CYTOKINE REGULATION OF EXPERIMENTAL INTESTINAL INFLAMMATION IN GENETICALLY-ENGINEERED AND T-LYMPHOCYTE RECONSTITUTED RODENTS

Phenotypically similar intestinal inflammation and systemic wasting de velops following overexpression or targeted deletion of several key im munoregulatory molecules and transfer of lymphocyte subsets into immun odeficient recipients, Although many of these recently described model s of intestinal inflammation have not been thoroughly investigated, se veral consistent features are present which provide important insights into the role of cytokines in the pathogenesis of intestinal inflamma tion: (i) entirely distinct genetic alterations of cytokine expression and T-lymphocyte activity can lead to phenotypically similar intestin al inflammation, suggesting that human inflammatory bowel disease coul d have marked genetic heterogeneity; (ii) dysregulation of any of a nu mber of immunoregulatory molecules can result in intestinal inflammati on, illustrating the complexity of the mucosal immune response; (iii) active immunosuppression is critical to maintaining mucosal homeostasi s; (iv) interferon-gamma and CD4(+) lymphocytes, probably of the TH1 p henotype, are required for progression of chronic intestinal inflammat ion; (v) monokines are consistently upregulated, but tumour necrosis f actor blockade is only partially protective, These models represent po werful new tools to understand better the basic mechanisms of mucosal immunoregulation and to develop novel therapeutic approaches of enhanc ing endogenous immunosuppressive pathways and blocking key regulatory cytokines and cells.