These investigators have a colony of SAMP1/Yit mice. One hundred percent of these mice develop a severe transmural ileitis by 30 weeks of age that remains unresolved and resembles Crohn's disease. These mice develop the disease only when colonized with normal murine intestinal flora and not when derived under germ-free conditions. The overall objective of this proposal is to investigate the pathogenic mechanisms underlying the spontaneous murine model. In order to achieve their goals the investigators will pursue three specific aims: The first specific aim is to characterize the features of intestinal inflammation in SAMP1/Yit mice. The incidence of intestinal inflammation as well as the clinical phenotype of SAMP1/Yit mice will be investigated. The similarities with human Crohn's disease will be studied in a systematic fashion. The second specific aim is to define the role of the immune response in the development of intestinal inflammation in SAMP1/Yit mice. A series of T-cell adoptive transfer experiments as well as studies using bone marrow chimeras will be performed to precisely define the role of T-cells in this model. Key immunologic mechanisms of gut inflammation will be studied using cellular immunologic techniques. The third specific aim is to characterize the role of primary immunoregulatory cytokines in mediating chronic intestinal inflammation in this model. The key role of proinflammatory and immunologic cytokines which have been implicated in the inductive phase of the Th1 polarization will be investigated by measuring their expression during the development of gut inflammation as well as by performing specific neutralization with monospecific antibody therapy.
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