Despite decades of research, the basic pathogenetic mechanisms involved in inflammatory bowel disease (IBD) remain elusive, but the answers appear to lie in the scientific fields of immunology and genetics and these are the major areas addressed in this proposal. The basic theme of this Program Project relates to the immunologic mechanisms determining chronic inflammation in the intestine, the impact of chronic enteritis on the mucosal immune system, the mechanism of antigen handling in the intact and inflamed colon, and the genetic influences that determine susceptibility to disease, as well as the interplay and interaction among these areas. The focus of these studies will be on newly developed mouse models of colitis including spontaneous colitis in C3H/HeJBir mice, a substrain which was generated during the initial phase of this project. Although no model exactly duplicates human IBD, models can allow important insights into certain disease mechanisms. The mouse has been chosen because of the rich array of techniques and reagents available only in this species in both immunology and genetics. The Program Project will consist of four Projects and two Cores. Project #1, will focus on the enteric bacterial antigens recognized by the immune system during chronic colitis, particularly by T cells, the role that such T cells play in disease pathogenesis, and how such T cells are regulated. Project #2 will study a number of issues of mucosal immunity, oral tolerance, and isotype regulation in the setting of chronic intestinal inflammation. Project #3 will exploit two powerful new technologies, a T cell transgenic mouse, and in situ hybridization techniques, to examine antigen handling and T cell induction in the normal and inflamed colon. Project #4 will be located at the Jackson Laboratory in Bar Harbor, ME. This project will map genes important in susceptibility to colitis induction in inbred mouse strains, including the G3H/HeJBir colitic substrain. These projects will be supported by an Administrative Core which will provide administrative and fiscal support and coordination, and an Animal Model Core which will centralize the production of mice with experimental colitis, maintain strict quality control, and provide a centralized pathologic analysis. These studies should generate new concepts and paradigms to test in man, and possibly new approaches to immunotherapy, as has happened with mouse models of other diseases.
Showing the most recent 10 out of 101 publications
