Mounting evidence indicates that the inflammatory response elicited by immune cells plays a crucial role in exacerbating radiation induced acute pneumonitis. After radiation, there is a rapid infiltration of monocytes/macrophages and neutrophils that mediate the inflammatory process. This proposal plans to focus on the role of a few crucial molecules that control adaptive and innate immunity in radiation-induced injury. The goal is to then device ways to manipulate these targets to alter the outcome of such injury. The first one, MyD88, is an adaptor of the toll-like receptors (TLR), IL-1R and IL-8R. It is a common thread of many inflammatory and innate signaling pathways. In addition to the TLR pathway, we recently described a family of genes, christened CATERPILLER (CLR), which can modulate TLR functions. Most notable is the gene CIAS (cold induced autoinflammatory syndrome gene). It is expressed by monocyte-myeloid cells but not other cell types. It appears to block inflammatory responses including NF-kB, AP-1 activation and inflammatory cytokine production in response to TLR activation. Thus it constitutes a negative regulator of the TLR pathway. Finally, structurally related to the CIAS gene/protein is the Class II transactivator (CIITA). CIITA controls all of MHC-II gene expression, and its mutation in human and mice causes severe defect in the CD4 T cell pathway. Thus CIITA is a pivotal control of adaptive immunity. A feature shared between CIAS and CIITA is that they are both nucleotide-binding proteins. This feature underscores the possible usage of small nucleotide analogs to alter these molecules for therapeutic reasons, such as that encountered during radiation-induced pneumonitis. Accordingly, we will: (1) Study the course of radiation induced pneumonitis in mice lacking MyD88; (2) Assess if the removal if CIAS in mice changes inflammatory responses and the course of acute pneumonitis and to study the nucleotide-binding properties of CIAS as a future deliverable. (3) Assess if the removal of CIITA alters adaptive immune responses and the course of acute pneumonitis, and delineate the nucleotide-binding properties of CIITA as a future deliverable.
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