The overall goal of this study is to establish the therapeutic efficacy of the cytokine tumor necrosis factor (TNF) for leukemia, and to determine the mechanism of its anti-leukemia effects. TNF, a product of cells of the macrophage/monocyte series, is cytotoxic to many tumor cells in vitro and causes necrosis of solid transplantable tumors in mice. TNF also exerts profound effects on hematopoiesis and hematopoietic progenitors. On this basis, we evaluated the effects of TNF on murine, Friend virus-induced leukemia and found that the cytokine significantly suppresses leukemic erythropoiesis in vivo and causes disease regression in a substantial proportion of the leukemic animals. Combination of TNF with interferon-gamma (IFN-gamma) increased the incidence of leukemia regression. The mechanisms of these effects remain unknown.
The aims of this study include: 1) to determine whether TNF acts directly on leukemic cells to cause regression of the disease; 2) to determine whether TNF causes leukemia regression by acting through effects on host T cells or macrophages; 3) to further evaluate the synergism between TNF and IFN-gamma and determine whether this occur: by direct action on leukemic cells or through T cells and macrophages; and, 4) to determine whether the effects of TNF on normal hematopoietic progenitors occurs by direct interaction or through production of mediators by mature hematopoietic cells. These studies will be carried out using the Friend virus-induced erythroleukemia a model system that is extensively characterized and highly manipulable. Macrophage and T cell function are known to influence the course of this disease. The results of this study could provide a rational basis for the use of TNF therapy of leukemias and related diseases.
