We propose to continue a program devoted to the study and treatment of patients with aplastic anemia, myelodysplastic syndromes, and inherited diseases of hematopoiesis, e.g. thalassemia major, sickle cell anemia, and inborn errors of metabolism. In vitro laboratory studies involving culture of hematopoietic cells and cellular interactions will focus on the etiology of aplastic anemia; in vitro study results will be correlated with clinical response to immunosuppressive therapy or to hematopoietic growth factors. Studies on marrow transplantation from HLA-identical siblings will be continued with emphasis on preventing graft rejection along with acute and chronic graft-versus-host disease. The use of less well matched family members and unrelated individuals as marrow donors will be explored. Marrow transplantation will be used for the treatment of patients with myelodysplastic syndromes. An initial exploratory meeting held here has set the stage for a consensus conference with regard to the applicability of marrow transplantation for the treatment of patients with sickle cell anemia. Infectious disease studies will concentrate on fungal and viral infections accompanying marrow transplantation. A new protocol will address the utility of marrow transplantation and antiretroviral therapy in patients who are found to be positive for the human immunodeficiency virus-1. Studies on late complications and the long-term outcome of marrow transplantation and immunosuppressive therapy for the prevention and treatment of chronic graft-versus-host disease will be carried out. Studies in a large random-bred animal model, the dog, will focus on exploring transfer of genes into pluripotent hematopoietic cells and their progeny via retroviral vectors. Marrow fibroblasts and skin keratinocytes are also being used as targets for gene transfer. If successful, the approach of gene transfer might be applicable to the treatment of certain genetically determined hematologic diseases. Other studies in the dog will focus on marrow graft rejection caused by sensitization through transfusion of blood products. We will try to understand the nature of the cells involved in sensitization and investigate approaches of changing the immunogenicity of blood products, thereby avoiding or abrogating sensitization. All of the clinical and laboratory studies are supported by a core project in pathology. Additionally, study design, data processing, and statistical analyses will provide maximum utilization of information generated. Many of the principles derived from these studies will be applicable to the treatment of other life-threatening diseases, e.g. hematologic malignancies.
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