Cholera toxin and the similar heat labile toxin of E. coli are among the most effective adjuvants known for enhancing mucosal immune responses. These toxins have been shown to enhance immune responses after both oral and intranasal immunization. The mechanism(s) which these molecules use to enhance immune responses are not well established, however, and their inherent toxicity is a major problem which makes their use in humans impractical. As probes into the mechanism(s) by which these toxin molecules enhance immune responses, the investigators have assembled a panel of genetically engineered toxin derivatives, many with reduced or absent toxicity. Using both model antigens and infectious challenge models in mice, they will investigate the mechanisms by which native and altered toxins enhance oral and intranasal immune responses. The investigators will determine how native and engineered toxin molecules affect uptake of model antigens into mucosal tissues such as Peyer's patches and enterocytes and whether antigen presentation and intracellular antigen processing is up regulated. They will also study the direct effects of cholera toxin/heat labile toxin and engineered derivatives upon antigen responsive B lymphocytes and the effects upon patterns of cytokine secretion by T lymphocytes. Ultimately, if non-toxic derivatives of cholera toxin or heat labile toxin which still stimulate mucosal immune responses are identified, they may find use as adjuvants for mucosal vaccines versus pathogenic organisms or even dietary carcinogens. Thus, they will also investigate the effectiveness of non-toxic-engineered cholera toxin/heat labile toxin derivatives in promoting protective immune responses in two infectious challenge models. The models which the investigators have chosen are intranasal Sendai virus infection and oral Helicobacter felis infection. Sendai virus infects the respiratory tract and is a murine parainfluenza virus. Helicobacter infections of gastric tissue have been implicated as causes of gastroduodenal ulcers and gastric cancer.
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