The broad objective of this proposal is to study the etiology of B lymphoid malignancies, and in particular the chronic lymphocytic leukemias of B cell origins (B-CLL). Using a rat model these studies will examine the role of the Peyer's patch, a gut associated lymphoid organ, in the induction of B lymphocytic malignancies by chemical carcinogens. The rationale for focusing these studies on the Peyer's patch is based on 1) the structural organization and functional characteristics which are unique for the Peyer's patch and 2) results from previous studies demonstrating the ability to reproducibly induce primary B-CLL with a reasonably high frequency by localizing a chemical carcinogen in the Peyer's patch. The general hypothesis to be tested is that the Peyer's patch has a unique role in the carcinogenesis of B lymphocytes. The specific objectives in testing this hypothesis are 1) to examine the role of the Peyer's patch in facilitating the absorption of lumenal carcinogens and subsequently the localization of carcinogens within the lymphoid follicles of the Peyer's patch, 2) to determine if chemical carcinogens are retained within the Peyer's patch, 3) to examine the susceptibility of resting versus proliferating B lymphocytes to carcinogenic events, 4) to establish whether B cell malignancies can be induced by chemical carcinogens introduced orally into the small intestinal lumen, 5) to determine if the Peyer's patch is the site of B lymphocyte transformation following exposure to a chemical carcinogen and 6) to determine if the Peyer's patch is a focal point of proliferation of the neoplastic B-CLL cells. Due to the paucity of animal models to study B-CLL, the ability to reproducibly induce primary B-CLL may be of particular importance. Furthermore the use of a primary B-CLL model may offer distinct advantages in the study of the initial induction events. And finally, in light of the recent interest in the environmental influences of chemical carcinogens on human cancer development, the proposed studies may prove useful in the development of adequate animal models to study the role of the gut associated Peyer's patches in the induction of lymphocytic malignancies by carcinogens introduced via the gastrointestinal tract.
Showing the most recent 10 out of 15 publications
