Sickle cell anemia and thalassemia are hemoglobinopathies associated with severe morbidity and mortality. No curative treatment is readily available for these patients. Recent advances in the prenatal diagnoses of these disorders permit the early identification of affected fetuses. However, the only intervention possible to date has been abortion of the fetus. Fetal transplantation of normal adult marrow in utero could correct these life-threatening disorders and offer an alternative to aborting affected fetuses. To accomplish this goal, techniques must be developed for fetal transplantation in man. However, little information is available about the growth of adult hematopoietic cells in a fetal environment. In this proposal, we will transplant baboon adult marrow cells into baboon fetuses at different gestational stages to determine: 1) Whether adult to fetal marrow transplantation is feasible in primates; 2) whether adult hematopoietic cells can grow in fetal liver, spleen, and marrow or can only grow in the marrow; and 3) whether adult marrow cells transplanted into a fetal microenvironment express an adult or fetal phenotype. In the first phase of these studies, 20 fetuses will be transplanted at different gestational ages and 28 days later, donor cells will be identified in cell suspensions of fetal liver, spleen and marrow using the genetic polymorphism we have recently demonstrated in baboons at the glucose phosphate isomerase (GPI) locus. We will also determine if donor hematopoietic progenitor cells are present in these organs using in vitro cultures of erythroid (CFU-E, BFU-E) and multipotent (CFU-GEMM) progenitor cells. The colonies will be tested for the presence of donor cells by means of GPI isozymes and the phenotype of the colonies assessed by analyzing the profile of surface membrane glycoproteins and expression of adult or fetal type hemoglobin. After determining the optimum fetal age for adult marrow engraftment, we will transplant 10 animals and """"""""sham transplant"""""""" 5 control animals. Hematologic chimerism will be determined in vivo using GPI determinations of peripheral blood cells. The presence of graft versus host disease will be determined and graded histologically. Surviving animals transplanted in the second phase of these studies will be followed for one year to determine if chimerism persists and the natural history of graft verus host disease.
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