Endogenous memory CD8 T cells infiltrate cardiac allografts within 24 hours of reperfusion and are activated to proliferate and produce IFN-γ in response to donor class І MHC. Endogenous memory CD8 T cells directly reject cardiac allografts subjected to prolonged cold ischemic storage (PCIS). The efficacy of anti-VLA-4 mAb in inhibiting endogenous memory CD8 T cell mediated rejection of cardiac allografts subjected to PCIS was tested. Anti-VLA-4 mAb (200 ¯o;g) given on days -1 and 0 to C57BL6 (H-2b) recipients of AJ (H-2a) heart grafts subjected to 0.5 or 8 hours of cold ischemic storage completely inhibited CD8 T cell allograft infiltration, significantly reduced intragraft expression levels of IFN-γ- induced genes and prolonged allograft survival from day 8 to 14. Peri-transplant anti-CD40L mAb extended survival of allografts subjected to PCIS to days 40-48 post-transplant and addition of peri-transplant anti-VLA-4 mAb extended survival to > 100 days. Thus peri-transplant anti-VLA-4 mAb inhibits endogenous memory CD8 T-cell infiltration into allografts subjected to PCIS and enhances the efficacy of costimulatory blockade. Targeting of VLA-4 will reduce the negative impact of early memory CD8 T cell-dependent inflammatory events on graft outcome that will be particularly important for recipients with high frequencies of donor-reactive memory CD8 T cells.

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