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.
Our project is to identify of the B lymphocytes associated with tolerance (acceptance) or chronic rejection of kidney transplants. If successful, this research will enhance the safety and feasibility of clinical tolerance trials and facilitate management of patients receiving immunosuppression.
| Firl, Daniel J; Benichou, Gilles; Kim, James I et al. (2017) A Paradigm Shift on the Question of B Cells in Transplantation? Recent Insights on Regulating the Alloresponse. Front Immunol 8:80 |
| Benichou, Gilles; Kim, James (2017) Editorial: Allorecognition by Leukocytes of the Adaptive Immune System. Front Immunol 8:1555 |
| Benichou, Gilles; Gonzalez, Bruno; Marino, Jose et al. (2017) Role of Memory T Cells in Allograft Rejection and Tolerance. Front Immunol 8:170 |
| Marino, Jose; Babiker-Mohamed, Mohamed H; Crosby-Bertorini, Patrick et al. (2016) Donor exosomes rather than passenger leukocytes initiate alloreactive T cell responses after transplantation. Sci Immunol 1: |
