The hematopoietic and immune systems are highly sensitive to the adverse effects of ionizing radiation. After relatively low level exposures (< 100 cGy total body), chromosomal aberrations in lymphocytes can be measured as well as decline in the white blood cell and platelet count. At levels of 200-400 cGy, marked leukopenia, lymphopenia, anemia, and thrombocytopenia can occur and 50% of those exposed to 400 cGy will die absent proper medical intervention. At higher levels of exposure (>400 - 1000 cGy), gastrointestinal and other organ toxicities can be seen, but the greatest risk to such patients is persistent failure of the hematopoietic and immune systems, resulting in life threatening complications (infections, bleeding). Unfortunately, specific therapies directed at accelerating the repair and recovery of the hematopoietic and immune systems following radiation injury have been few. In this project, we aim to characterize the capacity for human growth hormone (HGH), a recombinant product already in human use, to ameliorate the hematopoietic toxicities and immune failure that occur following radiation injury. HGH has postulated roles in stimulating thymopoiesis, lymphocyte recovery, erythropoiesis and granulopoiesis. However, its activity toward promoting the rapid recovery of the immunohematopoietic system after radiation exposure has not been demonstrated. In this project we will a) examine and characterize the activity of HGH to accelerate hematopoietic recovery in animals recently exposed to several levels of radiation and will determine whether HGH exerts its effect via hematopoeitic stem cell self-renewal or progenitor cell activation, b) characterize the activity of HGH toward recovering T and B cell function and thymopoiesis following radiation injury, and c) test these hypotheses in a large animal cynomolgus monkey model of radiation injury. Our overriding goal will be the demonstration of the unique radiotherapeutic capacity of HGH, a recombinant product ideally suited for addition to the National Stockpile of radiation countermeasures.
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