T-CELL ALTERATIONS IN CARDIAC ALLOGRAFT RECIPIENTS AFTER B7 (CD80 ANDCD86) BLOCKADE

Background. T-cell activation requires engagement of the T cell recept or with the antigen-MHC and simultaneous ligation of the coreceptor CD 28, CD28 binds both the CD80 (B7-1) and CD86 (B7-2) ligands on antigen -presenting cells, The functional role of these costimulatory pathways in transplantation is not completely understood, We tested the hypoth esis that in vivo blockade of the CD28 pathway via the anti-CD80 and a nti-CD86 monoclonal antibodies (mAbs) would prolong allograft survival . Methods. Neonatal C57BL/6J (H2(b)) hearts were transplanted to CBA/J (H2(k)) recipients in a heterotopic nonvascularized model, with anti- CD80 and/or anti-CD86 mAbs being administered intravenously at the tim e of allografting (day 0) and on the following day (day 1), Results. A nti-CD80 mAb (29.8+/-1.5 days) and anti-CD86 mAb (30.8+/-0.5 days) alo ne significantly prolonged allograft survival compared with the isotyp e control (10.7+/-0.4 days, P<0.01, Wilcoxon rank sum). The concurrent (days 0 and 1) and sequential administration of anti-CD86 mAb on days 0 and 1 plus anti-CD80 mAb on days 2 and 3 prolonged allograft surviv al to >80 days. Simultaneous administration of anti-CD80 and anti-CD86 mAbs significantly suppressed donor-specific cytotoxic T lymphocyte r esponses to alloantigen, Anti-CD86 mAb suppressed intragraft interleuk in (IL)-4, IL-10, IL-12 p40, and IL-15 mRNA expression. Conclusions. A nti-CD80 and/or anti-CD86 mAbs are potent immunosuppressants in prolon ging allograft survival. Combined blockade of the B7 (CD80 and CD86) l igands seems to be the most effective in prolonging allograft survival and suppressing donor-specific allogeneic cytotoxic T lymphocyte resp onses. In vivo blockade of CD86, in comparison to CD80, had the greate st immunosuppressive effect on day 7 intragraft cytokines, suggesting its role on early allogeneic immune responses.