New molecular techniques that permit overexpression or deletion of targeted genes have created a new class of rodent models of intestinal inflammation. Spontaneous colitis, with variable small bowel, duodenal, and systemic inflammation, develops in transgenic HLA-B27/β2-microglobulin rats; interleukin-2, interleukin-10, transforming growth factor-β1, T cell receptor, and G protein deficient (knockout) mice; the new C3H/HeJ Bir mouse substrain; following transfer of CD45RBhigh lymphocytes into immunodeficient mice; and following bone marrow transplantation into cyclosporin A-treated mice. These models provide the following important insights into the mechanisms of chronic intestinal inflammation: (a) Ubiquitous luminal bacteria have a critical role in induction and perpetuation of chronic intestinal and systemic inflammation in genetically susceptible hosts. (b) Defective immunoregulation, especially immunosuppression, can lead to chronic colitis. (c) Alteration of any of a number of immunoregulatory molecules can induce almost identical phenotypes of intestinal inflammation. (d) Host genetic susceptibility determines the incidence and aggressiveness of disease. (e) The immune system, especially immunoregulatory T lymphocytes, mediates chronic colitis. Results in these models are consistent with the hypothesis that chronic intestinal and related systemic manifestations are the result of an inappropriately aggressive immune response to ubiquitous luminal bacterial constituents, mediated by genetically determined defective immunosuppression. Furthermore, the diverse nature of immunoregulatory defects in these models that share similar clinical manifestations suggests that ulcerative colitis and Crohn's disease are heterogeneous groups of disorders with multiple etiologies.
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Balfour R. Sartor (1995) studied this question.