Regulation of the immune response to intestinal antigens

Abstract

The immune system of the gut has a complicated task. It should react aggressively to pathogenic bacteria, viruses and parasites, but at the same time tolerate the normal intestinal flora and those food antigens that are present. The maintenance of this tolerance is very important for the homeostasis of the gut, since severe inflammatory conditions might be induced if the tolerance is broken.This thesis is focused on different aspects of the regulation of the immune system of the gut, with emphasis on the development of tolerance to food proteins. Tolerance to ovalbumin (OvA) was induces in rats, by providing the rats OvA-containing food pellets. Subsequent immunisations with OvA and the bystander antigen (Ag) human serum albumin together with adjuvant, allowed an assessment of the degree of tolerance induced, and of the mechanism(s) responsible.It was shown that the down-regulated immune response induced by high dose Ag-feeding is due to regulatory T cells that actively suppress the activated cells in the surroundings, leading to a suppressed response also to bystander Ags. A few days after parenteral immunisation, TGF-b producing cells appeared in the lymph nodes draining the immunisation site in rats that had previously been fed Ag. In association with the appearance of these cells, there was a lack of immunisation-induced swelling of the lymph nodes. The suppressed immune response in Ag-fed rats was at least partly due to the TGF-b secretion, since the tolerance was broken if Ag-fed rats were given neutralising TGF-b antibodies before immunisation.In further experiments we showed that regulatory cells can express the surface marker CD25, usually considered as an activation marker of T cells. CD25+ regulatory T cells have previously been shown to be important in the maintenance of self-tolerance, and in the regulation of the immune response against the bacterial flora.When comparing the mechanisms of tolerance between young and adult rats, it was demonstrated that regulatory cells could be induced in the adult rats, while in young rats active mechanisms of tolerance were less obvious. There are accumulating evidence that this was related to the relative lack of MHC class II molecules in the intestinal epithelium of the young rats.It was further shown that intestinal epithelial cells could release exosomes (exocytosed vesicles) when cultured in vitro. If the cells had been cultured with enzymatically degraded Ag, the exosomes could induce tolerance after transfer into naive recipient rats. Exosome release from the intestinal epithelium might be the default pathway for induction of regulatory T cells.In a study where neonatal rats were given low amounts of anti-idiotypic antibodies orally, mimicking the maternal antibody transfer via the milk, it was demonstrated that long-lasting effects were inflicted on the immune system of the neonate. Thus, the offspring of female neonatally treated mice had an altered immune response to both idiotypically connected and spatially connected Ags.