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Abstract

Organ transplantation is the only treatment for end-stage organ failure. However, due to the genetic disparities between the donor and the recipient, transplanted organs are recognized by the recipient’s immune system as foreign and rejected, with the exception of transplantation between identical twins. Therefore, a lifelong regimen of immunosuppression is required for patients to prevent graft rejection. Such level of immunosuppression significantly increases susceptibility to infections and malignancies, and can trigger additional adverse side effects, creating a substantial burden on the healthcare system and reducing the well-being of patients who have no alternative treatment options. In this thesis, we used mouse models of minor-mismatch heart or skin transplantation to determine the extent to which the microbiota, the collection of commensal bacteria residing at barrier surfaces, impacts the outcome of organ transplantation. We established that the microbiota is indeed an environmental factor that can fine-tune alloreactivity, with the diverse microbiota from specific pathogen-free mice accelerating graft rejection, an effect that is associated with an enhanced capacity of antigen-presenting cells (APCs) to activate alloreactive T cells. However, not all bacteria were capable of accelerating graft rejection, as residual microbes after antibiotic treatment did not enhance the kinetics of graft rejection. Moreover, colonization of either donor or recipient skin with a single commensal was sufficient to accelerate skin graft rejection, demonstrating a role for microbiota outside to the gut on allograft outcome. In all, this work demonstrates that the microbiota is an environmental factor that can impact alloreactivity, implying that prolongation of graft survival might be achieved by therapeutic interventions targeting the microbiota of different body location.

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