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. Patients have evidence of activation of cytotoxic lymphocytes and excessive lymphokine production. Using molecular methods, we have shown that the genes for gamma-interferon and lymphotoxin are over-expressed locally in the bone marrow in patients with aplastic anemia. The bone marrow is also the local site of increased activated cytotoxic lymphocytes. Immunological activation in aplastic anemia may be due to a viral infection. The hepatitis/aplasia syndrome, which is non-A non-B non-C by serology and DNA studies, is the best clinical example of virus-incited marrow failure. However, we have been unable to detect viral sequences using a variety of molecular methodologies in fulminant hepatitis liver specimens of similar serologic and molecular character. The mechanism of interferon suppression of hematopoiesis has been elucidated by study of the Fas system. In tissue culture, gamma interferon induces Fas expression on hematopoietic cells, and activation of the Fas receptor is synergistic with lymphokine suppression of hematopoiesis at multiple stages of differentiation. Program cell death in hematopoiesis may be linked to nitric oxide production, and we have shown that CD34+ cells containing hematopoietic progenitors and stem cells are both susceptible to nitric oxide and contain an inducible nitric oxide synthetase. Finally, in our large clinical trial of intensive immunosuppression in severe aplastic anemia, which has enrolled over 55 patients, we have demonstrated a marked improvement in hematologic responses and survival compared to antithymocyte globulin alone. Therapy has been effective in children and in severely neutrophenic patients.