PATHOGENESIS AND TREATMENT OF APLASTIC ANEMIA

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Aplastic anemia and other types of bone marrow failure have clinical and laboratory features consistent with an autoimmune pathophysiology. Most patients respond with hematologic improvement to immunosuppression. Our laboratory studies have focused on the immune pathophysiology of this disease, identification of a putative viral antigen, and the mechanism of development of late clonal hematologic syndromes. Studies of the post-hepatitis aplastic anemia have shown that this is an immunologically-mediated disease without a known viral agent. Molecular methods developed for the study of bone marrow in aplastic anemia and of liver in fulminant hepatitis are now being applied to specimens of blood from patients with seronegative acute hepatitis. The immunological events that precipitate bone marrow failure through hematopoietic cell destruction have been defined. Recent observations include identification of appropriate inhibitory cytokine receptors on hematopoietic cells and characterization of the intracellular signaling pathway after gamma-interferon interferon receptor engagement. A practical method for the convenient assay of cytokine-containing peripheral blood and bone marrow lymphocytes has been developed which may be applicable to the evaluation of patients before and during immunosuppressive treatment. The problem of late clonal hematologic diseases, especially paroxysmal nocturnal hemoglobinuria, has been partly resolved with the discovery that cells with mutations in the PIG-A gene, and consequent absent expression of glycophosphoinositol-linked membrane proteins, are not susceptible to some types of immune system attack. Both primary lymphocytes from patients and a cell line, for which paired normal and mutant strains are available, have been used to show that T cells and natural killer cells are not effective in inducing cytotoxicity in glycophosphoinositol- linked membrane protein-deficient cells. Finally, further analysis of a large cohort of patients uniformly treated with intensive immunosuppression consisting of a combination of anti-thymocyte globulin and cyclosporine has revealed new features of treated aplastic anemia. Intensive immunosuppression is highly effective, inducing hematologic responses in about 70% of patients. Both children and patients with extremely severe neutropenia, two groups relatively refractory to more conventional forms of treatment, are responsive. Of note, many patients require continued treatment (usually reinstitution of cyclosporine) but, in contrast to the leukemias, "relapse" does not have an adverse effect on prognosis.