Blockade of 4-1BB (CD137)/4-1BB ligand interactions increases allograft survival

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Abstract
We investigated the role of 4‐1BB, a T cell co‐stimulatory molecule, in alloimmune responses. In vivo mixed lymphocyte reactions showed that 4‐1BB was preferentially expressed on actively dividing CD4+ and CD8+ T cells. Furthermore, following alloantigen challenge, the draining lymph nodes contained subpopulations of 4‐1BB‐expressing CD4+ and CD8+ T cells. 4‐1BB‐deficient C57BL/6 mice showed a delayed rejection of cardiac transplants mismatched for the major histocompatibility complex. Longer transplant survival was induced by blockade of 4‐1BB/4‐1BB ligand (4‐1BBL) interactions using an anti‐4‐1BBL monoclonal antibody. Histological analysis showed that prolonged transplant survival in the 4‐1BB‐deficient and anti‐4‐1BBL‐treated mice correlated with reduced lymphocytic infiltration and vasculitis in the donor heart tissue. Taken together, our data suggest that blockade of 4‐1BB/4‐1BBL interactions inhibited the expansion of alloreactive T cells and reduced CTL activity against host alloantigen, which in turn resulted in the prolongation of allograft survival. Blockade of the 4‐1BB co‐stimulatory pathway may be useful for preventing allograft rejection.

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