Estrogens and dioxins induce immunosuppression and thymic atrophy. Estrogens also are associated with autoimmune disease, while dioxin has been shown to be associated with induction of markers of hyper-immunity.
The first aims of this application is identification of the precise alteration(s) in intrathymic development that are associated with thymic atrophy induced by the above agents and related compounds, and, by using transgenic mice containing appropriate reporter constructs, to identify the particular intra-thymic hemopoietic or stromal cells in which either the dioxin receptor (AhR) or the estrogen receptors (ER) are activated to affect T-cell development. The specific cellular targets will be confirmed by use of transgenic mice lacking either the AhR or one or both of the defined ERs. Radiation induced hemopoietic chimeras of mice arrested in T- cell development, lacking receptor, and containing receptor reporter constructs, will be used to precisely define the cell target for atrophy. Once these target cells are defined, and the alteration (either proliferation/differentiation arrest or apoptosis) confirmed, the particular gene products produced in these cells by AhR or ER activation will be elucidated.
The second aim i s to determine whether there is a direct link between premature thymic atrophy induced by TCDD or E2 or DES and the development of autoimmunity, and if so, what is the mechanistic relation between the two processes. Such studies would provide insight into how estrogens contribute to autoimmunity, and what the risk might be of chronic administration of estrogenic compounds and 'environmental' estrogens. Specifically, this proposal seeks to determine what altered T- cell populations in the periphery and thymus contribute to the lupus-like autoimmune nephritis facilitated by E2, DES, and TCDD in the NZB x SWR (SNF/1) murine model. Whether thymic atrophy is essential to disease induction, will be explored by pre and post-exposure thymectomy, as well as by determining the minimal doses needed to induce the pathology associated markers.
| Feng, F; Silvin, C J; Fiore, N C et al. (2012) 17ýý-Estradiol (E-2) administration to male (NZB ýý SWR)Fýýý mice results in increased Id(LN)Fýýý-reactive memory T-lymphocytes and accelerated glomerulonephritis. Lupus 21:288-301 |
