[F32] Engineering the thymus to manipulate thymic selection and mitigate transplant rejection

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PROJECT SUMMARY/ABSTRACT Transplantation is the best option for patients facing organ failure. Despite the ability of immunosuppressive treatments to control acute rejection, they fail to prevent chronic rejection and require expensive lifelong care that is associated with many side effects. Minimizing immunosuppression via novel immunotherapies would make transplantation safer. Currently, there are efforts to leverage the training of T lymphocytes (key drivers of rejection) in the thymus (organ where T cell education occurs) to promote the development of T cells that are tolerant to transplanted tissues. This training involves interactions with cells in the thymus that select for T cells that are functional and safe (non-reactive to self). The most effective approach to date involves using bone marrow transplantation, where donor-hematopoietic-derived dendritic cells populate the recipient thymus and eliminate reactive thymocytes (T cell precursors). However, this approach carries significant risks to the patient and might not be sufficient to promote tolerance while preserving a fully functional immune system. Therefore, complementary or alternative approaches are needed to safely re-educate T cells and induce robust donor- specific transplant tolerance. The goal of this proposal is to define the therapeutic potential of manipulating a different cell population, thymic epithelial cells (TEC), to influence the selection of reactive thymocytes within the context of transplantation. The long-term goal of this project is to lay the groundwork for developing a new paradigm that promotes transplant tolerance by manipulating the thymic environment. To this end, I have successfully demonstrated that I can engraft donor TEC into a recipient thymus. Moreover, I have preliminary results showing that donor TEC engraftment as part of a short term conditioning promotes long term skin grafts survival. Altogether, this data suggests that my proposed study is feasible. In this proposal, I will determine the mechanism by which engrafted TEC can affect T cell development by determining the extent to which donor TEC can train T cells, quantifying donor TEC’s ability to remove alloreactive T cells, and determining how the engrafted TEC are organized in the recipient thymus by using light sheet microscopy. In parallel, I will determine the extent to which donor TEC influence peripheral T cell reactivity following skin transplantation and thereby protect against rejection. These findings will lay the groundwork for the development of a novel approach to enhance transplant tolerance. Istituzione: JOHNS HOPKINS UNIVERSITY PI: Lotte Maria van den Goor Progetto: 1F32AI197459-01A1

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Source: reporter.nih.gov