MECHANISMS OF CARCINOGEN-INDUCED IMMUNE DYSFUNCTION

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The ability of aflatoxin B1 (AFB1) and other carcinogens to induce immunosuppression in animals has been well documented. However, analysis of the molecular and cellular mechanisms involved have yet to be addressed. The Shasta strain of rainbow trout, aside from being an excellent animal model for the induction of hepatocellular carinomas by AFB1, also demonstrates the induction of immune dysfunctions to this agent. These dysfunctions are related to an inability to develop immunological memory and may be the result of deficits in immune regulation either by non-lymphoid or lymphoid cells. Conversely, they may be due to direct genotoxic damage to the B lymphocyte. Thus, the goals of this study are to 1) perform molecular and cellular analyses of the immune responses generated in AFB1-exposed fish to determine the origin of this immune dysfunction and 2) to examine other genotoxic carcinogens/immunotoxicants for similar forms of immunosuppression. Shifts in fine specificity of antibodies generated in AFB1 -exposed animals must be due to the altered expression of antibody by B cell populations. This may occur either through changes in the regulation of memory development or by direct effects on B lymphocytes. Characterization of antibodies by fine specificity, spectrotypic, and idiotypic analyses will permit the "fingerprinting" of these antibody populations, which in turn will be used to determine if the apparent shift in antibody repertoires are due to random or non-random processes. These techniques will also provide the necessary tools that will be required for future genetic analyses. The cellular origin of this memory dysfunction will be addressed by the use of precursor frequency analysis, mitogenic assays coupled with cellular partitioning techniques and adoptive cell transfers. Studies devoted to the study of the cellular mechanisms involved during embryonic and in vitro AFB1 exposure will require the development of autologous and syngeneic cell transfer systems. The use of syngeneic strains of trout will also be of benefit to immunological research in general and also provide the means by which the long-term propagation and study of tumor lines may be realized.