Endogenous memory CD8 T cells infiltrate MHC-mismatched cardiac allografts within 24 hrs after graft reperfusion in mice. Our recent studies indicate that prolonged cold ischemic graft storage provokes intense inflammation within hours after allograft reperfusion and promotes endogenous memory CD8 T cell rejection of the allograft. The current studies tested anti-VLA-4 mAb inhibition of this early CD8 T cell infiltration and activation in such higher risk allografts. Syngeneic or A/J (H-2^a) hearts were subjected to 8 hrs of cold ischemic storage in University of Wisconsin solution and then transplanted to C57BL/6 (H-2^b) mice. Anti-VLA-4 mAb (250 ug) was given on days -1 and 0. Grafts were harvested on day 2 and T cell, macrophage, and neutrophil infiltration into allografts was assessed by flow cytometry and immunohistochemistry. mRNA encoding inflammatory cytokines was measured by qRT-PCR from total graft homogenates. Peritransplant anti-VLA-4 mAb markedly decreased day 2 post-transplant infiltration of CD4 and CD8 T cell and macrophage, but not neutrophil, into the higher risk allografts to the levels observed in isografts and was accompanied by significant decreases in expression of genes encoding macrophage and T cell chemoattractant cytokines, but had little/no effect on expression of neutrophil chemokines. Anti-VLA-4 mAb also significantly reduced intragraft expression levels of TNF-α, CXCL9, CXCL10, and IFN-γ on day 2 post-transplant. Pre-transplant anti-CD4 mAb depletion of recipient CD4 T cells improved survival of higher risk cardiac allografts from day 7-8 to day 18-42 and peri-transplant treatment with anti-VLA-4 mAb pushed this increased survival further to day 65-75 post-transplant. Peritransplant treatment with anti-VLA-4 plus anti-CD154 mAb significantly prolonged higher risk allograft survival compared to anti-CD154 mAb treatment alone (MST: day 36 vs day 91; p < 0.02). These data indicate that peritransplant VLA-4 blockade inhibits early infiltration of endogenous memory CD8 T cell infiltration into higher risk cardiac allografts and the accompanying inflammation. Therapeutic targeting of this pathway may reduce the negative impact of early CD8 T cell-dependent inflammatory events in such higher risk allografts andimprove graft outcomeswhen combined with costimulatory blockade strategies.

CITATION INFORMATION: Miyairi S., Iida S., Tsuda H., Baldwin III W., Tanabe K., Fairchild R. VLA-4 Blockade Inhibits Early Endogenous Memory CD8 T Cell Infiltration into Higher Risk Cardiac Allografts and Donor-Reactive T Cell Priming Am J Transplant. 2017;17 (suppl 3).

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