Tolerância e inflamação: um estudo da imunoregulação em modelos experimentais de gastrite e colite induzidos por álcool

Abstract

The majority of natural contacts with antigens take place through the mucosa of the gastrointestinal tract. Usually, these contacts result in a state of systemic immunological hyporesponsiveness to the antigen named oral tolerance. Oral tolerance depends on regulatory mechanisms that are triggered in the microenvironment of the gut mucosa and local inflammatory disturbances may compromise its development. In this study, we report two novel experimental models of inflammatory pathologies in the mucosa adjacent to the small intestine, both induced by topic administration of alcohol: gastritis and colitis. Although they are induced in two different strains of mice, C57BL/6 and BALB/c respectively, both diseases are characterized by an inflammatory infiltrate of mono and polimorphonuclear cells and by the local production of a mixed profile of cytokines with the presence of IL-4 and IFN-y. In these experimental models, disturbances in the balance of cytokines occur not only locally but throughout the intestinal mucosa. IL-4 is the most affected cytokine. Animais with either gastritis or colitis are refractory to oral tolerance induction. The immunological effects of alcohol administration were studied in more detail in the gastritis model. Although alcohol is promptly metabolized, several local and systernic functional alterations can be detected in these mice, such as reduction in the proteolytic activity, in the production of mucus and secretory IgA in the stomach, anemia and leukopenia. In these animais, we also demonstrate that alcohol administration induces an allergic-type inflammatory response. There is an increase in the production of IL-4, both in the stomach and in the spleen, as well as a rise in the leveis of serum IgE in mice with gastritis. Oral administration of ovalbumin (Ova) to these animais induces an increase in local vascular permeability and in the recruitment of eosinophils to the stomach. It also primes the animais augmenting the serum leveis of specific IgG 1 and IgE antibodies after parenteral immunization. Interestingly, sensitized mice show aversion to the intake of a sweetened Ovacontaining solution. In addition, DTH reaction triggered in mice with gastritis is marked by the presence of eosinophils and it resembles, in the histology and in the kinetics, the late phase of the hypersensitivity type 1 reaction. Such inflammatory alterations along with disturbances in the systemic and local immunoregulatory mechanisms, such as IL- 1 O production by spleen cells, may be related to the interference in oral tolerance induction. Mice with gastritis are refractory to tolerance induction by oral and intravenous routes. Mice genetically selected for susceptibility to oral tolerance induction to Ova become refractory after alcohol treatment and oral tolerance already stablished to a dietary protein, casein, can be disrupted by oral administration of alcohol. We also observed that the clearance of subcutaneously injected Ovais impaired in mice with gastritis. Analysis of macrophage activity in these mice shows a significant reduction in the time and efficiency of phagocytosis as long as 30 days after alcohol treatment although effector functions, such as ll..,-6 and NO production are only affected shortly after treatment. Since antigen presentation is an important event on the activation of T lymphocytes, it might be one of the alterations related to oral tolerance abrogation in this model. In conclusion, the present study describes two novel models of inflammatory pathologies of the mucosa of the gastrointestinal tract and shows that short-term alcohol administration have local and systemic immunological effects and it may compromise the development of oral tolerance to natural antigens such as dietary proteins.