Although the effects of colony-stimulating factors (CSFs) on human lymphocytes have not been documented, both the lymphocytosis induced by recombinant human (rh) granulocyte- macrophage colony-stimulating factor (GM-CSF) in primates and the in vitro stimulating effects of murine interleukin (IL) 3 (multi- CSF) and GM-CSF on pre-B and pre-T cell clones and on helper T cells suggest that these CSFs can support the proliferation of cells within the lymphoid lineage. Our preliminary data indicate that rh preparations of GM-CSF and IL 3 can: a) both independently and synergistically support the continuous growth of human leukemia cell lines, including an undifferentiated T-cell leukemia and a biphenotypic B-myelomonocytic leukemia, and b) drastically potentiate peripheral blood T cell proliferation in the presence of rhIL 2. The overall goal of this proposal is to investigate the combined effects of the CSFs and ILs on the growth of mature and immature lymphocytes from healthy subjects and acute lymphoblastic leukemia patients. In particular, we will 1) examine the stimulatory effects of GM-CSF and IL 3 alone or in association with Il 1 alpha and IL 2 on the short- and long-term growth of natural killer (NK) cells, lymphokine- activated killer (LAK) cells, suppressor and helper T cells, and B lymphocytes; 2) investigate the biological and molecular mechanisms by whcih these hemopoietic growth factors induce proliferative responses, by analyzing the expression and cross- modulation of specific growth factor receptors and the induction of mRNA for specific lymphokines; and 3) determine the frequency with which undifferentiated T- and B-lymphoblastic leukemias proliferate in response to and become dependent on GM-CSF and/or IL 3. Success in optimizing the growth of human lymphocytes and preferentially expanding or cloning lymphocyte subsets endowed with specific phenotype and function would be greatly advantageous in many aspects of immunotherapy, allowing the possibility to reduce the toxicity associated with the administration of high doses of rhIL 2 along with LAK cells or tumor-specific cytotoxic T lymphocytes. Moreover, the establishment of permanent leukemia cell lines of lymphoblastic origin will provide a unique model system to evaluate both the growth factor requirements of leukemic pre-T and pre-B cell precursors and the mechanisms controlling their proliferation and differentiation.
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