Contribution of TFH and of TREG cells to DSA generation in sensitized KTx recipients

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

? DESCRIPTION (provided by applicant): Organ transplantation represents the treatment of choice for end-stage organ failure associated diseases. Despite the advancements in medicine and the availability of novel and more potent immunosuppressive regimens, the long-term allograft outcomes after organ transplantation remain poor, with an average of only 60% allograft survival by 10 years. Transplant rejection, is one of the most important causes of allograft dysfunction and loss, and consists of multi-layered cellular and humoral immunologic-triggered injuries. Approximately 30% of HLA-sensitized kidney transplant recipients present with DSA post-Tx, which significantly increase the risk for cellular- and antibody-mediated rejection (ACR, AMR). Although DSA represents an important biomarker for decreased allograft survival, till date the exact immune mechanisms implicated in DSA generation are not entirely understood. While DSA are affinity matured IgG Abs, indicating that they are generated with T cell help, the direct role of T follicular helper (TFH) cells during DSA development and maintenance, as well as their relationship with TREG and B cells has not been investigated in the field of transplantation, and remains to be elucidated. Our recent preliminary data show that in a cohort of Thymoglobulin-induced KTx recipients the overall % of circulating TFH cells in patients with DSA were not significantly different from those of age- and gender- matched healthy controls (HC) or of quiescent, DSA negative KTx recipients. However, DSA positive KTx patients display a significant skewing of TFH cell subsets toward a Th1-TFH phenotype, accompanied by a concomitant decrease in TREG that results in significantly elevated Th1-TFH:TREG ratio as compared to ratios from both control groups. Based on these results, our central hypothesis is that Th1-TFH, provide key help for memory B cells to differentiate into plasmablasts and produce recall DSA, and an imbalance between Th1-TFH and TREG which protect T helper cell immune homeostasis, correlates with the development of pathogenic DSA after KTx. Our specific aims are: 1) To determine the direct contribution of CXCR5+Th1 TFH to DSA generation in KTx recipients; 2) To study the role of TREG in tempering CXCR5+Th1 TFH cell function or in regulating B cell DSA production. This proposal will provide valuable mechanistic understanding of the roles of TFH and TREG in recall allo- immune responses that generate DSA after KTx. It will also provide a robust scientific platform for designing clinical studies aimed at enhancing the early detection and treatment of patients at risk of poor graft outcomes. Knowledge gained in kidney transplant recipients is likely to apply to recipients of other types of organ transplants, such as the heart and lung, where clinical outcomes lag significantly behind.