Carcinogens, whether present in the environment, ingested in food or other products, are harmless until they have been absorbed across the mucosal surface. Once within the body, they are metabolized and can result in neoplastic transformation of host cells. Aflatoxin B1 (AFB1) is a potent carcinogen which has been found naturally in many agricultural products including peanuts, corn, milk, and animal feed. In humans, AFB1 has been associated with hepatocellular carcinoma. Recent studies have shown that serum IgG antibodies against AFB1 and some of its metabolites may be elicited by using parenteral vaccines of AFB1 conjugated to carrier proteins. However, this does not effectively stimulate the immune system which normally guards mucosal surfaces against invasion by microorganisms or damage from toxic products, the secretory IgA system. By stimulating secretory IgA to AFB1 we should be able to interfere with the absorption of AFB1 across the intestine into the host tissues rendering it harmless. The success of this approach in infectious disease research (some carried out in our laboratory) has led to the protective oral cholera vaccine currently being tested by the World Health Organization. In the present studies, we would use an experimental model in rabbits to elicit intestinal secretory IgA against the carcinogen AFB1-carrier protein conjugates. We will determine the optimal conditions and optimal AFB1-carrier. Further, we will determine whether such IgA antibodies in secretion can alter the absorption of AFB1 in the diet and significantly reduce the amount of AFB1 metabolized to a form capable of damaging cellular macromolecules (specifically DNA). A carcinogenicity bioassay in rat is proposed in order to test whether secretory immunity to AFB1 can confer protection to animals subsequently challenged with a carcinogen containing diet. If this approach can be shown to be valid, it opens the way to develop mucosal vaccines which could prevent tumor formation by AFB1 and other mucosal carcinogens.
| Oliver, A R; Silbart, L K; Keren, D F et al. (1997) Mucosal unresponsiveness to aflatoxin B1 is not broken by cholera toxin. Immunol Cell Biol 75:47-53 |
| Oliver, A R; Silbart, L K; Keren, D F et al. (1996) Mucosal tolerance to aflatoxin B1. Ann N Y Acad Sci 778:422-4 |
