: progress, challenges and prospects. Am J Transplant 7;1457-1463, 2007 https://doi.org/10.1111/j.1600-6143.2007.01829.x
  33. Thomson CW, Lee BP, Zhang L: Double-negative regulatory T cells: non-conventional regulators. Immunol Res 35;163-178, 2006 https://doi.org/10.1385/IR:35:1:163
  34. Hayday A, Tigelaar R: Immunoregulation in the tissues by $\gamma$$\delta$T cells. Nat Rev Immunol 3;233-242, 2003 https://doi.org/10.1038/nri1030
  35. Zhang C, Zhang J, Tian Z: 2006. The regulatory effect of natural killer cells: do 'NK-reg cells' exist? Cell Mol Immunol 3;241-254, 2006
  36. Hori S, Sakaguchi S: Foxp3: a critical regulator of the development and function of regulatory T cells. Microbes Infect 6;745-751, 2004 https://doi.org/10.1016/j.micinf.2004.02.020
  37. Ziegler SE: FOXP3: of mice and men. Ann Rev Immunol 24;209-226, 2006 https://doi.org/10.1146/annurev.immunol.24.021605.090547
  38. Stein-Streilein J, Taylor AW: An eye's view of T regulatory cells. J Leukoc Biol 81;593-598, 2007 https://doi.org/10.1189/jlb.0606383
  39. Hawrylowicz CM: Regulatory T cells and IL-10 in allergic inflammation. J Exp Med 202;1459-1463, 2005 https://doi.org/10.1084/jem.20052211
  40. Ford McIntyre MS, Young KJ, Gao J, Joe B, Zhang L: Cutting edge: in vivo trogocytosis as a mechanism of double negative regulatory T cell-mediated antigen-specific suppression. J Immunol 181;2271-2275, 2008 https://doi.org/10.4049/jimmunol.181.4.2271
  41. Young KJ, DuTemple B, Phillips MJ, Zhang L: Inhibition of graft versus host disease by double negative regulatory T cells. J Immunol 171;134-141, 2003 https://doi.org/10.4049/jimmunol.171.1.134
  42. Morgan ME, van Bilsen JH, Bakker AM, Heemskerk B, Schilham MW, Hartgers FC, Elferink BG, van der Anaden L, De Vies RR, Huizinga TW, Ottenhoff TH, Toes RE: Expression of FOXP3 mRNA is not confined to CD4+CD25+ T regulatory cells in humans. Human Immunol 66;13-20, 2005
  43. Sakaguchi S, Ono M, Setoguchi R, Yagi H, Hori S, Fehervari Z, Shimizu J, Takahashi T, Nomura T: Fox3+CD25+CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev 212;8-27, 2006 https://doi.org/10.1111/j.0105-2896.2006.00427.x
  44. Dejaco C, Duftner C, Grubeck-Loebsenstein B, Schirmer M: Imbalance of regulatory T cells in human autoimmune diseases. Immunology 117;289-300, 2006 https://doi.org/10.1111/j.1365-2567.2005.02317.x
  45. Venken K, Hellings N, Thewissen M, Somers V, Hensen K, Rummens JL, Medaer R, Hupperts R, StinissenP: Compromised CD4+CD25high regulatory T-cell function in patients with relapsing-remitting multiple sclerosis is correlated with a reduced frequency of FOXP3-positive cells and reduced FOXP3 expression at the single-cell level. Immunology 123;79-89, 2008 https://doi.org/10.1111/j.1365-2567.2007.02690.x
  46. Zheng SG, Wang JH, Koss MN, Quisomorio F Jr, Gray JD, Horwitz DA: CD4+ and CD8+ regulatory T cells generated ex vivo with IL-2 and TGF-beta suppress a stimulatory graft-versus-host disease with a lupus-like syndrome. J Immunol 172;1531-1539, 2004 https://doi.org/10.4049/jimmunol.172.3.1531
  47. Yamaguchi T, Hirota K, Nagahama K, Ohkawa K, Takahashi T, Nomura T, Sakaguchi S: Control of immune responses by antigen-specific regulatory T cells expressing the folate receptor. Immunity 27;145-159, 2007 https://doi.org/10.1016/j.immuni.2007.04.017
  48. Yamaguchi T, Hirota K, Nagahama K, Ohkawa K, Takahashi T, Nomura T, Sakaguchi S: Control of immune responses by antigen-specific regulatory T cells expressing the folate receptor. Immunity 27;145-159, 2007 https://doi.org/10.1016/j.immuni.2007.04.017
  49. Chen ML, Yan BS, Bando Y, Kuchroo VK, Weiner HL: Latency-associated peptide identifies a novel CD4+CD25+ regulatory T cell subset with TGF beta-mediated function and enhanced suppression of experimental autoimmune encephalomyelitis. J Immunol 180;7327-7337, 2008 https://doi.org/10.4049/jimmunol.180.11.7327
  50. Bruder D, Probst-Kepper M, Westendorf AM, Geffers R, Beissert S, Loser K, von Boehmer H, Buer J, Hansen W: Neuropilin-1: a surface marker of regulatory T cells. Eur J Immunol 34;623-630, 2004 https://doi.org/10.1002/eji.200324799
  51. Glinka Y, Pud'homme GJ: Neruopilin-1 is a receptor for transforming growth factor $\beta$-1, activates its latent form, and promotes regulatory T cell activity. J Leukoc Biol 84;302-310, 2008 https://doi.org/10.1189/jlb.0208090
  52. Coleman CA, Muller-Trutwin MC, Apetrei C, Pandrea I: T regulatory cells: aid or hindrance in the clearance of disease? J Cell Mol Med 11;1291-1325, 2007 https://doi.org/10.1111/j.1582-4934.2007.00087.x
  53. Sakaguchi S, Powrie F: Emerging challenges in regulatory T cell function and biology. Science 317;627-629, 2007 https://doi.org/10.1126/science.1142331
  54. Bacchetta R, Gambineri E, Roncarolo MG: Role of regulatory T cells and FOXP3 in human diseases. J Allergy Clin Immunol 120;227-235, 2007 https://doi.org/10.1016/j.jaci.2007.06.023
  55. Sakaguchi S, Fukuma K, Kuribayashi K, Masuda T: Organ-specific autoimmune disease induced in mice by elimination of T-cell subset. I. Evidence for the active participation of T-cells in natural self-tolerance: deficit of a T-cell subset as a possible cause of autioimmune disease. J Exp Med 161;72-87, 1985 https://doi.org/10.1084/jem.161.1.72
  56. Gambinen E, Torgenson T, Ochs HD: Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. Curr Opin Reumatol 15;430-435, 2003 https://doi.org/10.1097/00002281-200307000-00010
  57. Nardekku DT, Cloute JP, Luk KH, Torrealba J, Warner TF, Callister SM, Schell RF: CD4(+)CD25(+) T cells prevent arthritis associated with Borrelia vaccination and infection. Clin Diag Lab Immunol 12;786-792, 2005
  58. Nguyen LT, Jacobs J, Mathis D, Benoist C: Where FoxP3-dependent regulatory T cells impinge on the development of inflammatory arthritis. Arthritis Rheum 56;509-520, 2007 https://doi.org/10.1002/art.22272
  59. Ehrenstein MR, Evans JG, Singh A, Moore S, Warnes G, Isenberg DA, Mauri C: Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNF$\alpha$ therapy. J Exp Med 200;277-285, 2004 https://doi.org/10.1084/jem.20040165
  60. Broere F, Wieten L, Koerkamp EI, van Roon JA, Guichelaar T, Lafeber FP, van Eden W: Oral or nasal antigen induces regulatory T cells that suppress arthritis and proliferation of arthritogenic T cells in joint draining lymph nodes. J Immunol 181;899-906, 2008 https://doi.org/10.4049/jimmunol.181.2.899
  61. Forger F, Marcoli N, Gadika S, Moller B, Villiger PM, Ostensen M: Pregnancy induces numerical and funtinal changes of $CD4+CD25^{high}$ regulatory T cells in patients with rheumatoid arthritis. Ann Rheum Dis 67;984-990, 2008 https://doi.org/10.1136/ard.2007.075283
  62. 0Kelchtemans H, Geboes L, Mitera T, Huskens D, Leclercq G, Matthys P: Activated CD4+CD25+ regulatory T cells inhibit osteoclastogenesis and collagen-induced arthritis. Ann Rheum Dis 2008
  63. von Boehmer H: Can studies of tolerance ever lead to therapy? Ann Rheum Dis 65(Suppl 3);iii41-iii43, 2006
  64. Leipe J, Skapenko A, Lipsky PE, Schulze-Koops H: Regulatory T cells in rheumatoid arthritis. Arthritis Res Ther 7;93, 2005 https://doi.org/10.1186/ar1718
  65. Wang J, Toes RE: Mechanisms of oral tolerance revisited. Arthritis Res Ther 10;108-109, 2008 https://doi.org/10.1186/ar2402
  66. Liu MF, Wang CR, Fung LL, Lin LH, Tsai CN: The presence of cytokine-suppressive CD4+CD25+ T cells in the peripheral blood and synovial fluid of patients with rheumatoid arthritis. Scand J Immunol 62;312-317, 2005 https://doi.org/10.1111/j.1365-3083.2005.01656.x
  67. Cao D, van Vollenhoven R, Klareskog L, Trollmo C, Malmstrom V: CD25brightCD4+ regulatory T cells are enriched in inflamed joints of patients with chronic rheumatic disease. Arthritis Res Ther 6;R335-R346, 2004 https://doi.org/10.1186/ar1192
  68. Behrens F, Himsel A, Rehart S, Stanczyk J, Beutel B, Zimmermann SY, Koehl U, Moeller B, Gay S, Kaltwasser JP, Pfeilschifter JM, Radkeke HH: Imbalance in distribution of functional autologous regulatory T cells in rheumatoid arthritis. Ann Rheum Dis 66;1151-1156, 2007 https://doi.org/10.1136/ard.2006.068320
  69. Cao D, Boerjesson O, Larsson P, Rudin A, Gunnarsson I, Klareskog L, Malmstroem V, Trollmo C: FOXP3 identifies regulatory $CD25^bright$ CD4+ T cells in rheumatic joints. Scand J Immunol 63;444-452, 2006 https://doi.org/10.1111/j.1365-3083.2006.001755.x
  70. Park MJ, Min SY, Park KS, Cho YG, Cho ML, Jung YK, Park HY, Chang SH, Cho SG, Min JK, Park SH, Kim HY: Indoleamine 2,3-dioxygenase-expresssing dendritic cells are involved in the generation of CD4+CD25+ regulatory T cells in Peyer's patches in an orally tolerized, collagen-induced arthritis mouse model. Arthritis Res Ther 10;R11, 2008 https://doi.org/10.1186/ar2361
  71. Ehrenstein MR, Evans JG, Singh A, Moore S, Warnes G, Isenberg DA, Mauri C: Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNF $\alpha$ therapy. J Exp Med 200;277-285, 2004 https://doi.org/10.1084/jem.20040165
  72. Morgan ME, Flierman R, van Duivenvoorde M, Witteveen HJ, van Ewijk W, van Laar JM, de Vries RR, Toes RE: Effective treatment of collagen-induced arthritis by adoptive transfer of CD25+ regulatory T cells. Arthritis Rheum 52;2212-2221, 2005 https://doi.org/10.1002/art.21195
  73. Nguyen LT, Jacobs J, Mathis D, Benoist C: Where FoxP3-dependent regulatory T cells impinge on the development of inflammatory arthritis. Arthritis Rheum 56;509-520, 2007 https://doi.org/10.1002/art.22272
  74. Sarkar S, Fox DA: Regulatory T cell defects in rheumatoid arthritis. Arthritis Rheum 56;710-713, 2007 https://doi.org/10.1002/art.22415
  75. Godebu E, Summers-Torres D, Lin MM, Baaten BJ, Bradley LM: Polyclonal adaptive regulatory CD4 cells that can reverse type 1 diabetes become oligoclonal long-term protective memory cells. J Immunol 181;1798-1805, 2008 https://doi.org/10.4049/jimmunol.181.3.1798
  76. 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 57;113-123, 2008 https://doi.org/10.2337/db06-1700
  77. Tang Q, Henriksen KJ, Bi M, Finger EB, Szot G, Ye J, Masteller EL, McDevitt H, Bonyhadi M, Bluestone JA: in vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med 199;1455-1465, 2004 https://doi.org/10.1084/jem.20040139
  78. 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 199;1467-1477, 2004 https://doi.org/10.1084/jem.20040180
  79. Masteller EL, Warner MR, Tang Q, Tarbell KV, McDevitt H, Bluestone JA: Expansion of functional endogenous antien-specific CD4+CD25+ regulatory T cells from nonobese diabetic mice. J Immunol 175;3053-3059, 2005 https://doi.org/10.4049/jimmunol.175.5.3053
  80. Tiittanen M, Huupponen JT, Knip M, Vaarala O: Insulin treatment in patients with type 1 diabetes induces upregulation of regulatory T-cell markers in peripheral blood mononuclear cells stimulated with insulin in vitro. Diabetes 55;3446-3454, 2006 https://doi.org/10.2337/db06-0132
  81. Richer MJ, Straka N, Fang D, Shanina I, Horwitz MS: Regulatory T-cells protect from type 1 diabetes after induction by Coxsackievirus infection in the context of transforming growth factor-$\beta$. Diabetes 57;1302-1311, 2008 https://doi.org/10.2337/db07-1460
  82. Gregori S, Giarratana N, Smiroldo S, Adorini L: Dynamics of pathogenic and suppressor T cells in autoimmune diabetes development. J Immunol 171;4040-4047, 2003 https://doi.org/10.4049/jimmunol.171.8.4040
  83. Kanagawa O, Militech A, Vaupel BA: Regulation of diabetes development by regulatory T cells in pancreatic islet antigen-specific TCR transgenic nonobese diabetic mice. J Immunol 168;6159-6164, 2002 https://doi.org/10.4049/jimmunol.168.12.6159
  84. Jaeckel E, von Boehmer H, Manns MP: Antigen-specific FoxP3-transduced T-cells can control established type 1 diabetes. Diabetes 54;306-310, 2005 https://doi.org/10.2337/diabetes.54.2.306
  85. Lee VW, Wang YM, Wnag YP, Zheng D, Polhill T, Cao Q, Wu H, Alexander IE, Alexander SI, Harris DC: Regulatory immune cells in kidney disease. Am J Physiol Renal Physiol 295;F335-F342, 2008 https://doi.org/10.1152/ajprenal.00077.2008
  86. Noris M, Casiraghi F, Todeschini M, Cravedi P, Cugini D, Monteferracnte G, Aiello S, Cassis L, Gotti E, Gaspari F, Cattaneo D, Perico N, Remuzzi G: Regulatory T cells and T cell depletion: role of immunosuppressive drugs. J Am Soc Nephrol 18;1007-1018, 2007 https://doi.org/10.1681/ASN.2006101143
  87. Wolf D, Hochgger K, Wolf AM, Rumpold HF, Gastl G, Tilg H, Mayer G, Gunsilius E, Rsenkranz AR: CD4+CD25+ regulatory T cells inhibit experimental anti-glomerular basement membrane glomerulonephritis in mice. J Am Soc Nephrol 16;1360-1370, 2005 https://doi.org/10.1681/ASN.2004100837
  88. Mahajan D, Wang Y, Qin X, Wang Y, Zheng G, Wang YM, Alexander SI, Harris DC: CD4+CD25+ regulatory T cell protect against injury in an innate murine model of chronic kidney disease. J Am Soc Nephrol 17;2731-2741, 2006 https://doi.org/10.1681/ASN.2005080842
  89. Wang YM, Zhang GY, Wang Y, Hu M, Wu H, Watson D, Hori S, Alexander IE, Harris DC, Alexander SI: Foxp3-transduced polyclonal regulatory T cells protect against chronic renal injury from adriamycin. J Am Soc Nephrol 17;697-706, 2006 https://doi.org/10.1681/ASN.2005090978
  90. Salma AD, Chaudhry AN, Holthaus KA, Mosley K, Kalluri R, Sayegh MH, Lecler RI, Pusey CD, Lightstone L: Regulation by CD25+ lymphocytes of autoantigen-specific T-cell responses in Goodpasture's (anti-GBM) disease. Kidney Int 64;1685-1694, 2003 https://doi.org/10.1046/j.1523-1755.2003.00259.x
  91. Mekal DJ, Alli RS, Geiger TL: IL-10-dependent infectious tolerance after the treatment of experimental allergic encephalomyelitis with redirected CD4+CD25+ T lymphocytes. Proc Natl Acad Sci USA 102;11817-11822, 2005
  92. Selvaraj RK, Geiger TL: Mitigation of experimental allergic encephalomyelitis by TGF-$\beta$ induced Foxp3+ regulatory T lymphocytes through the induction of anergy and infectious tolerance. J Immunol 180;2830-2838, 2008 https://doi.org/10.4049/jimmunol.180.5.2830
  93. Ochoa-Reparaz J, Riccardi C, Rynda A, Jun S, Callis G, Pascual DW: Regulatory T cell vaccination without autoantigen protects against experimental autoimmune encephalomyelitis. J Immunol 178;1791-1799, 2007 https://doi.org/10.4049/jimmunol.178.3.1791
  94. Mekala DJ, Geiger TL: Immunotherapy of autoimmune encephalomyelitis with redirected CD4+CD25+ T lymphocytes. Blood 105;2090-2092, 2005 https://doi.org/10.1182/blood-2004-09-3579
  95. Ochoa-Reparaz J, Rynda A, Ascon MA, Yang X, Kochetkova I, Riccardi C, Callis G, TrunkleT, Pascual DW: IL-13 production by regulatory T cells protects against experimental autoimmune encephalomyelitis independently of autoantigen. J Immunol 181;954-968, 2008 https://doi.org/10.4049/jimmunol.181.2.954
  96. Wang J, Takeuchi H, Sonobe Y, Jin S, Mizuno T, Miyakawa S, Fujiwara M, Nakamura Y, Kato T, Muramatsu H, Muramasu T, Suzumura A: Inhibition of midkine alleviates experimental autoimmune encephalomyelitis through the expansion of regulatory T cell population. Proc Natl Acad Sci U S A 105;3915-3920, 2008
  97. Suvas S, Kumaraguru U, Pack CD, Lee S, Rouse BT: CD4+CD25+ T cells regulate virus-specific primary and memory CD8+ T cell responses. J Exp Med 198;889-901, 2003 https://doi.org/10.1084/jem.20030171
  98. Kohm AP, Carpentier PA, Anger HA, Miller SD: Cutting edge: CD4+CD25+ regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. J Immunol 169;4712-4716, 2002 https://doi.org/10.4049/jimmunol.169.9.4712
  99. Gonzalez-Rey E, Fernandex-Martin A, Chorny A, Martin J, Pozo D, Ganea D, Delgado M: Therapeutic effect of vasoactive intestinal peptide on experimental autoimmune encephalomyelitis; down-regulaltion of inflammatory and autoimmune responses. Am J Pathol 168;1179-1188, 2006 https://doi.org/10.2353/ajpath.2006.051081
  100. Char JG, Coe D, Chen D, Simpson E, Dyson J, Scott D: in vitro expansion improves in vivo regulation by CD4+CD25+ regulatory T cells. J Immunol 180;858-869, 2008 https://doi.org/10.4049/jimmunol.180.2.858
  101. Venken K, Hellings N, Broekmans T, Hensen K, Rummens JL, Stinissen P: Natural naive CD4+CD25+ $CD127^{low}$ regulatory T cell (Treg) development and function are disturbed in multiple sclerosis patients: recovery of memory Treg homeostasis during disease progression. J Immunol 180;6411-6420, 2008 https://doi.org/10.4049/jimmunol.180.9.6411
  102. Venken K, Hellings N, Thewissen M, Somers V, Hensen K, Rummens JL, Medaer R, Hupperts R, Stinissen P: Compromised CD4+CD25high regulatory T-cell function in patients with relapsing-remitting multiple sclerosis is correlated with a reduced frequency of FOXP3-positive cells and reduced FOXP3 exxpression at the single-cell level. Immunology 123;79-89, 2008 https://doi.org/10.1111/j.1365-2567.2007.02690.x
  103. Saresella M, Marventano I, Longhi R, Trabattoni D, Mendozzi L, Caputo D, Clerici M: CD4+CD25+Fox3+ PD-regulatory T cells in acute and stable elapsing-remitting multiple sclerosis and their modulation by therapy. FASEB 22;3500-3508, 2008 https://doi.org/10.1096/fj.08-110650
  104. Zozulya AL, Wiendl H: The role of regulatory T cells in multiple sclerosis. Nat Clin Prat Neurol 4;384-398, 2008 https://doi.org/10.1038/ncpneuro0832
  105. Anderton SM, Liblau RS: Regulatory T cells in the control of inflammatory demyelingating diseases of the central nervous system. Curr Opin Neurol 21;248-254, 2008 https://doi.org/10.1097/WCO.0b013e3282febf58
  106. Danese S, Rutella S: The Janus faces of CD4+CD25+ regulatory T cells in cancer and autoimmunity. Curr Med Chem 14;649-666, 2007 https://doi.org/10.2174/092986707780059599
  107. Suarez A, Lopez P, Gomez J, Gutierrez C: Enrichment of CD4+CD25high T cell population in SLE patients treated with glucocorticoids. Ann Rheum Dis 65;1512-1517, 2006 https://doi.org/10.1136/ard.2005.049924
  108. Mellor-Pita S, Citores MJ, Castejon R, Tutor-Ureta P, Yebra-Bango M, Andreu JL, Vargas JA: Decrease of regulatory T cells in patients with systemic lupus erythematosus. Ann Rheum Dis 65;553-554, 2006 https://doi.org/10.1136/ard.2005.044974
  109. LaCava A: T-regulatory cells in systemic lupus erythematosus. Lupus 17;421-425, 2008 https://doi.org/10.1177/0961203308090028
  110. Lee HY, Hong YK, Yun HJ, Kim YM, Kim JR, Yoo WH: Altered frequency and migration capacity of CD4+CD25+ regulatory T cells in systemic lupus erythematosus. Rheumatology (Oxford) 47;789-794, 2008 https://doi.org/10.1093/rheumatology/ken108
  111. Azba NA, Bassyoun IH, Emad Y, Abd El-Wahab GA, Hamdy G, Mashahit MA: CD4+CD25+ regulatory T cells (TREG) in systemic lupus erythematousus (SLE) patients: the possible influence of treatment with corticosteroids. Clin Immunol 127;151-157, 2008 https://doi.org/10.1016/j.clim.2007.12.010
  112. Kang HK, Michaels MA, Berner BR, Datta SK: Very low-dose tolerance with nucleosomal peptides controls lupus and induces potent regulatory T cell subsets. J Immunol 174;3247-3255, 2005 https://doi.org/10.4049/jimmunol.174.6.3247
  113. Parietti V, Chifflot M, Muller S, Monneaux F: Regulatory T cells and systemic lupus erythematosus. Ann N Y Acad Sci 1108;64-75, 2007 https://doi.org/10.1196/annals.1422.007
  114. Kang HK, Datta SK: Regulatory T cells in lupus. Int Rev Immunol 25;5-25, 2006 https://doi.org/10.1080/08830180500544480
  115. Valencia X, Yarboro C, Illei G, Lipsky PE: Deficient CD4+CD25high T regulatory cell function in patients with active systemic lupus erythematosus. J Immunol 178;2579-2588, 2007 https://doi.org/10.4049/jimmunol.178.4.2579
  116. Braat H, McGuirk P, Ten Kate FJ, Hubiregtse I, Dunne PJ, Hommes D, Van Deventer SJ, Mills KH: Prevention of experimental colitis by parenteral administration of a pathogen-derived immunomodulatory molecule. Gut 56; 351-357, 2007 https://doi.org/10.1136/gut.2006.099861
  117. Saruta M, Yu QT, Fleshner PR, Mantel PY, Schmidt-Weber CB, Banham AH, Papadakis KA: Characterization of FOXP3+CD4+ regulatory T cells in Crohn's disease. Clin Immunol 125;281-290, 2007 https://doi.org/10.1016/j.clim.2007.08.003
  118. Coombes JL, Maloy KJ: Control of intestinal homeostasis by regulatory T cells and dendritic cells. Seminars Immunol 19;116-126, 2007
  119. Mottet C, Uhlig HH, Powrie F: cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J Immunol 170; 3939-3943, 2003 https://doi.org/10.4049/jimmunol.170.8.3939
  120. Denning TL, Kim G, Kronenberg M: Cutting edge: CD4+CD25+ regulatory T cells impaired for intestinal homing can prevent colitis. J Immunol 174;7487-7491, 2005 https://doi.org/10.4049/jimmunol.174.12.7487
  121. Uhlig HH, Coombes J, Mottet C, Izcue A, Thompson C, Fanger A, Tannapfel A, Fontenof JD, Ramsdell F, Powrie F: Characterization of Foxp3+ CD4+CD25+ and IL-10-secreting CD4+CD25+ T cells during cure of colitis. J Immunol 177;5852-5860, 2006 https://doi.org/10.4049/jimmunol.177.9.5852
  122. Sarkar S, Fox DA: Regulatory T cell defects in rheumatoid arthritis. Arthritis Rheum 56;710-713, 2007 https://doi.org/10.1002/art.22415
  123. DiPaola RJ, Glass DD, Bijwaard, KE, Shevach EM: CD4+CD25+T cells prevent the development of organ-specific autoimmune disease by inhibiting the differentiation of autoreactive effector T cells. J Immunol 175;7135-7142, 2005 https://doi.org/10.4049/jimmunol.175.11.7135
  124. Stummvoll GH, DiPaolo RJ, Huter EN, Davidson TS, Glass D, Ward JM, Shevach EM: Th1, Th2, and Th17 effector T cell-induced autoimmune gastritis differs in pathological pattern and in susceptibility to suppression by regulatory T cells. J Immunol 181;1908-1916, 2008 https://doi.org/10.4049/jimmunol.181.3.1908
  125. Aricha R, Feferman T, Fuchs S, Souroujon MC: Ex vivo generated regulatory T cells modulate experimental autoimmune myasthenia gravis J Immunol 180;2132-2139, 2008 https://doi.org/10.4049/jimmunol.180.4.2132
  126. Isaacs JD: Therapeutic T-cell manipulation in rheumatoid arthritis: past, present and future. Rheumatology (Oxford) 47;1461-1468, 2008 https://doi.org/10.1093/rheumatology/ken163
  127. Sheng JR, Li L, Ganesh BB, Vasu C, Prabhakar BS, Meriggioli MN: Regulatory T cells induced by GM-CSF suppress ongoing experimental myasthenia gravis. Clin Immunol 128;172-180, 2008 https://doi.org/10.1016/j.clim.2008.03.509
  128. Meriggioli MN, Sheng JR, Li L, Prabhakar BS: Strategies for treating auto immunity: novel insights from experimental myasthenia gravis. Ann N Y Acd Sci 1132;276-282, 2008 https://doi.org/10.1196/annals.1405.023
  129. Gang E, Vasu C, Cheatem D, Prabhakar BS: IL-10-producing CD4+CD25+ regulatory T cells play a critical role in granulocyte-marcrophage colony-stimulating factor-induced suppression of experimental autoimmune thyroiditis. J Immunol 174;7006-7013, 2005 https://doi.org/10.4049/jimmunol.174.11.7006
  130. Verginis P, Li HS, Carayanniotis G: Tolerogenic semimature dendritic cells suppress experimental autoimmune thyroiditis by activation of thyroglobulin-specific CD4+ CD25+ T cells. J Immunol 174;7433-7439, 2005 https://doi.org/10.4049/jimmunol.174.11.7433
  131. McLachlan SM, Nagayama Y, Pichurin PN, Mizutori Y, Chen CR, Misharin A, Aliesk HA, Rapopori B: The link between Graves' disease and Hashimoto's thyroiditis: a role for regulatory T cells. Endocrinology 148;5724-5733, 2007 https://doi.org/10.1210/en.2007-1024
  132. Solomou ED, Rezvan K, Mielke S, Malide D, Keyvanfar K, Visconte V, Kajigaya S, Barrett AJ, Young NS: Deficient CD4+CD25+FOXP3+ T regulatory cells in acquired aplastic anemia. Blood 110;1603-1606, 2007 https://doi.org/10.1182/blood-2007-01-066258
  133. Young NS, Scheinberg P, Calado RT: Aplastic anemia: Curr Opin Hematol 15;162-168, 2008 https://doi.org/10.1097/MOH.0b013e3282fa7470
  134. Wang J, Toes RE: Mechanisms of oral tolerance revisited. Arthritis Res Ther 10;108-109, 2008 https://doi.org/10.1186/ar2402
  135. Chorny A, Gonzales-Rey E, Ganea D, Delgado M: Vasoactive intestinal peptide generates CD4+CD25+ regulatory T cells in vivo: therapeutic applications in autoimmunity and transplantation. Ann NY Acad Sci 1070;190-195, 2006 https://doi.org/10.1196/annals.1317.011
  136. Delgado M, Chorny A, Gonzales-Rey E, Ganea D: Vasoactive intestinal peptide generates CD4+CD25+ regulatory T cells in vivo. J Leukc Biol 78;1327-1338, 2005 https://doi.org/10.1189/jlb.0605299
  137. Gonzalez-Rey E, Fernandez-Martin A, Chorney A, Delgado M: Vasoactive intestinal peptide induces CD4+, CD25+ T regulatory cells with therapeutic effect in collagen-induced arthritis. Arthritis Rheum 54;864-876, 2006 https://doi.org/10.1002/art.21652
  138. Delgado M, Chorny A, Gonazalez-Rey E, Ganea D: Vasoactive intestinal peptide generates CD4+CD25+ regulatory T cells in vivo. J Leukc Biol 78;1327-1338, 2005 https://doi.org/10.1189/jlb.0605299
  139. Delgado M, Toscano MG, Benabedellah K, Cobo M, O'Valle F, Gonzales-Rey E, Matin F: in vivo delivery of lentiviral vectors expressing vasoactive intestinal peptide complementary DNA as gene therapy for collagen-induced arthritis. Arthritis Rheum 58;1026-1037, 2008 https://doi.org/10.1002/art.23283
  140. Broere F, Wieten L, Koerkamp EI, van Roon JA, Guichelaar T, Lafeber FP, van Eden W: Oral or nasal antigen induces regulatory T cells that suppress arthritis and proliferation of arthritogenic T cells in joint draining lymph nodes. J Immunol 181;899-906, 2008 https://doi.org/10.4049/jimmunol.181.2.899
  141. Forger F, Marcoli N, Gadika S, Moller B, Villiger PM, Ostensen M: Pregnancy induces numerical and functional changes of $CD4+CD25^{high}$ regulatory T cells in patients with rheumatoid arthritis. Ann Rheum Dis 67;984-990, 2008 https://doi.org/10.1136/ard.2007.075283
  142. Kelchtemans H, Geboes L, Mitera T, Huskens D, Leclercq G, Matthys P: Activated CD4+CD25+ regulatory T cells inhibit osteoclastogenesis and collagen-induced arthritis. Ann Rheum Dis doi:10.1136, 14 May 2008
  143. Radbruch A, Thiel A: Cell therapy for autoimmune diseases: does it have a future? Ann Rheumatic Dis 63(Suppl 2);ii96-ii101, 2004
  144. O'connor RA, Anderton SM: Foxp3+ regulatory T cells in the control of experimental CNS autoimmune disease. J Neuroimmunol 193;1-11, 2008 https://doi.org/10.1016/j.jneuroim.2007.11.016
  145. Que-Gewirth NS, Sullenger BA: Gene therapy progress and prospects: RNA aptamers. Gene Ther 14;283-291, 2007 https://doi.org/10.1038/sj.gt.3302900
  146. Venken K, Hellings N, Broekmans T, Hensen K, Rummens JL, Stinissen P: Natural naive CD4+CD25+ CD127low regulatory T cell (Treg) development and function are disturbed in multiple sclerosis patients: recovery of memory Treg homeostasis during disease progression. J Immunol 180;6411-6420, 2008 https://doi.org/10.4049/jimmunol.180.9.6411
  147. Reynolds AD, Banerjee R, Liu J, Gendelman HE, Mosley RL: Neuroprotective activities of CD4+CD25+ regulatory T cells in an animal model of Parkinson's disease. J Leukoc Biol 82;1083-1094, 2007 https://doi.org/10.1189/jlb.0507296
  148. Karagiannidis C, Akdis M, Holopainen P, Wooley NJ, Hense G, Ruckert B, Mantel PY, Menz G, Akdis CA, Blasser K, Schmidt-Weber CB. Glucoorticoids upregulated FOXP3 expression and regulatory T cells in asthma. J Allergy Clin Immunol 114;1425-1433, 2004 https://doi.org/10.1016/j.jaci.2004.07.014
  149. Proft T, Fraser JD: Bacterial superantigens. Clin Exp Immunol 133;299-306, 2003 https://doi.org/10.1046/j.1365-2249.2003.02203.x
  150. Ou LS, Goleva E, Hall C, Leung DT: T regulatory cells in atopic dermatitis and subversion of their activity by superantigens. J Allergy Clin Immunol 113;756-763, 2004 https://doi.org/10.1016/j.jaci.2004.01.772
  151. Goleva E, Cardona ID, Ou LS, Leung DY.: Factors that regulate naturally occurring T regulatory cell-mediated suppression. J Allergy Clin Immunol 116;1000-1094, 2005 https://doi.org/10.1016/j.jaci.2005.08.011
  152. Feunou P, Vanwetswinkel S, Gaudray F, Goldman M, Matthys P, Braun MY: Foxp3+CD25+T regulatory cells stimulate IFN-gamma-independent CD152-mediated activation of tryptophan catabolisms that provides dendritic cells with immune regulatory activity in mice unresponsive to staphylococcal enterotoxin B. J Immunol 179;910-917, 2007 https://doi.org/10.4049/jimmunol.179.2.910
  153. Battaglia M, StabiliniA, Roncarolo MG: Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood 105;4743-4748, 2005 https://doi.org/10.1182/blood-2004-10-3932
  154. Chin KM, Foss FM: Biologic correlates of response and survival in patients with cutaneous T cell lymphoma treated with denileukin diftitox. Clin Lymphoma Myeloma 7;199-204, 2006 https://doi.org/10.3816/CLM.2006.n.059
  155. Battaglia M, Stabilini A, Migliavacca B, Horejs-Hoeck J, Kaupper T, Roncarolo MG: Rapamycin promotes expansion of functional CD4+CD25+ FOXP3+ regulatory T cells of both healthy subject and type 1 diabetic patients. J Immunol 177;8338-8347, 2006 https://doi.org/10.4049/jimmunol.177.12.8338
  156. Mira E, Leon B, Barber DF, Jimenez-Baranda S, Goya I, Almonacid L, Marquez G, Zaballos A, Martinex-A C, Stein JV, Ardavin C, Manes S: Statins induce regulatory T cell recruitment via CCL1 dependent pathway. J Immunol 181;3524-3534, 2008 https://doi.org/10.4049/jimmunol.181.5.3524