Immunomodulation of experimental colitis: the role of NK 1.1 liver lymphocytes and surrogate antigens - bystander effect

The imbalance between Th1 pro-inflammatory and Th2 anti-inflammatory cytoki ne-producing cells plays a major role in the pathogenesis of inflammatory b owel disease (IBD). Induction of oral tolerance to colitis-extracted protei ns was previously shown to down-regulate the anti-colon immune response, th ereby alleviating experimental colitis. Immune bystander effect and liver-a ssociated lymphocytes expressing the NK1.1 marker (NK1.1(+) LAL) have been suggested as being important in tolerance induction. The aims of the presen t study were to determine whether oral administration of inflammatory and n on-inflammatory colon-extracted proteins of different species can induce pe ripheral immune tolerance and alleviate experimental colitis; and to examin e the role of NK1.1(+) LAL in oral tolerance induction. Colitis was induced in C57/136 mice by intracolonic instillation of trinitrobenzene sulphonic acid (TNBS). Mice received six oral doses of colonic proteins extracted fro m TNBS-colitis colonic wall, or normal colonic wall, from four different sp ecies. Standard clinical, macroscopic, and microscopic scores were used for colitis assessment. Serum interferon gamma (IFN gamma) and interleukin 10 (IL10) levels were measured by ELISA. To evaluate the role of NK1.1(+) LAL in maintaining the balance between immunogenic and tolerogenic subsets of c ells, their cytotoxicity functions were tested in tolerized and non-toleriz ed-mice. The administration of mouse-derived colitis-extracted proteins, or of surrogate proteins extracted from normal mouse colon, or from rat or hu man inflammatory colons, was found to alleviate experimental colitis. Toler ized mice had less diarrhoea; showed a marked reduction of colonic ulcerati on, intestinal and peritoneal adhesions, wall thickness, and oedema; and de monstrated a significant improvement of all microscopic parameters for coli tis. Induction of tolerance led to an increase in IL10 and a decrease in IF N gamma serum levels. NK1.1(+) LAL cytotoxicity function increased markedly in tolerized mice. In contrast, mice fed with proteins extracted from norm al rat, rabbit, and human colon, or from rabbit inflammatory colon, develop ed severe colitis, with a marked increase in IFN gamma and a decrease in IL 10 serum levels, and down-regulation of NK1.1(+) LAL function. This study h as shown that oral tolerance can be induced in experimental colitis by mean s of the feeding of surrogate antigens; this alleviates experimental coliti s. NK1.1(+) LAL cytotoxicity function is associated with peripheral toleran ce induction and may help to maintain the Th1/Th2 immune balance. Copyright (C) 2001 John Wiley & Sons, Ltd.