These studies will continue to evaluate the role of colony stimulating factors (CSFs) in the regulation of granulopoiesis. They will examine the activity of the known CSFs in the control of baseline neutrophil and monocyte production. Experiments will be extended to determine both beneficial as well as potential deleterious effects when these factors are used as pharmacologic agents. Antibodies will e produced to the purified or recombinant growth factors and to the specific cellular receptors for these factors. These antibodies will be used not only in mice but in agar gel cultures, in long-term marrow cultures and in experiments utilizing peritoneal diffusion chambers in irradiated mice. The latter approaches will help determine the degree of CSF production by the local microenvironment and the role of such factors in cellular proliferation. Unique experiments will examine the access, after injection, of the various CSF preparations to the responsive hemopoietic progenitor cells in vivo. These findings will indicate how many receptors need to be saturated in order to induce effects and should provide guidelines for the optimal administration of these agents. The beneficial effects of the CSFs will then be explored in animals after high dose chemotherapy or irradiation and marrow transplantation. Experiments will determine whether the CSFs can induce stem cell exhaustion when administered after minimal doses of bone marrow cells in the transplantation model. Possible marrow protection with Interleukin-1 (IL-1) and additive or synergistic actions of IL-1 with the CSFs will be determined after irradiation and chemotherapy. Potential additive or synergistic effects of the know CSFs with each other will be explored in normal and in myelosuppressed animals. Experiments will determine whether the synergy of CSF-1 with GM-CSF and IL-3 that is seen in vitro will have potential therapeutic benefits in vivo.
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