Unexpected Efficacy of CTLA-4Ig in Controlling Ongoing Allospecific Responses and Treating Acute Rejection.

Abstract

Once rejection is initiated, halting the immune response becomes much more difficult because of increased frequencies of activated effector and memory alloreactive T and B cells and of plasma cells. Costimulation blockade targeting CD28-B7 and CD40-CD154 interactions is reported to be particularly ineffective at controlling memory T cell and T-dependent B cell responses. Here we report on the unexpected efficacy of CTLA-4Ig in controlling ongoing antibody responses and treating acute rejection. To test the efficacy of CTLA-4Ig at halting ongoing alloimmune response, C57BL/6 mice were sensitized with a subcutaneous injection of BALB/c splenocytes (DST) and treated with biweekly CTLA-4Ig from d0, d7, or d14 post-DST. Without CTLA-4Ig, donor-specific Abs (DSA) were detected on d7 and peaked on d21 post-DST. Delayed treatment with CTLA-4Ig from d7 or d14 post-DST halted the DSA response, and DSA titers tended towards baseline by d42. To test whether delayed CTLA-4Ig prevented development of memory responses, CTLA4-Ig treatment was stopped on d42 and 2 weeks later, the mice were challenged with DST without CTLA4-Ig. Mice receiving d0-42 CTLA-4Ig exhibited no increase in alloantibody production, consistent with tolerance, whereas those receiving d14-42 CTLA-4Ig exhibited recall antibody responses indistinguishable from untreated. Notably, mice receiving d7-42 CTLA-4Ig exhibited a blunted antibody relative to recall as well as to primary response. Finally in a BALB/c into C57BL/6 heart transplantation model, where unmodified rejection occurs on d7-8 post-transplant, biweekly treatment with CTLA4-Ig from 6d post-transplant prevented rejection in 2 of 3 recipients (>42d). A second BALB/c heart transplanted on d21 was also accepted (>21d). These results demonstrate the unexpected efficacy of delayed CTLA4-Ig at halting ongoing alloreactive responses, inhibiting memory formation, facilitating the development of a hyporesponsive state and in treating acute rejection.