Immunomodulation of experimental colitis: the role of NK1.1 liver lymphocytes and surrogate antigens – bystander effect

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Abstract
The imbalance between Th1 pro‐inflammatory and Th2 anti‐inflammatory cytokine‐producing cells plays a major role in the pathogenesis of inflammatory bowel disease (IBD). Induction of oral tolerance to colitis‐extracted proteins was previously shown to down‐regulate the anti‐colon immune response, thereby alleviating experimental colitis. Immune bystander effect and liver‐associated lymphocytes expressing the NK1.1 marker (NK1.1+ LAL) have been suggested as being important in tolerance induction. The aims of the present study were to determine whether oral administration of inflammatory and non‐inflammatory colon‐extracted proteins of different species can induce peripheral immune tolerance and alleviate experimental colitis; and to examine the role of NK1.1+ LAL in oral tolerance induction. Colitis was induced in C57/B6 mice by intracolonic instillation of trinitrobenzene sulphonic acid (TNBS). Mice received six oral doses of colonic proteins extracted from TNBS‐colitis colonic wall, or normal colonic wall, from four different species. Standard clinical, macroscopic, and microscopic scores were used for colitis assessment. Serum interferon γ (IFNγ) 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 cells, their cytotoxicity functions were tested in tolerized and non‐tolerized‐mice. The administration of mouse‐derived colitis‐extracted proteins, or of surrogate proteins extracted from normal mouse colon, or from rat or human inflammatory colons, was found to alleviate experimental colitis. Tolerized mice had less diarrhoea; showed a marked reduction of colonic ulceration, intestinal and peritoneal adhesions, wall thickness, and oedema; and demonstrated a significant improvement of all microscopic parameters for colitis. Induction of tolerance led to an increase in IL10 and a decrease in IFNγ serum levels. NK1.1+ LAL cytotoxicity function increased markedly in tolerized mice. In contrast, mice fed with proteins extracted from normal rat, rabbit, and human colon, or from rabbit inflammatory colon, developed severe colitis, with a marked increase in IFNγ and a decrease in IL10 serum levels, and down‐regulation of NK1.1+ LAL function. This study has shown that oral tolerance can be induced in experimental colitis by means of the feeding of surrogate antigens; this alleviates experimental colitis. NK1.1+ LAL cytotoxicity function is associated with peripheral tolerance induction and may help to maintain the Th1/Th2 immune balance. Copyright © 2001 John Wiley & Sons, Ltd.