(taken from the application) Helicobacter pylori is usually acquired during childhood and its prevalence in adults ranges from 20-30% in industrialized countries to 80-90% in developing countries. The prevalence of H. pylori infection is considerably higher in minorities in the US compared to the general population. Infection elicits a sustained host immune response but this is not effective in eliminating the organism. In contrast, oral immunization in mice and ferrets with various H. pylori antigens can prevent and even cure Helicobacter infection, indicating that H. pylori is not beyond the reach of an effective immune response. The mechanisms by which H. pylori persists despite the natural host immune response and those by which oral immunization provides protection or cure remain undefined. The long term goal of this proposal is to develop an effective human vaccine against H. pylori. This will allow control of the infection in the population, a goal that is unlikely to be achieved by antibiotic-based therapies. The immediate goal of this proposal is to acquire a better understanding of the mechanisms by which oral immunization confers protection, thereby enabling the design of an effective human vaccine. Using H. felis infection and urease-based immunization as models, this proposal aims at delineating the origin and the homing pattern of the immune cells that participate in the protection of the gastric mucosa. First, the role of alpha4 Beta7+ lymphocytes in protective immunity after oral immunization with H. pylori urease will be examined in mice. In vivo injection of anti-alpha4 Beta7+ integrin antibodies and passive transfer of alpha4 Beta7+ lymphocytes will be used to define the role of alpha4 Beta7+ lymphocytes in protection. The antigen specificity of alpha4 Beta7+ cells will also be determined. Second, the contribution of MAdCAM-1 addressin to gastric homing of immune cells will be determined in vitro by immunohistochemistry and in vivo by anti-MAdCAM-1 antibody treatment of immunized and challenged animals. Third, alpha4 Beta7+ lymphocytes will be quantified in the peripheral blood of human volunteers immunized with H. pylori urease by different routes of mucosal immunization. The antigen specificity of these cells will also be determined. These experiments will allow a better definition of the immune effector mechanisms engaged in mice during H. felis infection and during mucosal immunization in both mice and humans. These studies may also contribute to the development of effective vaccination strategies against other enteric pathogens.
| Michetti, M; Kelly, C P; Kraehenbuhl, J P et al. (2000) Gastric mucosal alpha(4)beta(7)-integrin-positive CD4 T lymphocytes and immune protection against helicobacter infection in mice. Gastroenterology 119:109-18 |
| Verdu, E F; Bercik, P; Cukrowska, B et al. (2000) Oral administration of antigens from intestinal flora anaerobic bacteria reduces the severity of experimental acute colitis in BALB/c mice. Clin Exp Immunol 120:46-50 |
| Michetti, P; Kreiss, C; Kotloff, K L et al. (1999) Oral immunization with urease and Escherichia coli heat-labile enterotoxin is safe and immunogenic in Helicobacter pylori-infected adults. Gastroenterology 116:804-12 |
