Mechanisms behind Thymic Involution and Immunosuppression after exposure to Dioxin
Funding:
Institute for Clinical and Translational Research
Principal Investigator:
Project Summary:
The thymus represents the primary lymphoid organ in which T cells mature and become functional, and over time the organ undergoes physiologic involution, which remains poorly understood.
The Aryl Hydrocarbon Receptor (AHR) is the primary receptor for 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD, dioxin), with its activation leading to rapid thymic involution. It has long been held that the AHR has a role in organ development and physiology. Recent data suggests that AHR may be central to T cell differentiation, with cells either developing regulatory (Foxp3+) or effector (Th17) phenotypes depending on interactions with the AHR.
The hypothesis of this proposal is that the AHR is a critical component of the mechanisms resulting in thymic involution. As the thymus plays a key role in auto and allo immune tolerance, activation of the AHR by environmental or natural ligands results in altered immune regulation and modulates autoimmunity and organ transplant rejection. Three aims will be addressed.
Specific Aim 1: To establish an in vitro model of TCDD-mediated thymic involution and use this model to determine the important effector molecules that induce TCDD-mediated thymic involution.
Specific Aim 2. Determine if the AHR plays a role in the natural course of thymic involution or its ability to repopulate after involution.
Specific Aim 3: Determine the degree to which modulation of the AHR can lead to thymic-dependent immunosuppression, partially attributable to generation of Tregs. This can have an effect on organ rejection and development of tolerance.
Understanding the role that the AHR plays in thymic physiology may provide the key for manipulating thymic involution, as well as understanding why T cells differentiate to become regulators versus effectors of rejection. This may represent a novel target for future endeavors at transplant immunosuppression or tolerance.
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First published: 07/15/02 Last updated: 11/24/09
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