Chronic intestinal inflammation is the major pathophysiological manifestation of Crohn's disease. No etiologic agent has been identified which might initiate and sustain this inflammation. It is postulated that Crohn's disease develops due to abnormal control mechanisms which regulate mucosal inflammatory responses to common enteral antigens. Immunologic abnormalities, inconsistently identified in patients with Crohn's disease, include altered lymphocyte activation, identified in patients with Crohn's disease, include altered lymphocyte activation, proliferation and suppression of immunoglobulin synthesis. The scientific goal of this proposal is to determine whether altered immunoregulatory function contributes to the pathogenesis of Crohn's disease. This will be accomplished by a comprehensive comparison of the immunoregulatory function of specific CD4 T cell and CD8 T cell subpopulations isolated from the intestinal lamina propria, GALT, and peripheral blood. Two hypotheses that could explain the persistent intestinal inflammation in Crohn's disease will be tested. Central to these hypotheses is the fact that, in contrast to the peripheral blood, the lamina propria normally contains CD4, Leu-8- T cells (helper cells). The CD4, Leu-8+ T cell is of central importance because it can directly suppress immunoglobulin production, and can induce the function of CD8 T suppressor cells. The specific hypotheses are: (1) intestinal inflammation develops due to altered CD4, Leu-8+ T cell suppressor function, and (2) intestinal inflammation develops due to excessive polyclonal helper T cell function which is not sufficiently downregulated by CD4, Leu-8+ T cells. To test these hypotheses, a comprehensive phenotypic characterization (FACS analysis) of both the states of activation and differentiation of B cells, CD4 T cells, and CD8 T cells in controls and patients with Crohn's disease will be performed. The immunoregulatory function of isolated CD4 and CD8 T cells and of highly purified, subpopulations of CD4 T cells and CD8 T cells (Leu-8, CD45R, 4F2, Ta1) will be defined. The critical functions to be examined, which might be aberrant in Crohn's disease, include help and suppression of polyclonal immunoglobulin production, mitogen and cytokine stimulated proliferation, and cytokine production (INF-gamma, IL-2, IL-4). Proliferation, differentiation, and isotype-specific immunoglobulin production by B cells will be examined. These results will elucidate the role of the immune system in the pathogenesis of Crohn's disease and will impact on the design of more specific and effective medical interventions.
| Kanof, M E; Strober, W; Kwan, W C et al. (1991) CD4+ Leu-8+ T cell supernatant activity that inhibits Ig production. J Immunol 147:155-61 |
