*Purpose: Intra-graft inflammation initiated by ischemia-reperfusion injury (IRI) is an unavoidable consequence of transplantation surgery and constitutes a key source of alloimmune responses. IRI leads to activation of intra-graft dendritic cells (DCs), which in turn promote alloreactive T cell responses and enhance chronic alloimmune injury. Cellular senescence has been commonly associated with chronic inflammation, following sustained exposure to stress inducers, such as proinflammatory cytokines. Senescence also induces additional phenotypic alterations in the cells, including increased proinflammatory secretome referred to as the senescence-associated secretory phenotype, which can contribute significantly to tissue damage. Here, we hypothesize that prevention of senescence in intra-graft DCs will reduce chronic allograft rejection by suppressing the production of pro-inflammatory cytokines and chemokines.

*Methods: We generated CD11c^Cre x p16^fl/fl mice, in which the key senescence gene p16 is deficient specifically in DCs, and hearts were transplanted from either these mice or wild-type (WT) C57BL/6 mice into BM12 mice. Then, we compared the survival of cardiac allografts transplanted from either CD11c^Cre x p16^fl/fl mice or WT C57BL/6 mice into BALB/c mice treated with a low dose of the costimulatory blockade agent CTLA4-Ig.

*Results: We observed significantly less rejection, as indicated by lower cellular infiltrates and vascular injury in the BM12 recipients of CD11c^Cre x p16^fl/fl hearts than C57BL/6 WT hearts. Immunofluorescent staining of these heart grafts revealed lower infiltration of CD3⁺ T cells and CD11b⁺ cells in the CD11c^Cre x p16 group than the C57BL/6 WT group. The grafts from the CD11c^Cre x p16^fl/fl mice also had less evidence of chronic rejection than the WT C57BL/6 grafts, as indicated by less extensive fibronectin staining. Treatment with low-dose CTLA4-Ig resulted in longer survival in the BALB/c recipients of CD11c^Cre x p16^fl/fl hearts than WT C57BL/6 hearts (median survival time >80 days vs 68 days, respectively).

*Conclusions: These data indicate the importance of senescence in DCs of the allograft to the propagation of the pro-inflammatory intra-graft immune response following transplantation and chronic reaction, and they set the stage for therapeutic trials of senescence inhibitor administration to the grafts prior to their placement in the recipient.

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