CTLA-4Ig: Uses and future directions

Recent Patents on Inflammation and Allergy Drug Discovery

Volumn 3, Issue 2, 2009, Pages 132-142

  Ben Shoshan, Moshe ^a,b  

^a MCGILL UNIVERSITY HEALTH CENTRE   (Canada)

^b NONE   (Canada)

Author keywords

Abatacept; CD 152; CTLA 4; CTLA 4Ig

Indexed keywords

ABATACEPT; B7 ANTIGEN; BELATACEPT; CALCINEURIN INHIBITOR; CORTICOSTEROID; CYCLOPHOSPHAMIDE; CYCLOSPORIN; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; DISEASE MODIFYING ANTIRHEUMATIC DRUG; HYDROXYCHLOROQUINE; INFLIXIMAB; LEFLUNOMIDE; METHOTREXATE; PLACEBO; TUMOR NECROSIS FACTOR ALPHA INHIBITOR; ANTIBODY CONJUGATE; ANTIRHEUMATIC AGENT; CD28 ANTIGEN; CD86 ANTIGEN; CYTOTOXIC T-LYMPHOCYTE ANTIGEN 4; HYBRID PROTEIN; IMMUNOSUPPRESSIVE AGENT; LEUKOCYTE ANTIGEN;

ACUTE GRAFT REJECTION; ADVANCED CANCER; ALLERGIC ASTHMA; ALLOGRAFT; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ARTICLE; AUTOIMMUNE DISEASE; AUTOIMMUNE THYROIDITIS; AUTOIMMUNITY; BINDING COMPETITION; CHRONIC OBSTRUCTIVE LUNG DISEASE; CLINICAL TRIAL; COLON ADENOMA; COMORBIDITY; COUGHING; CYTOKINE PRODUCTION; DEMYELINATING DISEASE; DIABETES MELLITUS; DIZZINESS; DRUG DOSE COMPARISON; DRUG EFFICACY; DRUG FATALITY; DRUG HYPERSENSITIVITY; DRUG INDUCED HEADACHE; DRUG MECHANISM; DRUG POTENTIATION; DRUG SAFETY; DRUG STRUCTURE; DRUG SUBSTITUTION; DRUG TREATMENT FAILURE; DRUG WITHDRAWAL; DYSPNEA; FOOD ALLERGY; GRAFT SURVIVAL; HEART ARREST; HUMAN; IMMUNOGENICITY; IMMUNOMODULATION; IMMUNOPATHOGENESIS; IMMUNOREGULATION; IMMUNOSUPPRESSIVE TREATMENT; INTESTINE ISCHEMIA; KERATOCONJUNCTIVITIS SICCA; LUPUS ERYTHEMATOSUS NEPHRITIS; LYMPHOCYTE ACTIVATION; MAJOR HISTOCOMPATIBILITY COMPLEX; MELANOMA; MULTIPLE SCLEROSIS; MUSCULOSKELETAL DISEASE; NONHUMAN; NOSE CONGESTION; ONSET AGE; OPPORTUNISTIC INFECTION; PRIORITY JOURNAL; PSORIASIS; RHEUMATOID ARTHRITIS; RISK REDUCTION; SKIN CARCINOMA; SQUAMOUS CELL CARCINOMA; SYSTEMIC LUPUS ERYTHEMATOSUS; TUBERCULOSIS; UNSPECIFIED SIDE EFFECT; UPPER RESPIRATORY TRACT INFECTION; VASCULITIS; ANIMAL; HYPERSENSITIVITY; IMMUNOLOGY; METABOLISM; NEOPLASM; T LYMPHOCYTE SUBPOPULATION;

ANIMALS; ANTIGENS, CD; ANTIGENS, CD28; ANTIGENS, CD80; ANTIGENS, CD86; ANTIRHEUMATIC AGENTS; AUTOIMMUNE DISEASES; CLINICAL TRIALS AS TOPIC; HUMANS; HYPERSENSITIVITY; IMMUNOCONJUGATES; IMMUNOSUPPRESSIVE AGENTS; LYMPHOCYTE ACTIVATION; NEOPLASMS; RECOMBINANT FUSION PROTEINS; T-LYMPHOCYTE SUBSETS;

EID: 68949176952     PISSN: 1872213X     EISSN: None     Source Type: Journal    
DOI: 10.2174/187221309788489760     Document Type: Article

References (144)

1. Brandle D, Muller S, Muller C, Hengartner H, Pircher H. Regulation of RAG-1 and CD69 expression in the thymus during positive and negative selection. Eur J Immunol 1994; 24(1): 145-151.
2. Starr TK, Jameson SC, Hogquist KA. Positive and negative selection of T cells. Annu Rev Immunol 2003; 21: 139-176.
3. Ashton-Rickardt PG, Van Kaer L, Schumacher TN, Ploegh HL, Tonegawa S. Peptide contributes to the specificity of positive selection of CD8+ T cells in the thymus. Cell 1993; 73(5): 1041-1049.
4. Germain RN. T-cell development and the CD4-CD8 lineage decision. Nat Rev Immunol 2002; 2(5): 309-322.
5. Kisielow P, Bluthmann H, Staerz UD, Steinmetz M, von Boehmer H. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature 1988; 333(6175): 742-746.
6. Lindh E, Lind SM, Lindmark E, et al. AIRE regulates T-cell-independent B-cell responses through BAFF. Proc Natl Acad Sci USA 2008; 105(47): 18466-18471.
7. Pontynen N, Strengell M, Sillanpaa N, et al. Critical immunological pathways are downregulated in APECED patient dendritic cells. J Mol Med 2008; 86(10): 1139-1152.
8. Bouneaud C, Kourilsky P, Bousso P. Impact of negative selection on the T cell repertoire reactive to a self-peptide: A large fraction of T cell clones escapes clonal deletion. Immunity 2000; 13(6): 829-840.
9. Allen S, Read S, DiPaolo R, et al. Promiscuous thymic expression of an autoantigen gene does not result in negative selection of pathogenic T cells. J Immunol 2005; 175(9): 5759-5764.
10. Abbas AK, Lohr J, Knoechel B, Nagabhushanam V. T cell tolerance and autoimmunity. Autoimmun Rev 2004; 3(7-8): 471-475.
11. Abbas AK, Perez VL, Van Parijs L, Wong RC. Differentiation and tolerance of CD4+ T lymphocytes. Ciba Found Symp 1995; 195: 7-13.
12. Barron L, Knoechel B, Lohr J, Abbas AK. Cutting edge: Contributions of apoptosis and anergy to systemic T cell tolerance. J Immunol 2008; 180(5): 2762-2766.
13. Alferink J, Tafuri A, Vestweber D, Hallmann R, Hammerling GJ, Arnold B. Control of neonatal tolerance to tissue antigens by peripheral T cell trafficking. Science 1998; 282(5392): 1338-1341.
14. Jenkins MK, Schwartz RH. Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J Exp Med 1987; 165(2): 302-319.
15. Mellor AL, Munn DH. IDO expression by dendritic cells: Tolerance and tryptophan catabolism. Nat Rev Immunol 2004; 4(10): 762-774.
16. Lechner O, Lauber J, Franzke A, Sarukhan A, von Boehmer H, Buer J. Fingerprints of anergic T cells. Curr Biol 2001; 11(8): 587-595.
17. Perez VL, Van Parijs L, Biuckians A, Zheng XX, Strom TB, Abbas AK. Induction of peripheral T cell tolerance in vivo requires CTLA-4 engagement. Immunity 1997; 6(4): 411-417.
18. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multi organ tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 1995; 3(5): 541-547.
19. Ueda H, Howson JM, Esposito L, et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 2003; 423(6939): 506-511.
20. Margalit M, Ilan Y. Induction of immune tolerance: A role for Natural killer T lymphocytes? Liver Int 2005; 25(3): 501-504.
21. Parekh VV, Lalani S, Kim S, et al. PD-1/PD-L blockade prevents anergy induction and enhances the anti-tumor activities of glycolipid-activated invariant NKT cells. J Immunol 2009; 182(5): 2816-26.
22. Coutinho A, Hori S, Carvalho T, Caramalho I, Demengeot J. Regulatory T cells: The physiology of auto reactivity in dominant tolerance and "quality control" of immune responses. Immunol Rev 2001; 182: 89-98.
23. Bach JF. Regulatory T cells under scrutiny. Nat Rev Immunol 2003; 3(3): 189-198.
24. Sakaguchi S, Sakaguchi N. Regulatory T cells in immunologic self-tolerance and autoimmune disease. Int Rev Immunol 2005; 24(3-4): 211-226.
25. Sakaguchi S, Toda M, Asano M, Itoh M, Morse SS, Sakaguchi N. T cell-mediated maintenance of natural self-tolerance: Its breakdown as a possible cause of various autoimmune diseases. J Autoimmun 1996; 9(2): 211-220.
26. Shevach EM. CD4+ CD25+ suppressor T cells: More questions than answers. Nat Rev Immunol 2002; 2(6): 389-400.
27. Bala KK, Moudgil KD. Induction and maintenance of self tolerance: The role of CD4+CD25+ regulatory T cells. Arch Immunol Ther Exp (Warsz) 2006; 54(5): 307-321.
28. Weiner HL, Friedman A, Miller A, et al. Oral tolerance: Immunologic mechanisms and treatment of animal and human organ-specific autoimmune diseases by oral administration of autoantigens. Annu Rev Immunol 1994; 12: 809-837.
29. Groux H, O'Garra A, Bigler M, et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 1997; 389(6652): 737-742.
30. Roncarolo MG, Bacchetta R, Bordignon C, Narula S, Levings MK. Type 1 T regulatory cells. Immunol Rev 2001; 182: 68-79.
31. Veldman C, Nagel A, Hertl M. Type I regulatory T cells in autoimmunity and inflammatory diseases. Int Arch Allergy Immunol 2006; 140(2): 174-183.
32. Bacchetta R, Gregori S, Roncarolo MG. CD4+ regulatory T cells: Mechanisms of induction and effector function. Autoimmun Rev 2005; 4(8): 491-496.
33. Karim M, Kingsley CI, Bushell AR, Sawitzki BS, Wood KJ. Alloantigen-induced CD25+CD4+ regulatory T cells can develop in vivo from CD25-CD4+ precursors in a thymus-independent process. J Immunol 2004; 172(2): 923-928.
34. Papiernik M, de Moraes ML, Pontoux C, Vasseur F, Penit C. Regulatory CD4 T cells: Expression of IL-2R alpha chain, resistance to clonal deletion and IL-2 dependency. Int Immunol 1998; 10(4): 371-378.
35. Apostolou I, Sarukhan A, Klein L, von Boehmer H. Origin of regulatory T cells with known specificity for antigen. Nat Immunol 2002; 3(8): 756-763.
36. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor FOXP3. Science 2003; 299(5609): 1057-1061.
37. Kolar P, Knieke K, Hegel JK, et al. CTLA-4 (CD152) controls homeostasis and suppressive capacity of regulatory T cells in mice. Arthritis Rheum 2009; 60(1): 123-132.
38. Schmidt EM, Wang CJ, Ryan GA, et al. CTLA-4 controls regulatory T cell peripheral homeostasis and is required for suppression of pancreatic islet autoimmunity. J Immunol 2009; 182(1): 274-282.
39. Flores-Borja F, Jury EC, Mauri C, Ehrenstein MR. Defects in CTLA-4 are associated with abnormal regulatory T cell function in rheumatoid arthritis. Proc Natl Acad Sci USA 2008; 105(49): 19396-19401.
40. Fisher GH, Rosenberg FJ, Straus SE, et al. Dominant interfering FAS gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 1995; 81(6): 935-946.
41. Carreno BM, Collins M. The B7 family of ligands and its receptors: New pathways for costimulation and inhibition of immune responses. Annu Rev Immunol 2002; 20: 29-53.
42. Riley JL, June CH. The CD28 family: A T-cell rheostat for therapeutic control of T-cell activation. Blood 2005; 105(1): 13-21.
43. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol 2005; 23: 515-548.
44. Carreno BM, Carter LL, Collins M. Therapeutic opportunities in the B7/ CD28 family of ligands and receptors. Curr Opin Pharmacol 2005; 5(4): 424-430.
45. Carter L, Fouser LA, Jussif J, et al. PD-1: PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2. Eur J Immunol 2002; 32(3): 634-643.
46. Carter LL, Leach MW, Azoitei ML, et al. PD-1/PD-L1, but not PD-1/ PD-L2, interactions regulate the severity of experimental autoimmune encephalomyelitis. J Neuroimmunol 2007; 182(1-2): 124-134.
47. Carter LL, Carreno BM. Cytotoxic T-lymphocyte antigen-4 and programmed death-1 function as negative regulators of lymphocyte activation. Immunol Res 2003; 28(1): 49-59.
48. Golshayan D, Buhler L, Lechler RI, Pascual M. From current immunosuppressive strategies to clinical tolerance of allografts. Transpl Int 2007; 20(1): 12-24.
49. Guntermann C, Alexander DR. CTLA-4 suppresses proximal TCR signaling in resting human CD4(+) T cells by inhibiting ZAP-70 Tyr(319) phosphorylation: A potential role for tyrosine phosphatases. J Immunol 2002; 168(9): 4420-4429.
50. Brunner MC, Chambers CA, Chan FK, Hanke J, Winoto A, Allison JP. CTLA-4-mediated inhibition of early events of T cell proliferation. J Immunol 1999; 162(10): 5813-5820.
51. Walunas TL, Lenschow DJ, Bakker CY, et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1994; 1(5): 405-413.
52. Leung HT, Bradshaw J, Cleaveland JS, Linsley PS. Cytotoxic T lymphocyte-associated molecule-4, a high-avidity receptor for CD80 and CD86, contains an intracellular localization motif in its cytoplasmic tail. J Biol Chem 1995; 270(42): 25107-25114.
53. Chuang CW, Cheng MT, Yang SJ, Hwang JC. Activation of ventrolateral medulla neurons by arginine vasopressin via V1A receptors produces inhibition on respiratory-related hypoglossal nerve discharge in the rat. Chin J Physiol 2005; 48(3): 144-154.
54. Bradshaw JD, Lu P, Leytze G, et al. Interaction of the cytoplasmic tail of CTLA-4 (CD152) with a clathrin-associated protein is negatively regulated by tyrosine phosphorylation. Biochemistry 1997; 36(50): 15975-15982.
55. Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med 1991; 174(3): 561-569.
56. Bandyopadhyay G, De A, Laudanski K, et al. Negative signaling contributes to T-cell anergy in trauma patients. Crit Care Med 2007; 35(3): 794-801.
57. Greenwald RJ, Oosterwegel MA, van der WD, et al. CTLA-4 regulates cell cycle progression during a primary immune response. Eur J Immunol 2002; 32(2): 366-373.
58. Schneider H, Valk E, Leung R, Rudd CE. CTLA-4 activation of phosphatidylinositol 3-kinase (PI 3-K) and protein kinase B (PKB/AKT) sustains T-cell energy without cell death. PLoS ONE 2008; 3(12): e3842.
59. Vanasek TL, Khoruts A, Zell T, Mueller DL. Antagonistic roles for CTLA-4 and the mammalian target of rapamycin in the regulation of clonal anergy: Enhanced cell cycle progression promotes recall antigen responsiveness. J Immunol 2001; 167(10): 5636-5644.
60. Egen JG, Allison JP. Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity 2002; 16(1): 23-35.
61. Egen JG, Kuhns MS, Allison JP. CTLA-4: New insights into its biological function and use in tumor immunotherapy. Nat Immunol 2002; 3(7): 611-618.
62. Prasad DV, Richards S, Mai XM, Dong C. B7S1, a novel B7 family member that negatively regulates T cell activation. Immunity 2003; 18(6): 863-873.
63. Sica GL, Choi IH, Zhu G, et al. B7-H4, a molecule of the B7 family, negatively regulates T cell immunity. Immunity 2003; 18(6): 849-861.
64. Zang X, Loke P, Kim J, Murphy K, Waitz R, Allison JP. B7x: A widely expressed B7 family member that inhibits T cell activation. Proc Natl Acad Sci USA 2003; 100(18): 10388-10392.
65. Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev 2008; 224: 166-182.
66. Vanderlugt CL, Karandikar NJ, Lenschow DJ, Dal Canto MC, Bluestone JA, Miller SD. Treatment with intact anti-B7-1 mAb during disease remission enhances epitope spreading and exacerbates relapses in R-EAE. J Neuroimmunol 1997; 79(2): 113-118.
67. Luhder F, Hoglund P, Allison JP, Benoist C, Mathis D. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) regulates the unfolding of autoimmune diabetes. J Exp Med 1998; 187(3): 427-432.
68. O'Day SJ, Hamid O, Urba WJ. Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4): A novel strategy for the treatment of melanoma and other malignancies. Cancer 2007; 110(12): 2614-27
69. Di Giacomo AM, Danielli R, Guidoboni M, et al. Therapeutic efficacy of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with metastatic melanoma unresponsive to prior systemic treatments: clinical and immunological evidence from three patient cases. Cancer Immunol Immunother 2009. Jan 13. [Epub ahead of print]
70. Bluestone JA, St Clair EW, Turka LA. CTLA4Ig: Bridging the basic immunology with clinical application. Immunity 2006; 24(3): 233-238.
71. Lakkis FG, Konieczny BT, Saleem S, et al. Blocking the CD28-B7 T cell costimulation pathway induces long term cardiac allograft acceptance in the absence of IL-4. J Immunol 1997; 158(5): 2443-2448.
72. Finck BK, Linsley PS, Wofsy D. Treatment of murine lupus with CTLA4Ig. Science 1994; 265(5176): 1225-1227.
73. Li Y, Li XC, Zheng XX, Wells AD, Turka LA, Strom TB. Blocking both signal 1 and signal 2 of T-cell activation prevents apoptosis of alloreactive T cells and induction of peripheral allograft tolerance. Nat Med 1999; 5(11): 1298-1302.
74. Wells AD, Li XC, Li Y, et al. Requirement for T-cell apoptosis in the induction of peripheral transplantation tolerance. Nat Med 1999; 5(11): 1303-1307.
75. Alegre ML, Fallarino F. Mechanisms of CTLA-4-Ig in tolerance induction. Curr Pharm Des 2006; 12(2): 149-160.
76. Dumont FJ. Technology evaluation: abatacept, bristol-myers squibb. Curr Opin Mol Ther 2004; 6(3): 318-330.
77. Buch MH, Vital EM, Emery P. Abatacept in the treatment of rheumatoid arthritis. Arthritis Res Ther 2008; 10 (Suppl 1): S5.
78. Furst DE, Keystone EC, Kirkham B, et al. Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2008. Ann Rheum Dis 2008; 67 (Suppl 3): iii2-25.
79. Flores-Borja F, Mauri C, Ehrenstein MR. Restoring the balance: Harnessing regulatory T cells for therapy in rheumatoid arthritis. Eur J Immunol 2008; 38(4): 934-937.
80. Abrams JR, Lebwohl MG, Guzzo CA, et al. CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris. J Clin Invest 1999; 103(9): 1243-1252.
81. Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 2008; 59(6): 762-784.
82. Fan PT, Leong KH. The use of biological agents in the treatment of rheumatoid arthritis. Ann Acad Med Singapore 2007; 36(2): 128-134.
83. Moreland LW, Alten R, Van den BF, et al. Costimulatory blockade in patients with rheumatoid arthritis: A pilot, dose-finding, doubleblind, placebo-controlled clinical trial evaluating CTLA-4Ig and LEA29Y eighty-five days after the first infusion. Arthritis Rheum 2002; 46(6): 1470-1479.
84. Kremer JM, Westhovens R, Leon M, et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med 2003; 349(20): 1907-1915.
85. Kremer JM, Dougados M, Emery P, et al. Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: Twelve-month results of a phase II B, double-blind, randomized, placebo-controlled trial. Arthritis Rheum 2005; 52(8): 2263-2271.
86. Weinblatt M, Schiff M, Goldman A, et al. Selective costimulation modulation using abatacept in patients with active rheumatoid arthritis while receiving etanercept: A randomised clinical trial. Ann Rheum Dis 2007; 66(2): 228-234.
87. Kremer JM, Genant HK, Moreland LW, et al. Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: A randomized trial. Ann Intern Med 2006; 144(12): 865-876.
88. Schiff M, Keiserman M, Codding C, et al. Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: A phase III, multicentre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis 2008; 67(8): 1096-1103.
89. Genovese MC, Becker JC, Schiff M, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med 2005; 353(11): 1114-1123.
90. Schiff MH, Pritchard C, Huffstutter JE, et al. The 6-month safety and efficacy of abatacept in patients with rheumatoid arthritis who underwent a washout after anti-TNF therapy or were directly switched to abatacept: The ARRIVE trial. Ann Rheum Dis 2008; doi: 10.1136/ ard.2008.099218.
91. Einarsdottir E, Soderstrom I, Lofgren-Burstrom A, et al. The CTLA4 region as a general autoimmunity factor: An extended pedigree provides evidence for synergy with the HLA locus in the etiology of type 1 diabetes mellitus, Hashimoto's thyroiditis and Graves' disease. Eur J Hum Genet 2003; 11(1): 81-84.
92. You S, Alyanakian MA, Segovia B, et al. Immunoregulatory pathways controlling progression of autoimmunity in NOD mice. Ann N Y Acad Sci 2008; 1150: 300-310.
93. Balic I, Angel B, Codner E, Carrasco E, Perez-Bravo F. Association of CTLA-4 polymorphisms and clinical-immunologic characteristics at onset of type 1 diabetes mellitus in children. Hum Immunol 2009; 70(2): 116-120.
94. Tomer Y. Genetic dissection of familial autoimmune thyroid diseases using whole genome screening. Autoimmun Rev 2002; 1(4): 198-204.
95. Khalilzadeh O, Mojazi AH, Tahvildari M, et al. Pretibial myxedema is associated with polymorphism in exon 1 of CTLA-4 gene in patients with Graves' ophthalmopathy. Arch Dermatol Res 2008; Nov. 17.
96. Hudson LL, Rocca K, Song YW, Pandey JP. CTLA-4 gene polymorphisms in systemic lupus erythematosus: A highly significant association with a determinant in the promoter region. Hum Genet 2002; 111(4-5): 452-455.
97. Davidson A, Diamond B, Wofsy D, Daikh D. Block and tackle: CTLA4Ig takes on lupus. Lupus 2005; 14(3): 197-203.
98. Schiffer L, Sinha J, Wang X, et al. Short term administration of costimulatory blockade and cyclophosphamide induces remission of systemic lupus erythematosus nephritis in NZB/W F1 mice by a mechanism downstream of renal immune complex deposition. J Immunol 2003; 171(1): 489-497.
99. Aran AA, Putterman C. Treatment of lupus nephritis: Facing the era of immunotherapy. Panminerva Med 2008; 50(3): 235-245.
100. Dooley MA, Falk RJ. Human clinical trials in lupus nephritis. Semin Nephrol 2007; 27(1): 115-127.
101. Gould DS, Auchincloss H Jr. Direct and indirect recognition: The role of MHC antigens in graft rejection. Immunol Today 1999; 20(2): 77-82.
102. Rogers NJ, Lechler RI. Allorecognition. Am J Transplant 2001; 1(2): 97-102.
103. Jiang S, Herrera O, Lechler RI. New spectrum of allorecognition pathways: Implications for graft rejection and transplantation tolerance. Curr Opin Immunol 2004; 16(5): 550-557.
104. Liu Z, Sun YK, Xi YP, et al. Contribution of direct and indirect recognition pathways to T cell alloreactivity. J Exp Med 1993; 177(6): 1643-1650.
105. Auchincloss H Jr, Lee R, Shea S, Markowitz JS, Glimcher LH. The role of "indirect" recognition in initiating rejection of skin grafts from major histocompatibility complex class II-deficient mice. Proc Natl Acad Sci USA 1993; 90(8): 3373-3377.
106. Baker RJ, Hernandez-Fuentes MP, Brookes PA, Chaudhry AN, Lechler RI. The role of the allograft in the induction of donor-specific T cell hyporesponsiveness. Transplantation 2001; 72(3): 480-485.
107. Golshayan D, Lechler R. Commentary: Priming of alloreactive T cells-where does it happen? Eur J Immunol 2004; 34(12): 3301-3304.
108. Mason PD, Robinson CM, Lechler RI. Detection of donor-specific hyporesponsiveness following late failure of human renal allografts. Kidney Int 1996; 50(3): 1019-1025.
109. Frasca L, Amendola A, Hornick P, et al. Role of donor and recipient antigen-presenting cells in priming and maintaining T cells with indirect allospecificity. Transplantation 1998; 66(9): 1238-1243.
110. Vella JP, Spadafora-Ferreira M, Murphy B, et al. Indirect allorecognition of major histocompatibility complex allopeptides in human renal transplant recipients with chronic graft dysfunction. Transplantation 1997; 64(6): 795-800.
111. Hernandez-Fuentes MP, Lechler RI. Chronic graft loss. Immunological and non-immunological factors. Contrib Nephrol 2005; 146: 54-64.
112. Pascual M, Theruvath T, Kawai T, Tolkoff-Rubin N, Cosimi AB. Strategies to improve long-term outcomes after renal transplantation. N Engl J Med 2002; 346(8): 580-590.
113. Sayegh MH, Turka LA. The role of T-cell costimulatory activation pathways in transplant rejection. N Engl J Med 1998; 338(25): 1813-1821.
114. Zheng XX, Sanchez-Fueyo A, Sho M, Domenig C, Sayegh MH, Strom TB. Favorably tipping the balance between cytopathic and regulatory T cells to create transplantation tolerance. Immunity 2003; 19(4): 503-514.
115. Bluestone JA, Liu W, Yabu JM, et al. The effect of costimulatory and interleukin 2 receptor blockade on regulatory T cells in renal transplantation. Am J Transplant 2008; 8(10): 2086-2096.
116. Levisetti MG, Padrid PA, Szot GL, et al. Immunosuppressive effects of human CTLA4Ig in a non-human primate model of allogeneic pancreatic islet transplantation. J Immunol 1997; 159(11): 5187-5191.
117. Larsen CP, Pearson TC, Adams AB, et al. Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am J Transplant 2005; 5(3): 443-453.
118. Adams AB, Shirasugi N, Durham MM, et al. Calcineurin inhibitor-free CD28 blockade-based protocol protects allogeneic islets in nonhuman primates. Diabetes 2002; 51(2): 265-270.
119. Vincenti F, Larsen C, Durrbach A, et al. Costimulation blockade with belatacept in renal transplantation. N Engl J Med 2005; 353(8): 770-781.
120. Guo L, Fujino M, Kimura H, et al. Simultaneous blockade of costimulatory signals, CD28 and ICOS, induced a stable tolerance in rat heart transplantation. Transpl Immunol 2003; 12(1): 41-48.
121. Lee SY, Lee YH, Shin C, et al. Association of asthma severity and bronchial hyperresponsiveness with a polymorphism in the cytotoxic T-lymphocyte antigen-4 gene. Chest 2002; 122(1): 171-176.
122. Rutkowski R, Stasiak-Barmuta A, Moniuszko T, et al. CD28 and CTLA-4 costimulatory molecules expression on T lymphocytes and NK cells in nonallergic bronchial asthma. Pol Merkur Lekarski 2006; 20(116): 139-144.
123. Wan H, Zhou M, Xu Q, Huang S, Deng W. The role of CTLA4-Ig in a mouse model against allergic asthma. Chin Med J (Engl) 2003; 116(3): 462-464.
124. van Wijk F, Nierkens S, de Jong W, et al. The CD28/CTLA-4-B7 signaling pathway is involved in both allergic sensitization and tolerance induction to orally administered peanut proteins. J Immunol 2007; 178(11): 6894-6900.
125. Weinblatt M, Combe B, Covucci A, Aranda R, Becker JC, Keystone E. Safety of the selective costimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease-modifying antirheumatic drugs: A one-year randomized, placebo-controlled study. Arthritis Rheum 2006; 54(9): 2807-2816.
126. Furst DE. The risk of infections with biologic therapies for rheumatoid arthritis. Semin Arthritis Rheum 2008.
127. Liu Z, Liu Q, Pesce J, et al. Requirements for the development of IL-4-producing T cells during intestinal nematode infections: What it takes to make a Th2 cell in vivo. Immunol Rev 2004; 201: 57-74.
128. Lu P, Zhou X, Chen SJ, et al. CTLA-4 ligands are required to induce an in vivo interleukin 4 response to a gastrointestinal nematode parasite. J Exp Med 1994; 180(2): 693-698.
129. Lepenies B, Jacobs T. The role of negative costimulators during parasitic infections. Endocr Metab Immune Disord Drug Targets 2008; 8(4): 279-288.
130. Haggerty HG, Abbott MA, Reilly TP, et al. Evaluation of immunogenicity of the T cell costimulation modulator abatacept in patients treated for rheumatoid arthritis. J Rheumatol 2007; 34(12): 2365-2373.
131. Huang D, Liu L, Noren K, et al. Genetic association of CTLA-4 to myasthenia gravis with thymoma. J Neuroimmunol 1998; 88(1-2): 192-198.
132. Wang XB, Kakoulidou M, Qiu Q, et al. CDS1 and promoter single nucleotide polymorphisms of the CTLA-4 gene in human myasthenia gravis. Genes Immun 2002; 3(1): 46-49.
133. Alizadeh M, Babron MC, Birebent B, et al. Genetic interaction of CTLA-4 with HLA-DR15 in multiple sclerosis patients. Ann Neurol 2003; 54(1): 119-122.
134. Ligers A, Xu C, Saarinen S, Hillert J, Olerup O. The CTLA-4 gene is associated with multiple sclerosis. J Neuroimmunol 1999; 97(1-2): 182-190.
135. Slot MC, Sokolowska MG, Savelkouls KG, Janssen RG, Damoiseaux JG, Cohen TJW. Immunoregulatory gene polymorphisms are associated with ANCA-related vasculitis. Clin Immunol 2008; 128(1): 39-45.
136. Gunesacar R, Erken E, Bozkurt B, et al. Analysis of CD28 and CTLA-4 gene polymorphisms in Turkish patients with Behcet's disease. Int J Immunogenet 2007; 34(1): 45-49.
137. Zhou Y, Huang D, Paris PL, Sauter CS, Prock KA, Hoffman GS. An analysis of CTLA-4 and proinflammatory cytokine genes in Wegener's granulomatosis. Arthritis Rheum 2004; 50(8): 2645-2650.
138. Huang D, Giscombe R, Zhou Y, Lefvert AK. Polymorphisms in CTLA-4 but not tumor necrosis factor-alpha or interleukin 1beta genes are associated with Wegener's granulomatosis. J Rheumatol 2000; 27(2): 397-401.
139. Choi JM, Kim SH, Shin JH, et al. Transduction of the cytoplasmic domain of CTLA-4 inhibits TcR-specific activation signals and prevents collagen-induced arthritis. Proc Natl Acad Sci USA 2008; 105(50): 19875-19880.
140. Peach, R.J., Naemura, J.R., Linsley, P.S., Bajorath, J.: US20067094874 (2006).
141. Anderson, D.R., Hanna, N., Brams, P.: US20077175847 (2007).
142. Hwang KW, Sweatt WB, Brown IE, et al. Cutting edge: targeted ligation of CTLA-4 in vivo by membrane-bound anti-CTLA-4 antibody prevents rejection of allogeneic cells. J Immunol 2002: 169: 633-663.
143. Collisson, E.W., Choi, I., Winslow, B., Cochran, M.D.: US20060188925 (2006).
144. Collisson, E.W., Choi, I., Winslow, B., Cochran, M.D., Hash, S.M.: US20080145382 (2008).