There is increasing evidence that CD4+ T cells and their cytokines may play a key role in the pathogenesis of Crohn's disease (CD), one of the known idiopathic inflammatory bowel disease (IBD's). One of the difficulties encountered in identifying the primary immunological and/or cytokine-induced abnormality(ies) in CD has been the lack of appropriate animal models. The unique feature of this proposal is that we will use a new strain of mice, referred to as SAMP1/Yit, that develop enteritis spontaneously without genetic or immunologic manipulation. These mice develop disease only when colonized with normal murine intestinal flora, and not when housed under free conditions. Therefore, the overall objective of Project 1 is to investigate the key pathogenic mechanisms, particularly those involving T cells and Thy cytokines, underlying this spontaneous murine model which closely resembles human CD. In order to achieve our goals we will: (1) Characterize the features of intestinal inflammation as well as the response to conventional immunosuppressive therapy in SAMP1/Yit mice. The penetrance of disease, the clinical phenotype of SAMP1/Yit mice at different ages as well as the response to steroids and immunosuppressive agents will be investigated. The similarities with human CD will be clearly defined in a systematic fashion. (2) Define the role of the immune response in the develop inflammation in SAMP1/Yit mice. Characterization of T cell phenotype and function in conjunction with a series of T-cell adoptive transfer as well as studies using bone marrow chimeras will be performed to precisely define the role of T-cells in this model. (3) To characterize the role of primary immunoregulatory cytokines in mediating chronic intestinal inflammation in SMP1/Yit mice. The key role of pro- inflammatory and immunological cytokines which have been implicated in the inductive phase of Th1 polarization including TNF, IL-12, and IL- 18 will be investigated by measuring their expression during the development of gut disease as well as by specific neutralization with monoclonal antibody therapy. In addition, the critical role if each cytokines will be assessed by studying the effects of specific genetic deletions of TNF, IL-12 and IL-18 on the development of intestinal inflammation in this model. The ultimate goal of Project 1 is to define the key pathogenic mechanisms in experimental CD mediated by CD4+ T cell and cytokines in order to develop disease-modifying treatment modalities for this devastating disease.
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