This application deals with the relationship of erythropoiesis to immune function in the context of a fatal leukemia in inbred mice. Erythropoiesis in mice can be transformed by Friend viruses which cause anemia, hepato-splenomegally, and hemorrhagic death in infected animals (FVA). With the FVA virus complex applied to these studies, erythroleukemic cells maintained their erythropoietin dependence, so that although neoplastic growth occurred, the neoplasm retained some of the homeostatic characteristics of erythropoiesis. Most mouse strains are susceptible to FVA, and those which are not exhibit a well-described phenotype of resistance at the Fv-2 locus. It has only recently been shown that a cogenitally immunodeficient (xid-) strain, CBA/N, is resistant to FVA, and that CBA/N does not fit the pattern for mice genetically resistant at the Fv-2 locus. Even more important that its apparent resistance to FVA, CBA/N mice could be rendered susceptible to FVA by vigorous immune challenge prior to virus exposure. This series of observations creates an ideal opportunity for the development of a mouse model system to study the relationship of steady-state and potentiated immune function to erythropoiesis, both normal and leukemic. The present proposal outlines studies of erythropoiesis, using established in vitro techniques, along with assays of lymphocyte function, and analysis of erythroid and lymphoid cell surface phenotypes using flow cytometry, before and after CBA/N mice become susceptible to FVA. The following unanswered questions will be experimentally addressed: What is the status of etythropoiesis on CBA/N mice and how is that status altered by changes in immune activity? Does the genetically altered immunologic capacity of CBA/N affect erythropoiesis? Can immunologic defects influence the availability of erythroid target cells for leukemic transformation? Are there hymphocyte subsets which can promote erythroleukemic transformation? These are the specific hypotheses to be explored by this grant. These are also basic and fundamental issues involving the regulatory interactions of blood cell lines in mammals, under both normal and pathological conditions, and some of the knowledge gained will serve as a template for understanding similar processes in the context of human health and disease.
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