Shu Li,Liuyang Wang,Victoria A Bendersky,Qimeng Gao,Jun Wang,He Xu,Allan D Kirk
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Immunomodulation of T cell-mediated Alloimmunity by Proximity to Endothelial Cells under mTOR Blockade.
Endothelial cells (ECs) are an initial barrier between vascularized organ allografts and the host immune system and are thus well positioned to initiate and influence alloimmune rejection. The mTOR inhibitor rapamycin is known to inhibit T cell activation and attenuate acute allograft rejection (AR). It also has numerous effects on ECs. We hypothesized that mTOR blockade might directly alter EC alloimmunogenicity and reduce alloimmune responses independent of its effects on T cell function. Here we report that rapamycin treatment modulates EC coinhibitory ligand expression and alters cytokine/chemokine production. It alters the EC transcriptome broadly associated with negative regulation of immune responses. Rapamycin-treated ECs suppress EC-specific T cell proliferation independent of PD1/PD ligand interactions, and inhibit T cells responding to adjacent allogeneic cells in a contact-independent manner via secreted inhibitory mediators above 10 kDa. The T cell hypo-responsiveness induced by rapamycin-pretreated ECs was rescued by exogenous IL-2. Pre-exposing donor hearts to rapamycin improves the effect of B7 costimulation blockade in prolonging heart allograft survival in an MHC-mismatched mouse model. Our results indicate that rapamycin treated ECs have reduced alloimmunogenicity and create a local, contact-independent environment that limits T cell alloreactivity via anergy induction and improves the efficacy of B7 costimulation blockade.
期刊介绍:
The American Journal of Transplantation is a leading journal in the field of transplantation. It serves as a forum for debate and reassessment, an agent of change, and a major platform for promoting understanding, improving results, and advancing science. Published monthly, it provides an essential resource for researchers and clinicians worldwide.
The journal publishes original articles, case reports, invited reviews, letters to the editor, critical reviews, news features, consensus documents, and guidelines over 12 issues a year. It covers all major subject areas in transplantation, including thoracic (heart, lung), abdominal (kidney, liver, pancreas, islets), tissue and stem cell transplantation, organ and tissue donation and preservation, tissue injury, repair, inflammation, and aging, histocompatibility, drugs and pharmacology, graft survival, and prevention of graft dysfunction and failure. It also explores ethical and social issues in the field.