Mechanisms behind Thymic Involution and Immunosuppression after exposure to Dioxin
Funding:
American Society of Transplant Surgeons
Principal Investigator:
Project Summary:
The Aryl Hydrocarbon Receptor (AHR) is the primary receptor to the environmental toxin 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD, dioxin). TCDD-mediated activation of the AHR leads to rapid thymic involution and immunosuppression. No specific mechanisms have been identified to explain these findings. However, preliminary data from our lab demonstrates that TCDD-mediated activation of the AHR alters thymocyte development and up-regulates numerous genes that are typically associated with cell trafficking and cell cycling. Research published this year also suggests that the AHR may be central to T cell differentiation between T regulatory and T effector cells, and that AHR activation by dioxin prevents autoimmunity in a murine model. Little is known on the ability to prevent allograft rejection by targeting the AHR. We have recently observed that treatment of mice with one dose of dioxin one day prior to transplantation leads to prolonged skin allograft survival (up to 35 days versus 10 days for untreated controls) in a high responder strain combination. Based on these findings, we hypothesize that the Aryl Hydrocarbon Receptor plays a central role in the differentiation of T cells to either effector or regulatory phenotypes. This differentiation is directly related to the rapid thymic involution that is seen after binding of ligands to this receptor, and leads to prolongation of graft survival in relevant models of organ transplantation.
Our experimental design is to 1) develop and characterize the effect of TCDD treatment on transplant rejection, 2) determine the role of the thymus and cell trafficking in the TCDD-mediated skin allograft survival, and 3) determine the important effector molecules that induce TCDD-mediated thymic involution by utilizing an in vitro model of TCDD-mediated thymic involution. We believe this research will lead to a greater understanding of biology of the AHR in thymic involution, T cell differentiation, and their effects on skin graft survival. It will also present a unique model to characterize the effects of thymic manipulation on immune modulation in a transplant model. There is likely a role for alterations in thymic emigration and trafficking to lymph nodes and skin grafts, leading to the generation of regulatory cells and graft prolongation. Most importantly, this work will identify an entirely new target for strategies for immunosuppression and even tolerance after organ transplantation.
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First published: 07/15/02 Last updated: 11/24/09
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