KFO 243: Early Immunological Determinants of Late Transplant Outcome (ELITE)

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Prior to challenge, the immune system is equally capable of responding to a novel antigen with a robust self-perpetuating tolerance, or mounting a destructive reaction; the immune system decides upon the most appropriate response depending on the context in which the antigen is encountered. However, once the system has collapsed towards either destructive reaction or tolerance, and the adaptive response is primed, then it becomes committed to that decision. Therein lie the two greatest obstacles to long-term graft acceptance: the inevitable inflammation associated with solid organ transplantation, and the existence of T cell memory for alloantigen. Similarly, the reconstitution of a properly regulated immune system is essential for successful bone marrow engraftment. From this view, it follows that peritransplant control of immunological reactions and education of recipients responses towards graft acceptance might positively influence long-term outcomes in transplantation. The aim of the Clinical Research Unit is to understand how early immunologic factors determine long-term allograft success. With this purpose, research from our workgroups will be directed towards two principal immunologic aspects that are likely to affect transplant outcome, namely recipient innate and adaptive immune responses. Non-specific innate recognition mechanisms are particularly important in shaping very early reactions to allogeneic transplanted tissues, establishing the chain of consequences that ultimately results in chronic allograft-related pathology. Orchestrating this response is the balance between effector and regulatory subsets of key cell types, including T cells, B cells, NK cells and macrophages. The integration of information obtained from studying both the innate and adaptive cellular and humoral immune responses within our Clinical Research Unit is expected to reveal new insights into which immunological factors are critical in forming favourable, versus poor, allogeneic transplant outcomes. By understanding these complex early events more fully, we hope to develop novel therapeutic strategies to control and monitor pathologic posttransplant alloreactivity, thereby improving long-term transplant outcome.