Despite recent evidence of improved graft outcomes and safety, high incidence of early acute cellular rejection with belatacept has limited its use in clinical transplantation. Experimental and clinical data suggest that belatacept-resistant rejection may be due to the incomplete control of memory donor-reactive T cells. We tested this hypothesis using an experimental model where C57BL/6 mice sensitized to BALB/c splenocytes harbored elevated numbers of endogenous donor-specific memory T cells and increased alloantibodies compared to naïve recipients. Approximately 60% of sensitized recipients experienced CTLA4-Ig-resistant graft rejection by day 30 post-transplantation, and 30% of grafts survived for >60 days post-transplantation. Continuous CTLA4-Ig treatment from the time of transplantation of BALB/c heart allograft was unexpectedly efficacious at inhibiting endogenous graft-reactive T cell expansion D30 post transplantation, but was not able to inhibit late CD4⁺ and CD8⁺ T cell accumulation into the allografts. However, when CTLA4-Ig was used in combination with the sphingosine 1-phosphate receptor-1 (S1PR1) functional antagonist, FTY720, it was found that alloantibody production was inhibited, late T cell recruitment into the graft was restrained, and graft survival was improved with combination therapy (10 of 12 survived >30 days post-transplantation). Notably, the frequencies of donor-specific IFNg-producing T cells in the recipients treated with FTY720 plus CTLA4-Ig were significantly reduced compared to monotherapy groups, and approached frequencies observed in tolerant non-sensitized recipients. Thus, a rationally designed combinatorial strategy with CTLA4-Ig plus FTY720, that is able to inhibit memory T cell expansion and trafficking into the allograft, respectively, not only promotes long-term allograft survival but may also serve as a novel T cell desensitizing protocol to reduce the frequency of donor-reactive T cells in allosensitized recipients to levels that are lower than that observed in pre-transplant.

CITATION INFORMATION: Khiew S, Yang J, Young J, Chen J, Wang Q, Ying D, Vu V, Miller M, Sciammas R, Alegre M.-L, Chong A. CTLA4-Ig in Combination with FTY720 Reduces the Frequency of Memory Alloreactive T Cells and Promotes Heart Allograft Survival in Sensitized Recipients. Am J Transplant. 2017;17 (suppl 3).

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