PDL1 is required for peripheral transplantation tolerance and protection from chronic allograft rejection

K Tanaka, MJ Albin, X Yuan, K Yamaura… - The Journal of …, 2007 - journals.aai.org
K Tanaka, MJ Albin, X Yuan, K Yamaura, A Habicht, T Murayama, M Grimm, AM Waaga
The Journal of Immunology, 2007journals.aai.org
The PD-1: PDL pathway plays an important role in regulating alloimmune responses but its
role in transplantation tolerance is unknown. We investigated the role of PD-1: PDL
costimulatory pathway in peripheral and a well established model of central transplantation
tolerance. Early as well as delayed blockade of PDL1 but not PDL2 abrogated tolerance
induced by CTLA4Ig in a fully MHC-mismatched cardiac allograft model. Accelerated
rejection was associated with a significant increase in the frequency of IFN-γ-producing …
Abstract
The PD-1: PDL pathway plays an important role in regulating alloimmune responses but its role in transplantation tolerance is unknown. We investigated the role of PD-1: PDL costimulatory pathway in peripheral and a well established model of central transplantation tolerance. Early as well as delayed blockade of PDL1 but not PDL2 abrogated tolerance induced by CTLA4Ig in a fully MHC-mismatched cardiac allograft model. Accelerated rejection was associated with a significant increase in the frequency of IFN-γ-producing alloreactive T cells and expansion of effector CD8+ T cells in the periphery, and a decline in the percentage of Foxp3+ graft infiltrating cells. Similarly, studies using PDL1/L2-deficient recipients confirmed the results with Ab blockade. Interestingly, while PDL1-deficient donor allografts were accepted by wild-type recipients treated with CTLA4Ig, the grafts developed severe chronic rejection and vasculopathy when compared with wild-type grafts. Finally, in a model of central tolerance induced by mixed allogeneic chimerism, engraftment was not abrogated by PDL1/L2 blockade. These novel data demonstrate the critical role of PDL1 for induction and maintenance of peripheral transplantation tolerance by its ability to alter the balance between pathogenic and regulatory T cells. Expression of PDL1 in donor tissue is critical for prevention of in situ graft pathology and chronic rejection.
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