B Cells in Tolerance and Chronic Rejection of Monkey Kidney Allografts

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PROJECT SUMMARY / ABSTRACT Transient mixed hematopoietic chimerism and long-term survival of kidney allografts in the absence of immunosuppression has been achieved in monkeys and patients via non-myeloablative conditioning, infusion of donor bone marrow cells and short-term leukocyte costimulation blockade. However, a significant proportion of monkey kidney allografts (50%) undergoing long-term survival display features of chronic rejection (CR) within one year post-transplantation, a phenomenon also observed among many patients treated with a similar procedure at MGH. Recently, B cells have been implicated in both transplant rejection and tolerance. However, the nature of the B cells involved in these processes and their mechanisms of action are still unclear. Our proposed research will use a large collection of specimens (from blood and lymphoid organs) to characterize the phenotype as well as cytokine and gene expression profiles of the B cell subsets involved in chronic rejection vs. tolerance of kidney allografts in monkeys treated with our mixed chimerism procedure. In addition, we have recently identified a novel population of B cells in monkeys (and humans), which are CD19+ CD20+ BCR+ and unexpectedly CD8+. Most importantly, preliminary studies show an expansion of these unconventional B cells in the peripheral blood of chimeric monkeys, which became tolerant. To our knowledge, the nature, functions and association with tolerance of these B cells have never been investigated. Further characterization of the phenotype, cytokine signatures and regulatory properties of newly discovered CD8+ B cells (found in monkeys and humans) and evaluation of their association with immune tolerance has potential implications both in basic and clinical immunology Specific aim 1. To identify B cell subsets and signatures involved in chronic rejection vs. tolerance of kidney allografts. Specific Aim 2. To further characterize newly described CD8+ B lymphocytes and investigate their relationships with tolerance In addition to the theoretical implications of the work related to basic B cell biology, identification of the B cell subsets and signatures of transplant tolerance will enhance the safety and feasibility of clinical tolerance trials and facilitate management of patients receiving immunosuppression.