CD3-specific antibody-induced active tolerance: From bench to bedside

Nature Reviews Immunology

Volumn 3, Issue 2, 2003, Pages 123-132

  Chatenoud, Lucienne ^a  

^a BICHAT HOSPITAL   (France)

Author keywords

[No Author keywords available]

Indexed keywords

CD4 ANTIGEN; IMMUNOSUPPRESSIVE AGENT; INTERLEUKIN 2 RECEPTOR; MONOCLONAL ANTIBODY CD3; OKT 3; TRANSFORMING GROWTH FACTOR BETA; CD3 ANTIGEN;

ALLOGRAFT; ANIMAL CELL; ANTIBODY SPECIFICITY; AUTOIMMUNE DISEASE; CELL FUNCTION; COMPLEX FORMATION; DIABETES MELLITUS; GENETIC ENGINEERING; GRAFT REJECTION; HUMAN; HUMAN CELL; IMMUNOLOGICAL TOLERANCE; LYMPHOCYTE CULTURE; MOUSE; NONHUMAN; PANCREAS ISLET BETA CELL; PRIORITY JOURNAL; REVIEW; T LYMPHOCYTE ACTIVATION; TARGET CELL; TISSUE SPECIFICITY; ANIMAL; BIOLOGICAL MODEL; GENETICS; IMMUNOLOGY; INSULIN DEPENDENT DIABETES MELLITUS; LYMPHOCYTE ACTIVATION; NONOBESE DIABETIC MOUSE; PROTEIN ENGINEERING; T LYMPHOCYTE SUBPOPULATION;

ANIMALS; ANTIGENS, CD3; DIABETES MELLITUS, TYPE 1; HUMANS; IMMUNE TOLERANCE; IMMUNOSUPPRESSIVE AGENTS; LYMPHOCYTE ACTIVATION; MICE; MICE, INBRED NOD; MODELS, IMMUNOLOGICAL; MUROMONAB-CD3; PROTEIN ENGINEERING; T-LYMPHOCYTE SUBSETS;

EID: 0037313086     PISSN: 14741733     EISSN: None     Source Type: Journal    
DOI: 10.1038/nri1000     Document Type: Review

References (117)

1. Kung, P., Goldstein, G., Reinherz, E. L. & Schlossman, S. F. Monoclonal antibodies defining distinctive human T-cell surface antigens, Science 206, 347-349 (1979).
2. Cosimi, A. B. et al. Use of monoclonal antibodies to T-cell subsets for immunologic monitoring and treatment in recipients of renal allografts. N. Engl. J. Med. 305, 308-314 (1981). The first pilot clinical trial to indicate that OKT3 can reverse ongoing renal-allograft rejection.
3. Cosimi, A. B. et al. Treatment of acute renal allograft rejection with OKT3 monoclonal antibody. Transplantation 32, 535-539 (1981).
4. Clevers, H., Alarcon, B., Wileman, T. & Terhorst, C. The T-cell receptor/CD3 complex: a dynamic protein ensemble. Annu. Rev. Immunol. 6, 629-662 (1988).
5. Davis, M. M. & Chien, Y. H. in Fundamental Immunology (ed. Paul, W. E.) 341-366 (Raven Press, New York, 1999).
6. Ortho Multicenter Transplant Study Group. A randomized clinical trial of OKT3 monoclonal antibody for acute rejection, of cadaveric renal transplants. N. Engl. J. Med. 313, 337-342 (1985). The first randomized, multi-centre trial to show the clinical effectiveness of OKT3 as an immunosuppressant in renal transplantation.
7. Vigeral, P. et al. Prophylactic use of OKT3 monoclonal antibody in cadaver kidney recipients. Utilization of OKT3 as the sole immunosuppressive agent. Transplantation 41, 730-733 (1986).
8. Debure, A. et al. One-month prophylactic use of OKT3 in cadaver kidney transplant recipients Transplantation 45, 546-553 (1988).
9. Frey, D. J. et al. Sequential therapy - a prospective randomized trial of MALG versus OKT3 for prophylactic immunosuppression in cadaver renal allograft recipients. Transplantation 54, 50-56 (1992).
10. Abramowicz, D. et al. The long-term effects of prophylactic OKT3 monoclonal antibody in cadaver kidney transplantation - a single-center, prospective, randomized study. Transplantation 54, 433-437 (1992).
11. Woodle, E. S. et al. OKT3 therapy for hepatic allograft rejection. Differential response in adults and children. Transplantation 51, 1207-1212 (1991).
12. Gilbert, E. M. et al. Treatment of refractory cardiac allograft rejection with OKT3 monoclonal antibody. Am. J. Med. 82, 202-206 (1987).
13. Farges, O. et al. A randomized trial of OKT3-based versus cyclosporine-based immunoprophylaxis after liver transplantation. Long-term results of a European and Australian multicenter study. Transplantation 58, 891-898 (1994).
14. Millis, J. M. et al. Randomized prospective trial of OKT3 for early prophylaxis of rejection after liver transplantation. Transplantation 47, 82-88 (1989).
15. Robbins, R. C., Oyer, P. E., Stinson, E. B. & Starnes, V. A. The use of monoclonal antibodies after heart transplantation. Transplant. Sci. 2, 22-27 (1992).
16. Deeb, G. M. et al. A randomized prospective comparison of MALG with OKT3 for rescue therapy of acute myocardial rejection, Transplantation 51, 180-183 (1991).
17. Goldstein, G., Kremer, A. B., Barnes, L. & Hirsch, R. L. OKT3 monoclonal antibody reversal of renal and hepatic rejection in pediatric patients. J. Pediatr. 111, 1046-1050 (1987).
18. Niaudet, P., Jean, G., Broyer, M. & Chatenoud, L. Anti-OKT3 response following prophylactic treatment in paediatric kidney transplant recipients. Pediatr. Nephrol. 7, 263-267 (1993).
19. Leone, M. R. et al. Monoclonal antibody OKT3 therapy in pediatric kidney transplant recipients J. Pediatr. 116, S86-S91 (1990).
20. Broyer, M. et al. Prophylactic OKT3 monoclonal antibody versus antilymphocyte globulins: a prospective, randomized study in 148 first cadaver kidney grafts. Transplant. Proc. 25, 570-571 (1993).
21. Chatenoud, L. et al. Human in vivo antigenic modulation induced by the anti-T-cell OKT3 monoclonal antibody. Eur. J. Immunol. 12, 979-982 (1982). The first demonstration that T-cell receptor down-modulation is an important mode of action of OKT3.
22. Chatenoud, L. et al. Restriction of the human in vivo immune response against the mouse monoclonal antibody OKT3 J. Immunol. 137, 830-838 (1986). The first detailed analysis of the fine specificity of the humoral response that is elicited in patients after injection of OKT3. Human antibodies are directed exclusively against isotypic and idiotypic determinants of the xenogeneic antibody molecule. Only idiotype-specific antibodies are neutralizing.
23. Leo, O., Foo, M., Sachs, D. H., Samelson, L. E. & Bluestone, J. A. Identification of a monoclonal antibody specific for a murine T3 polypeptide. Proc. Natl Acad. Sci. USA 84, 1374-1378 (1987)
24. Hirsch, R., Eckhaus, M., Auchincloss, H. Jr. Sachs, D. H. & Bluestone, J. A. Effects of in vivo administration of anti-T3 monoclonal antibody on T-cell function in mice. I. Immunosuppression of transplantation responses. J. Immunol. 140, 3766-3772 (1988).
25. 2 fragments in vivo to modulate graft-versus-host disease without loss of graft-versus-leukemia reactivity after MHC-matched bone-marrow transplantation J. Immunol. 154, 5542-5554 (1995).
26. Hughes, C., Wolos, J. A., Giannini, E. H. & Hirsch, R. Induction of T-helper cell hyporesponsiveness in an experimental model of autoimmunity by using nonmitogenic anti-CD3 monoclonal antibody. J. Immunol. 153, 3319-3325 (1994).
27. Herold, K. C. et al. Prevention of autoimmune diabetes with nonactivating anti-CD3 monoclonal antibody. Diabetes 41, 385-391 (1992).
28. Chatenoud, L., Thervet, E., Primo, J. & Bach, J. F. Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Proc. Natl Acad. Sci. USA 91, 123-127 (1994). The first report to show that a short treatment with CD3-specific antibodies restores self-tolerance, thereby inducing stable remission of established diabetes in non-obese diabetic (NOD) mice.
29. Nooij, F. J. & Jonker, M. The effect on skin allograft survival of a monoclonal antibody specific for a polymorphic CD3-like cell-surface molecule in rhesus monkeys. Eur. J. Immunol. 17, 1089-1093 (1987).
30. H2 cytokines not anergy. Transplantation 67, 605-613 (1999).
31. Chatenoud, L., Primo, J. & Bach, J. F. CD3 antibody-induced dominant self-tolerance in overtly diabetic NOD mice J. Immunol. 158, 2947-2954 (1997).
32. 2 fragments induce a selective T-helper dysfunction. J. Immunol. 147, 2088-2093 (1991).
33. Isaacs, J. D., Clark, M. R., Greenwood, J. & Waldmann, H. Therapy with monoclonal antibodies. An in vivo model for the assessment of therapeutic potential. J. Immunol. 148, 3062-3071 (1992).
34. + T-cell subsets with bispecific monoclonal antibodies: evidence for inter-T-cell-mediated cytolysis. Clin. Immunol. Immunopathol. 58, 236-250 (1991).
35. Jung, G., Martin, D. E. & Muller Eberhard, H. J. Induction of cytotoxicity in human peripheral-blood mononuclear cells by monoclonal antibody OKT3. J. Immunol. 139, 639-644 (1987).
36. Spits, H., Yssel, H., Leeuwenberg, J. & de Vries, J. E. Antigen-specific cytotoxic T-cell and antigen-specific proliferating T-cell clones can be induced to cytolytic activity by monoclonal antibodies against T3. Eur. J. Immunol. 15, 88-91 (1985).
37. Wesselborg, S., Janssen, O. & Kabelitz, D. Induction of activation-driven death (apoptosis) in activated but not resting peripheral-blood T cells. J. Immunol. 150, 4338-4346 (1993).
38. Janssen, O., Wesselborg, S. & Kabelitz, D. Immunosuppression by OKT3 - induction of programmed cell death (apoptosis) as a possible mechanism of action. Transplantation 53, 233-234 (1992).
39. Carpenter, P. A. et al. Non-Fc-receptor-binding humanized anti-CD3 antibodies induce apoptosis of activated human T cells. J. Immunol. 165, 6205-6213 (2000).
40. Chatenoud, L. & Bach, J. F. Antigenic modulation: a major mechanism of antibody action. Immunol. Today 5, 20-26 (1984).
41. Caillat-Zucman, S. et al. The OKT3 immunosuppressive effect. In situ antigenic modulation of human graft-infiltrating T cells Transplantation 49, 156-160 (1990).
42. Woodle, E. S. et al. 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 (1999).
43. Friend, P. J. et al. Phase I study of an engineered aglycosylated humanized CD3 antibody in renal transplant rejection. Transplantation 68, 1632-1637 (1999). References 42 and 43 describe pilot studies in renal-allograft recipients to test the safety of the two engineered, humanized, non-mitogenic CD3-specific monoclonal antibodies that are available at present for clinical use.
44. Hirsch, R., Gress, R. E., Pluznik, D. H., Eckhaus, M. & Bluestone, J. A. Effects of in vivo administration of anti-CD3 monoclonal antibody on T-cell function in mice. II. In vivo activation of T cells. J. Immunol. 142, 737-743 (1989).
45. Abbs, I. C. et al. Sparing of first dose effect of monovalent anti-CD3 antibody used in allograft rejection is associated with diminished release of pro-inflammatory cytokines. Therapeut. Immunol. 1, 325-331 (1994).
46. Routledge, E. G., Lloyd, I., Gorman, S. D., Clark, M. & Waldmann, H. A humanized monovalent CD3 antibody which can activate homologous complement. Eur. J. Immunol. 21, 2717-2725 (1991).
47. Goldstein, G. Overview of the development of Orthoclone OKT3: monoclonal antibody for therapeutic use in transplantation. Transplant. Proc. 19, 1-6 (1987).
48. Abramowicz, D., Crusiaux, A. & Goldman, M. Anaphylactic shock after retreatment with OKT3 monoclonal antibody. N. Engl. J. Med. 327, 736 (1992).
49. Baudrihaye, M. F., Chatenoud, L., Kreis, H., Goldstein, G. & Bach, J. F. Unusually restricted anti-isotype human immune response to OKT3 monoclonal antibody. Eur. J. Immunol. 14, 686-691 (1984).
50. Jonker, M. & Den Brok, J. H. Idiotype switching of CD4-specific monoclonal antibodies can prolong the therapeutic effectiveness in spite of host anti-mouse IgG antibodies. Eur. J. Immunol. 17, 1547-1553 (1987).
51. Chatenoud, L., Jonker, M., Villemain, F., Goldstein, G. & Bach, J. F. The human immune response to the OKT3 monoclonal antibody is oligoclonal. Science 232, 1406-1408 (1986). The first demonstration of the oligoclonality of the human (and monkey) immune response to xenogeneic T-cell-specific monoclonal antibodies in general, and to OKT3 in particular.
52. Hricik, D. E., Mayes, J. T. & Schulak, J. A. Inhibition of anti-OKT3 antibody generation by cyclosporine - results of a prospective randomized trial. Transplantation 50, 237-240 (1990).
53. Lazarovits, A. I. et al. Human mouse chimeric CD7 monoclonal antibody (SDZCHH380) for the prophylaxis of kidney transplant rejection J. Immunol. 150, 5163-5174 (1993).
54. Vincenti, F. et al. Interleukin-2-receptor blockade with daclizumab to prevent acute rejection in renal transplantation. Daclizumab Triple Therapy Study Group. N. Engl. J. Med. 338, 161-165 (1998).
55. Nashan, B. et al. Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients. CHIB 201 International Study Group. Lancet 350, 1193-1198 (1997).
56. Maini, R. N. et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor-α monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum. 41, 1552-1563 (1998).
57. Herold, K. C. et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N. Engl. J. Med 346, 1692-1698 (2002). The first report of a pilot clinical study using a humanized, non-mitogenic CD3-specific antibody in overt autoimmunity (insulin-dependent diabetes mellitus).
58. Utset, T. O. et al. Modified anti-CD3 therapy in psoriatic arthritis: a phase I/II clinical trial. J. Rheumatol. 29, 1907-1913 (2002).
59. Elliott, M. J. et al. Repeated therapy with monoclonal antibody to tumour-necrosis factor-α (cA2) in patients with rheumatoid arthritis. Lancet 344, 1125-1127 (1994).
60. Routledge, E. G., Falconer, M. E., Pope, H., Lloyd, I. S. & Waldmann, H. The effect of aglycosylation on the immunogenicity of a humanized therapeutic CD3 monoclonal antibody. Transplantation 60, 847-853 (1995).
61. Alegre, M. L. et al. An anti-murine CD3 monoclonal antibody with a low affinity for Fcγ receptors suppresses transplantation responses while minimizing acute toxicity and immunogenicity. J. Immunol. 155, 1544-1555 (1995).
62. Van Wauwe, J. P., de Mey, J. R. & Goossens, J. G. OKT3: a monoclonal anti-human T-lymphocyte antibody with potent mitogenic properties. J. Immunol. 124, 2708-2713 (1980).
63. Van Lier, R. A., Boot, J. H., de Groot, E. R., & Aarden, L. A., Induction of T-cell proliferation with anti-CD3 switch-variant monoclonal antibodies: effects of heavy chain isotype in monocyte-dependent systems. Eur. J. Immunol. 17, 1599-1604 (1987).
64. Chatenoud, L. et al. Systemic reaction to the anti-T-cell monoclonal antibody OKT3 in relation to serum levels of tumor-necrosis factor and interferon-γ. N. Engl. J. Med 320, 1420-1421 (1989).
65. Abramowicz, D. et al. Release of tumor-necrosis factor, interleukin-2, and γ-interferon in serum after injection of OKT3 monoclonal antibody in kidney transplant recipients. Transplantation 47, 606-608 (1989).
66. Ferran, C. et al. Cytokine-related syndrome following injection of anti-CD3 monoclonal antibody: further evidence for transient in vivo T-cell activation. Eur. J. Immunol. 20, 509-515 (1990).
67. Alegre, M. et al. Hypothermia and hypoglycemia induced by anti-CD3 monoclonal antibody in mice: role of tumor-necrosis factor. Eur. J. Immunol. 20, 707-710 (1990).
68. Ferran, C. et al. Anti-tumor-necrosis factor modulates anti-CD3-triggered T-cell cytokine gene expression in vivo. J. Clin. Invest. 93, 2189-2196 (1994).
69. Durez, P. et al. In vivo induction of interleukin-10 by anti-CD3 monoclonal antibody or bacterial lipopolysaccharide: differential modulation by cyclosporin A. J. Exp. Med. 177, 551-555 (1993).
70. Yoshimoto, T. & Paul, W. E. CD4pos, NK1.1pos T cells promptly produce interleukin-4 in response to in vivo challenge with anti-CD3. J. Exp. Med. 179, 1285-1295 (1994).
71. Ferran, C. et al. Inter-mouse strain differences in the in vivo anti-CD3-induced cytokine release. Clin. Exp. Immunol. 88, 537-543 (1991).
72. Ferran, C. et al. Cascade modulation by anti-tumor necrosis factor monoclonal antibody of interferon-γ, interleukin-3 and interleukin-6 release after triggering of the CD3/T-cell receptor activation pathway. Eur. J. Immunol. 21, 2349-2353 (1991).
73. Chatenoud, L., Legendre, C., Kurrle, R., Kreis, H. & Bach, J. F. Absence of clinical symptoms following the first injection of anti-T-cell receptor monoclonal antibody (BMA 031) despite isolated TNF release. Transplantation 55, 443-445 (1993).
74. Charpentier, B. et al. Evidence that antihuman tumor-necrosis factor monoclonal antibody prevents OKT3-induced acute syndrome. Transplantation 54, 997-1002 (1992).
75. 2 fragments are immunosuppressive in vivo without evoking either the strong humoral response or morbidity associated with whole mAb. Transplantation 49, 1117-1123 (1990).
76. Woodle, E. S. et al. Anti-CD3 monoclonal antibody therapy. An approach toward optimization by in vitro analysis of new anti-CD3 antibodies. Transplantation 52, 361-368 (1991).
77. Parlevliet, K. J. et al. In vivo effects of IgA and IgG2a anti-CD3 isotype switch variants. J. Clin. Invest. 93, 2519-2525 (1994).
78. Bolt, S. et al The generation of a humanized, non-mitogenic CD3 monoclonal antibody which retains in vitro immunosuppressive properties. Eur. J. Immunol. 23, 403-411 (1993).
79. Alegre, M. L. et al. A non-activating 'humanized' anti-CD3 monoclonal antibody retains immunosuppressive properties in vivo. Transplantation 57, 1537-1543 (1994). References 78 and 79 characterize the two engineered, humanized, non-mitogenic CD3-specific monoclonal antibodies that are available at present for clinical use.
80. Chatenoud, L., Legendre, C., Ferran, C., Bach, J. F. & Kreis, H. Corticosteroid inhibition of the OkT3-induced cytokine-related syndrome - dosage and kinetics prerequisites, Transplantation 51, 334-338 (1991).
81. Riechmann, L., Clark, M., Waldmann, H. & Winter, G. Reshaping human antibodies for therapy. Nature 332, 323-327 (1988).
82. Monaco, A. P., Wood, M. L. & Russell, P. S. Studies on heterologous antilymphocyte serum in mice. III. Immunological tolerance and chimerism produced across the H2-locus with adult thymectomy and antilymphocyte serum. Ann. NY Acad. Sci. 129, 190-209 (1966).
83. Wood, M. L., Monaco, A. P., Gozzo, J. J. & Liegeois, A. Use of homozygous allogeneic bone marrow for induction of tolerance with antilymphocyte serum: dose and timing. Transplant. Proc. 3, 676-679 (1971).
84. Benjamin, R. J. & Waldmann, H. Induction of tolerance by monoclonal antibody therapy. Nature 320, 449-451 (1986).
85. Gutstein, N. L., Seaman, W. E., Scott, J. H. & Wofsy, D. Induction of immune tolerance by administration of monoclonal antibody to L3T4. J. Immunol. 137, 1127-1132 (1986).
86. Pearson, T. C., Madsen J. C., Larsen C. P., Morris, P. J., & Wood, K. J. Induction of transplantation tolerance in adults using donor antigen and anti-CD4 monoclonal antibody. Transplantation 54, 475-483 (1992).
87. Shizuru, J. A., Taylor-Edwards, C., Banks, B. A., Gregory, A. K. & Fathman, C. G. Immunotherapy of the nonobese diabetic mouse: treatment with an antibody to T-helper lymphocytes. Science 240, 659-662 (1988).
88. Qin, S. X., Cobbold, S., Benjamin, R. & Waldmann, H. Induction of classical transplantation tolerance in the adult. J. Exp. Med. 169, 779-794 (1989).
89. Qin, S. et al. 'Infectious' transplantation tolerance. Science 259, 974-977 (1993).
90. Larsen, C. P. et al. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature 381, 434-438 (1996).
91. Lenschow, D. J. et al. Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4lg. Science 257, 789-792 (1992).
92. Lakkis, F. G. et al. Blocking the CD28-B7 T-cell costimulation pathway induces long-term cardiac allograft acceptance in the absence of IL-4. J. Immunol. 158, 2443-2448 (1997).
93. Kirk, A. D. et al. Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates, Nature Med. 5, 686-693 (1999).
94. Nicolls, M. R. et al. Induction of long-term specific tolerance to allografts in rats by therapy with an anti-CD3-like monoclonal antibody. Transplantation 55. 459-468 (1993). The first demonstration of the tolerogenic properties of CD3-specific antibodies in a cardiac-allograft rat transplant model.
95. H subsets. J. Immunol. 160, 4841-4849 (1998).
96. Oldstone, M. B., Nerenberg, M., Southern, P., Price, J. & Lewicki, H. Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune response. Cell 65, 319-331 (1991).
97. Von Herrath, M. G., Dockter, J. & Oldstone, M. B. How virus induces a rapid or slow onset insulin-dependent diabetes mellitus in a transgenic model. Immunity 1, 231-242 (1994).
98. Ohashi, R. S. et al. Ablation of 'tolerance' and induction of diabetes by virus infection in viral antigen transgenic mice. Cell 65, 305-317 (1991).
99. Seewaldt, S. et al. Virus-induced autoimmune diabetes: most β-cells die through inflammatory cytokines and not perforin from autoreactive (anti-viral) cytotoxic T-lymphocytes. Diabetes 49, 1801-1809 (2000).
100. Von Herrath, M. G., Coon, B., Wolfe, T. & Chatenoud, L. Nonmitogenic CD3 antibody reverses virally induced (rat insulin promoter-lymphocytic choriomeningitis virus) autoimmune diabetes without impeding viral clearance. J. Immunol. 168, 933-941 (2002).
101. Askenase, P. W., Hayden, B., J. & Gershon, R. K. Augmentation of delayed-type hypersensitivity by doses of cyclophosphamide which do not affect antibody responses. J. Exp. Med. 141, 697-702 (1975).
102. Miyazaki, C., Nakamura, T., Kaneko, K., Mori, R. & Shibasaki, H. Reinduction of experimental allergic encephalomyelitis in convalescent Lewis rats With cyclophosphamide. J. Neurol. Sci. 67, 277-284 (1985).
103. Kardys, E. & Hashim, G. A. Experimental allergic encephalomyelitis in Lewis rats: immunoregulation of disease by a single amino-acid substitution in the disease-inducing determinant. J. Immunol. 127, 862-866 (1981).
104. Asano, M., Toda, M., Sakaguchi, N. & Sakaguchi, S. Autoimmune disease as a consequence of developmental abnormality of a T-cell subpopulation. J. Exp. Med. 184, 387-396 (1996).
105. + naturedly anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J. Immunol. 162, 5317-5326 (1999).
106. Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases, J. Immunol. 155, 1151-1164 (1995).
107. Sakaguchi, S., Takahashi, T. & Nishizuka, V. Study on cellular events in postthymectomy autoimmune oophoritis in mice. I. Requirement of Lyt-1 effector cells for oocytes damage after adoptive transfer. J. Exp. Med. 156, 1565-1576 (1982).
108. Suri-Payer, E., Kehn, P. J., Cheever, A. W. & Shevach, E. M. Pathogenesis of post-thymectomy autoimmune gastritis. Identification of anti-H/ K adenosine triphosphatase-reactive T cells. J. Immunol. 157, 1799-1805 (1996).
109. +, T cells inhibit both the induction and effector function of autoreactive T cells and represent a unique lineage of immunoregulatory cells. J. Immunol. 160, 1212-1218 (1998).
110. + regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J. Exp. Med. 192, 303-310 (2000).
111. + immunoregulatory T cells that control autoimmune diabetes. Immunity 12, 431-440 (2000).
112. Ludviksson, B. R., Ehrhardt, R. O., & Strober, W. TGF-β production regulates the development of the 2,4,6-trinitrophenol-Conjugated keyhole limpet hemocyanin-induced colonic inflammation in IL-2-deficient mice. J. Immunol. 159, 3622-3628 (1997).
113. Smith, J. A., Tso, J. Y., Clark, M. R., Cole, M. S. & Bluestone, J. A. Nonmitogenic anti-CD3 monoclonal antibodies deliver a partial T-cell receptor signal and induce clonal energy. J. Exp. Med. 185, 1413-1422 (1997).
114. Chau, L. A., Tso, J. Y., Melrose, J. & Madrenas, J. HuM291 (Nuvion), a humanized Fc-receptor-non-binding antibody against CD3, anergizes peripheral-blood T cells as partial agonist of T-cell receptor. Transplantation 71, 941-950 (2001).
115. Bank, I. & Chess, L. Perturbation of the T4 molecule transmits a negative signal to T cells. J. Exp. Med. 162. 1294-1303 (1985).
116. Jabado, N. et al. CD4 ligands inhibit the formation of multifunctional transduction complexes involved in T-cell activation J. Immunol. 158, 94-103 (1997).
117. Jauliac, S. et al. Ligands of CD4 inhibit the association of phospholipase Cγ1 with phosphoinositide 3-kinase in T cells: regulation of this association by the phosphoinositide 3-kinase activity. Eur. J. Immunol. 28, 3183-3191 (1998).