New Evidence for a Role of Allograft Accommodation in Long-Term Tolerance

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Abstract
Progressively better therapies have largely prevented or at least effectively treated acute allograft rejection. Consequently, the long-term survival of solid organ transplants has increasingly become limited primarily by the development of chronic allograft rejection. The mechanisms of chronic rejection remain largely unknown and the induction of specific tolerance would be the ultimate achievement in transplant immunology. We previously demonstrated, in a fully major histocompatibility complex (MHC)-mismatched rat cardiac allograft combination, that a 20-day treatment with a deoxyspergualin (DSG) analogue, LF15-0195, induces allograft tolerance with the development of potent CD4CD25 regulatory T cells. In order to better characterize the mechanisms involved in allograft tolerance, we compared long-term tolerated allografts with allografts exhibiting signs of chronic rejection induced by donor-specific blood transfusion. We analyzed both types of allografts for infiltration, alloantibody production and gene expression by histology, exhaustive microarray and quantitative reverse-transcriptase polymerase chain reaction. Interestingly, we observed in tolerated allografts an infiltrate as dense as the one observed in chronically rejected allografts and alloantibody deposits on graft endothelial cells. Prominent gene expression of many putative proinflammatory cytokines and genes related to cell activation or cytotoxicity were observed in tolerated allografts. However, we observed a specific upregulation of cytoprotective genes such as nitric oxide synthase, BclXL, and indoleamine 2,3 dioxygenase, and a poor in situ expression of immunoglobulin chain gene. This study demonstrates a state of accommodation of tolerated allografts and suggests the importance of early control of humoral immunity for the prevention of chronic rejection and the maintenance of long-term tolerance.