We propose to use human recombinant hematopoietic growth factors, given either alone or in combinations, to investigate four important questions in the areas of total body irradiation (TBI) and marrow transplantation. We plan to carry out these studies in a well established preclinical model using random-bred dogs. We will first answer the question whether otherwise lethal irradiation injury to the marrow can be altered by the use of hematopoietic growth factors. This question will be addressed in dogs given single-dose TBI. This study has obvious therapeutic implications, not only for victims of radiation accidents, but also for patients with cancer in whom the marrow has been damaged by chemoradiation therapy. We then plan to address the second question, comparing the marrow toxicity of single-dose versus fractionated TBI attempting to amplify the marrow reserve surviving these two modes of TBI with help of hematopoietic growth factors. Results of this study will be important for the design of clinical TBI regimens used in marrow transplantation. A third question concerns acceleration of hematopoietic recovery after allogeneic DLA- identical marrow grafts; shortening the period of pancytopenia after grafting is likely to decrease the risk of infections after transplantation. WE would like to determine whether the potential benefit of growth factors may be offset by side effects, such as an increase in graft-versus-host disease or graft failure. Fourthly, we will address the usefulness of hematopoietic growth factors in the setting of T-depleted DLA-identical or non-T-depleted DLA-nonidentical marrow grafts, both of which carry in a high risk of graft failure. We propose to determine whether hematopoietic growth factors can substitute for the graft enhancing effect of viable donor lymphocytes without the added risk of graft-versus- host disease. Additionally, we plan to study whether IL-2 dependent cytotoxic cell lines specific for host antigens can also be used instead of peripheral blood lymphocytes. Results from these studies have direct implications for patients undergoing HLA-identical or HLA-nonidentical marrow transplants for malignant and nonmalignant hematological diseases. Along with the planned in vivo studies, we propose to clone the genes encoding for canine hematopoietic growth factors and produce the equivalent proteins which will allow us to substitute canine for human recombinant growth factors.
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