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

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 gamma (IFNgamma) 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 IFNgamma 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 IFNgamma 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.

Oral Tolerance to Nickel Requires CD4+ Invariant NKT Cells for the Infectious Spread of Tolerance and the Induction of Specific Regulatory T Cells

“…One line of thought proposes that the liver could function as a second security line after the intestine, to ensure tolerance toward Ags that are orally ingested (32), and indeed, hepatic NKT cells were shown to be required for the induction of oral tolerance in TNBS-induced colitis, a Th1-mediated disease (33,34). Furthermore, oral administration of colitis-extracted proteins, without an exogenous adjuvant, was shown not only to increase the number and cytolytic function of these NKT cells but also to shift their Th1-cytokine response to a Th2-type response (35,36). In vivo, the depletion of NK1.1 ϩ cells can prevent this shift and subsequently prevent the ability to induce tolerance (37).…”

Association between chronic liver and colon inflammation during the development of murine syngeneic graft-versus-host disease

“…31), are positively selected to the nonclassical MHC molecule CD1d, have strong reactivity to the glycosphingolipid ␣-GalCer, and are present in high numbers in the liver. Liver iNKT cells have been shown to participate in the induction of oral tolerance (29,57), tolerance to antigens in privileged sites (47), and inhibit the development of experimental colitis in mice (41,46,56).…”

The Gut Mucosa as a Site for Induction of Regulatory T-Cells

“…Another important component of oral tolerance is the existence of a bystander effect [64]. This mechanism involves induction of regulatory T-cells in a non-antigenspecific manner within a given microenvironment [37].…”

“…Induction of oral tolerance activates NKT-cells and is linked to suppression of colitis and hepatitis in both animal models and humans [64,162,[170][171][172][173]. In a murine model of hepatocellular carcinoma (HCC), NKT-cells were shown to have a role in oral immune regulation with HCC lysate and HBV envelope proteins, and in adoptive transfer of dendritic cells pulsed ex vivo with the same antigens [174][175][176].…”