Cutting edge: transplantation tolerance through enhanced CTLA-4 expression.
Knockout and blocking studies have shown a critical role for CTLA-4 in peripheral tolerance, however, it is unknown whether augmenting CTLA-4 expression actually promotes tolerance. Here we demonstrate a specific and requisite role for CTLA-4 and its up-regulation in tolerance through anti-CD45RB. First, long-term murine islet allograft survival induced by anti-CD45RB is prevented by CTLA4-Ig, which interferes with B7:CTLA-4 interactions. Second, anti-CD45RB is ineffective in recipients lacking CTLA-4, B7-1, and B7-2. In contrast, CTLA4-Ig, which targets B7 on allogeneic cells, promotes long-term engraftment in these mice. Moreover, anti-CD45RB was effective in B7-deficient controls expressing CTLA-4. Finally, in wild-type mice, CTLA-4 expression returned to baseline 17 days after receiving anti-CD45RB, and was refractory to further increase. Transplantation and anti-CD45RB therapy at this time could neither augment CTLA-4 nor prolong engraftment. These data demonstrate a specific role for CTLA-4 in anti-CD45RB-mediated tolerance and indicate that CTLA-4 up-regulation can directly promote allograft survival.
Ariyan
Charlotte
C
Department of Surgery, Yale Medical School, New Haven, CT 06520, USA.
Salvalaggio
Paolo
P
Fecteau
Scott
S
Deng
Songyan
S
Rogozinski
Linda
L
Mandelbrot
Didier
D
Sharpe
Arlene
A
Sayegh
Mohamed H
MH
Basadonna
Giacomo P
GP
Rothstein
David M
DM
D000069594:Abatacept; D000276:Adjuvants, Immunologic / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D060908:CTLA-4 Antigen; D006082:Graft Enhancement, Immunologic / Q000379:methods; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D018796:Immunoconjugates / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D016381:Islets of Langerhans Transplantation / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D023001:Transplantation Tolerance / Q000235:genetics / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D000069594:Abatacept; D017493:Leukocyte Common Antigens