Purpose: Our goal was to determine the efficacy and immune mechanisms of costimulation blockade by CTLA-4Ig when treatment begins after an immune response is already established.

Methods: C57BL/6 mice were given heart transplants from BALB/c donors, and treated with CTLA-4Ig starting 6d post-transplant. Mice were monitored for graft survival and grafts were examined histologically. Additionally, splenocytes were examined for endogenous donor MHC Class I (H-2K^d)-reactive germinal center (GC) B cells, and CD4 and CD8⁺ T cells producing IFNγ in response to stimulus by BALB/c antigen presenting cells.

Results: In C57BL/6 recipients of BALB/c hearts, a delayed start in CTLA-4Ig treatment 6d post-transplant (just 2 days before complete cessation of heart beat) inhibited alloantibody production and prevented acute rejection. 10 of 15 grafts survived to ≥ 30d post-transplant, despite significant T cell infiltration and C4d deposition in the graft at d6. To understand the mechanism by which CTLA-4Ig rescued heart allografts from acute rejection, we examined endogenous H-2K^d-reactive B cells and observed that CTLA-4Ig starting 6d post-transplant collapsed the germinal center response and reduced the number of H-2K^d-reactive GC B cells to levels comparable to naïve mice. Furthermore, surviving grafts examined on d30 post-transplant had reduced C4d deposition compared to d6 allografts, when CTLA-4Ig treatment was initiated. Delayed CTLA-4Ig treatment had no significant effect on the alloreactive CD4⁺ IFNγ⁺ response compared to untreated controls, but prevented the increase in the CD8⁺ IFNγ⁺ response that occurred in untreated recipients between d6 and d14 post-transplant.

Conclusions: Once rejection is initiated, halting the immune response becomes more difficult and effective therapies are necessary. While there is extensive evidence that CTLA-4Ig is ineffective at inducing tolerance in recipients with high frequencies of donor-specific memory T cells, we here report that CTLA-4Ig is unexpectedly effective at controlling established B cell responses and treating already established acute rejection. Taken together, the reversal of graft-specific B cell responses and the blunting of CD8⁺IFNγ⁺ T cell responses may independently contribute to the efficacy of delayed CTLA-4Ig at treating acute rejection.

CITATION INFORMATION: Young J, Chen J, Yin D, Sciammas R, Vu V, Alegre M.-L, Chong A. Successful Treatment of Established Acute Allograft Rejection with Delayed CTLA-4Ig. Am J Transplant. 2016;16 (suppl 3).

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