Oral administration of unmodified colonic but not small intestinal antigens protects rats from hapten-induced colitis

Abstract

SUMMARYColonic administration of a hapten, 2,4,6-trinitrobenzene sulphonic acid (TNBS) has been shown to induce colitis in rats. We are using this model to investigate the role of colonic antigens in the immunopathology. In this study, we show that colitis can be suppressed by oral administration of haptenized colonic antigens prior to the TNBS enema. Moreover, our data suggest that haptenization of the colonic antigens is not essential because oral feeding of non haptenized colonic antigens too protects rats from TNBS-induced colitis. Thus, unmodified colonic antigens may be involved in the induction of oral tolerance, and possibly in the pathogenesis in this model of colitis. Further, we show that the protective immunity or oral tolerance induced by non haptenized colonic antigens can be passively transferred to naõ Ève rats by mesenteric T lymphocytes. Interestingly, oral feeding of small intestinal antigens, haptenized and non haptenized, does not protect rats from colitis, suggesting a specific role for colonic antigens. These data underscore the usefulness of this rat model in the identification of pathogenic antigens in colitis and in the development of therapeutic strategies based on oral tolerance.

Oral Tolerance: Therapeutic Implications for Autoimmune Diseases

“…TNBS-induced colitis in rats can also be prevented by feeding either human colon epithelial cells or rat colonic epithelial extracts, but not human fibroblasts nor rat small intestine extracts, showing that tolerance is organ specific. Protected animals had low IFN-g and high TGF-b levels and tolerance could be transferred by mesenteric lymph nodes cells (Dasgupta et al 2001). In addition, colitis can be suppressed via bystander suppression by transfer of OVA transgenic CD4þ -CD45 high T cells (from DO.11.10 mice) into SCID mice (Zhou et al 2004).…”

Oral Immune Regulation toward Disease‐Associated Antigens: Results of Phase I Clinical Trials in Crohn's Disease and Chronic Hepatitis

“…Lamina propria CD4 + T cells exhibit a Th1 pattern of cytokine secretion, with an increase in IFN‐γ and IL‐2 and a decrease in IL‐4 secretion. Induction of oral immune regulation toward colitis‐extracted proteins (CEP) alleviated experimental colitis, manifested by a decrease in diarrhea, percentage of affected colonic area, degree of colonic ulceration, intestinal and peritoneal adhesions, and wall thickness 12–14. Histologic evaluation of bowel tissue showed marked reduction in inflammatory response and mucosal ulceration (Fig.…”

“…When suppressor T cells activated by antigen‐presenting cell (APC) presentation of these proteins encounter similar epitopes in the colon, they secrete anti‐inflammatory cytokines 17. A recent study demonstrates that cellular proteins from human colon epithelial cells, but not from human fibroblasts, can induce oral tolerance in experimental colitis 13,14. It was recently suggested that haptenization of the colonic antigens is nonessential because oral feeding of nonhaptenized colonic antigens also protects rats from TNBS‐induced colitis 14…”

“…17 A recent study demonstrates that cellular proteins from human colon epithelial cells, but not from human fibroblasts, can induce oral tolerance in experimental colitis. 13,14 It was recently suggested that haptenization of the colonic antigens is nonessential because oral feeding of nonhaptenized colonic antigens also protects rats from TNBS-induced colitis. 14…”

The effect of oral tolerance on the roles of small intestinal intraepithelial lymphocytes in murine colitis induced by dextran sodium sulfate

“…It has also been reported that oral colitis-extracted proteins (CEP) or normal colon-extracted proteins with five low doses can prevent experimental colitis induced by TNBS in rodent animals. Tolerance induction was mediated by immunosuppressive cytokines such as TGF-β and so on [24][25][26]. Dextran sodium sulfate (DSS)-induced colitis is also a widely used animal model for researching the pathogenesis and treatment of human IBD [27][28][29].…”