The objective of this proposal is to define mechanisms that control the type and extent of an autoimmune inflammatory response using well-defined routine models of autoimmune thyroiditis. These provide a unique opportunity to study 3 distinct outcomes of autoimmune inflammation, i.e. chronic unresolving inflammation, granulomatous inflammation that resolves in 2-3 weeks, and massive inflammatory destruction leading to fibrosis, in a single organ. For example, the site of expression of pro- and antiapoptotic molecules in thyroids can contribute to the outcome of thyroid inflammation. Expression of FLIP and FasL on thyroid follicular cells (TFC) is associated with early resolution, whereas their expression by inflammatory cells is associated with chronic inflammation. CD8+ T cells are required for early resolution of G-EAT and for upregulation of FasL and FLIP on TFC. Absence of IFNgamma-/- promotes early resolution when wild-type (WT) mice develop fibrosis, and inhibition of fibrosis promotes resolution. These studies will test the hypothesis that the site of expression of pro- and antiapoptotic molecules can contribute to the outcome of inflammation and that alterations in the site of expression of certain molecules can alter the outcome of the inflammatory response. Induction of FasL on TFC is critical for inducing apoptosis of inflammatory cells, thus promoting resolution.
Aim 1 will seek to better understand the role of CD8+ T cells in resolution and FasL upregulation by determining how CD8+ T cells are activated, whether they need to express functional FasL to promote upregulation of FasL on TFC, and if an intact Fas pathway is required for resolution.
Aim 2 will determine if changing the site of expression of FLIP can alter the outcome of inflammation and will determine the role of Bct-2, Bcl-xL and TRAIL in these models.
Aim 3 will focus on defining the mechanisms that dictate early resolution of inflammation in mice lacking IFNgamma, with a major emphasis being to understand how differences in apoptosis and eosinophil vs. neutrophil infiltration can influence the outcome. Information gained from these studies should be useful in designing rational and specific approaches to promote resolution and prevent the undesirable outcomes of chronic inflammation or fibrosis. Although these studies involve inflammatory responses localized to the thyroid, the potential knowledge to be gained should be applicable for understanding mechanisms that control outcome of autoimmune inflammation in any tissue or organ.
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