INTRODUCTION: We recently reported that endogenous memory CD8 T cells infiltrate MHC-mismatched cardiac allografts and produce IFN-Γ in response to donor class I MHC molecules within 24 hours after reperfusion in mice. The current studies were conducted to analyze the efficacy of anti-VLA-4 mAb to inhibit this early CD8 T cell allograft infiltration and activation during cardiac allograft rejection.

METHODS: A/J hearts were transplanted into C57BL/6 recipients. Anti-VLA-4 mAb was given on days -1 and 0. Grafts were harvested on day 2 or 7 post-transplant and mRNA encoding inflammatory cytokines was measured by qRT-PCR. Infiltration of CD4,CD8 T-cells, macrophages, and neutrophils was assessed by flow cytometry. Donor-specific T cells producing IFN-Γ and IL-2 were assessed by ELISPOT. The effect of combined blockade of VLA-4 and CD40L on allograft survival in recipients with adoptively transferred donor-primed memory CD8 T cells was also investigated.

RESULTS: Anti-VLA-4 mAb decreased allograft infiltration of CD4, CD8 T cell and macrophages, but not neutrophils, compared to allografts in control IgG treated recipients on day 2 post-transplant and completely inhibited donor-reactive CD4 and CD8 T cell priming to IFN-Γ and IL-2 producing cells in the recipient spleen until day 14. Anti-VLA-4 mAb also significantly reduced intragraft expression levels of CXCL9, CXCL10, and IFN-Γ on day 2 post-transplant. These effects were accompanied by a substantial prolongation in allograft survival (MST:day12.5 vs day7.5 in control-Ig treated recipients, p < 0.01). In allograft recipients with adoptively transferred donor-primed memory CD8 T cells, peritransplant treatment with anti-VLA-4 plus anti-CD154 mAb significantly prolonged allograft survival compared to anti-CD154 mAb treatment alone (MST:day87 vs day60 in anti-CD154 mAb alone treated recipients, p= 0.021).

CONCLUSIONS: Peri-transplant anti-VLA-4 mAb inhibits early infiltration of endogenous memory CD8 T-cells into the allograft and delays donor-reactive T cell priming. Therapeutic targeting of this pathway may reduce the negative impact of early CD8 T cell-dependent inflammatory events during the rejection and when combined with costimulatory blockade is an effective immunosuppression regimen, especially for recipients with high frequencies of donor-specific memory T cells.

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