Blocking the common gamma-chain of cytokine receptors induces T cell apoptosis and long-term islet allograft survival.
The common gammac-chain is an essential signaling component shared by all known T cell growth factor (TCGF) receptors (i.e., IL-2, IL-4, IL-7, IL-9, and IL-15). In the present study, we have studied the effect of gammac-chain blockade on T cell activation and allograft rejection. Treatment of B6AF1 (H-2b/d.k) recipient mice with anti-gammac mAbs induced long-term survival of DBA/2 (H-2d) islet allografts (>150 days, n = 8), whereas control Ab-treated mice rejected the islet allografts within 17 days (n = 6). The state of engraftment induced by the anti-gammac mAbs was remarkably stable, as recipient mice bearing the primary islet allografts accepted a second DBA/2 islet allograft without further immunosuppression and systemic administration of high doses of IL-2Ig fusion protein failed to provoke rejection. Blocking the gammac-chain inhibited T cell proliferation and induced T cell apoptosis by repressing expression of Bcl-2. Our data suggest that one means of inducing T cell apoptosis and stable allograft survival can be achieved via gammac-chain blockade.
Li
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Department of Medicine, Division of Immunology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. xli@caregroup.harvard.edu
Ima
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Li
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Zheng
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Malek
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Strom
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D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology*; D017209:Apoptosis / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000276:immunology*; D019409:Interleukin-15 / Q000378:metabolism / Q000494:pharmacology; D007376:Interleukin-2 / Q000378:metabolism / Q000494:pharmacology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009392:Nephrectomy; D018121:Receptors, Cytokine / Q000037:antagonists & inhibitors* / Q000276:immunology* / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014184:Transplantation, Homologous
D019138:Antibodies, Blocking; D019409:Interleukin-15; D007376:Interleukin-2; D018121:Receptors, Cytokine