TOLERANCE EXISTS TOWARDS RESIDENT INTESTINAL FLORA BUT IS BROKEN IN ACTIVE INFLAMMATORY BOWEL-DISEASE (IBD)

Hyporesponsiveness to a universe of bacterial and dietary antigens fro m the gut lumen is a hallmark of the intestinal immune system. Since h yperresponsiveness against these antigens might be associated with inf lammation, we studied the immune response to the indigenous intestinal microflora monocuclear cells (LPMC) isolated from inflamed intestine but not peripheral blood mononuclear cells (PBMC) of IBD patients with active inflammatory disease strongly proliferated after co-culture wi th sonicates of bacteria from autologous intestine (BsA). proliferatio n was inhibitable by anti-MHC class II MoAb, suggesting that it was dr iven by antigen. LPMC from adjacent non-inflamed intestinal areas of t he same IBD patients and PBMC or LPMC isolated From non-inflamed intes tine of controls and patients with IBD in remission, in contrast, did not proliferate. PBMC or LPMC which had been tolerant to bacteria from autologous intestine, however, strongly proliferated after co-culture with bacterial sonicates from heterologous intestine (BsH). This prol iferation was associated with an expansion of CD8(+) T cells, increase d expression of activation markers on both CD4(+) and CD8(+) lymphocyt e subsets, and production of IL-12, interferon-gamma (IFN-gamma), and IL-10 protein. These results show that tolerance selectively exists to intestinal flora from autologous but not heterologous intestine, and that tolerance is broken in intestinal inflammation. This may be an im portant mechanism for the perpetuation of chronic IBD.