PATHOGENESIS AND TREATMENT OF APLASTIC ANEMIA

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Aplastic anemia and other forms of bone marrow failure have clinical and laboratory features consistent with a possible viral etiology followed by immunological pathophysiology. Aplastic anemia may follow on a viral infection, especially non-A non-B hepatitis. Patients have evidence of activation of cytotoxic lymphocytes, and excessive lymphokine production. During the past year, we have documented that these immunologic abnormalities are more striking when the bone marrow is examined compared to the peripheral blood. For lymphokine production, gamma-interferon mRNA expression, as determined by gene amplification, is prevalent and highly specific for aplastic anemia compared to normal and hematologic control specimens. Lymphotoxin gene expression, although present in normal bone marrow, is also increased in aplastic anemia. Lymphocyte phenotyping of aplastic bone marrow has shown increased cytotoxic lymphocytes, increased natural killer cells, and gamma delta T-cells in the majority of patients with this disease, indicating a broad immunologic response. The explanation for immunological activation in aplastic anemia has been hypothesized to be due to viral antigens. We have established that the hepatitis/aplasia syndrome is non-A non-B non- C. In experiments employing a sophisticated gene amplification methodology, we were unable to demonstrate the presence of novel DNA in fulminant hepatitis (related to hepatitis/aplasia), implicating an RNA rather than DNA virus in these syndromes. Finally, in clinical studies we have continued a program of intensive immunosuppressive therapy consisting of combined antithymocyte globulin and cyclosporin. Response rates continue to be approximately 70% in patients with severe aplastic anemia, higher than the hematologic improvement rates observed with antithymocyte globulin treatment alone. Of note, both children and patients with absolute neutropenia respond at a high rate to this therapy.