title: Antigen exposure during enhanced CTLA-4 expression promotes allograft tolerance in vivo.
abstract: The role of CTLA-4 in tolerance is primarily inferred from knockout and blocking studies. Anti-CD45RB mediates allograft tolerance in mice by inducing CTLA-4 expression on CD4 cells, providing a novel opportunity to determine how therapeutic enhancement of CTLA-4 promotes tolerance. We now show that induced CTLA-4 expression normally resolves by day 17. Although thymectomy prolongs enhanced CTLA-4 expression, long-term engraftment is unaffected. To address the temporal relationship between increased CTLA-4 expression and engraftment, transplantation was delayed for various times after anti-CD45RB treatment. Delaying transplantation for 7 days (when CTLA-4 expression had peaked but treatment mAb was no longer detectable), resulted in long-term engraftment comparable to transplantation with no delay (day 0). Delaying transplantation from 10 to 18 days led to a progressively poorer outcome as CTLA-4 expression returned to baseline. This suggested that Ag exposure while CTLA-4 expression is enhanced is sufficient to induce long-term engraftment. To substantiate this, on day 0, anti-CD45RB-treated mice received BALB/c vs unrelated alloantigen, followed by transplantation of BALB/c islets 10 days later. Whereas recipients exposed to unrelated Ag experienced acute rejection, recipients exposed to donor Ag achieved long-term engraftment. Anti-CD45RB-treated mice exposed to alloantigen exhibited anergic CD4(+)CD25(-) effector cells and regulatory CD4(+)CD25(+) cells. Moreover, CD25 depletion in the peritransplant period prevented anti-CD45RB-mediated engraftment. Thus, exposure of CD4 cells expressing CTLA-4 to donor Ag is necessary and sufficient to induce long-term engraftment which appears to be mediated by both regulation and anergy.
authors.affiliation: Department of Surgery, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Paolo R O
authors.initials: PR
authors.lastname: Salvalaggio
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Camirand
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Ariyan
authors.forename: Songyan
authors.initials: S
authors.lastname: Deng
authors.forename: Linda
authors.initials: L
authors.lastname: Rogozinski
authors.forename: Giacomo P
authors.initials: GP
authors.lastname: Basadonna
authors.forename: David M
authors.initials: DM
authors.lastname: Rothstein
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000941:Antigens / Q000276:immunology*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism*; D060908:CTLA-4 Antigen; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D017493:Leukocyte Common Antigens / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D013934:Thymectomy; D013997:Time Factors; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D000941:Antigens; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D017493:Leukocyte Common Antigens