The working hypothesis guiding our research on the nature of inflammatory bowel diseases (IBD) is that these diseases, particularly Crohn's disease, are due to abnormal regulation of responses to ubiquitous mucosal antigens. In recent years, this hypothesis has resolved itself into studies on the ability of T cells obtained from IBD patients to produce immunoregulatory lymphokines under various conditions. During the current period we have first defined the capacity of control T cells derived from lamina propria and the peripheral blood (LP and PB T cells, respectively) to undergo proliferation and to produce lymphokines when stimulated via defined T cell activation pathways. We found that when stimulated via the TCR/CD3 pathway (with several different CD3 and TCR antibodies) LP T cells exhibited 10-fold less proliferation than PB cells; on the other hand, when stimulated via the CD2 accessory pathway, LP T cells exhibited considerably more normal proliferative responses (as compared to PB T cells). This non-responsiveness was probably a form of peripheral T cell anergy, since partial recovery of cell function was obtained by pre-incubation of T cells with IL-2 (in the absence of TCR/CD3 stimulation). In contrast to this """"""""proliferative unresponsiveness"""""""", LP T cells exhibit a greatly heightened capacity to produce lymphokines, including IL-2, IFN-gamma and IL-4. In this regard, while LP T cells secreted 5-10-fold more IL-2 than BP T cells under all stimulatory conditions, they secreted remarkable amounts of IL-2 (>30,000 pg/m1/105 cells) when stimulated via accessory pathways. In comparable studies of IBD lamina propria T cells, several important differences were noted. Firstly, while responses induced via the TCR/CD3 pathway were 5- fold lower than the already reduced control LP T cell responses, responses induced via accessory pathways (CD2 and CD28) were preserved. Secondly, T cells from ulcerative colitis patients, stimulated via accessory pathways, manifested somewhat reduced IL-2 and IL-4 secretion (but not IFN-gamma secretion). Thirdly, T cells from Crohn's disease patients stimulated in a similar fashion manifested reduced IL-2 secretion, but vastly increased IFN-gamma and IL-4 secretion (5-10-fold increases). These studies therefore define a basic lymphokine secretory defect associated with Crohn's disease.
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