Aplastic anemia and other forms of bone marrow failure have clinical and laboratory features consistent with a possible viral etiology followed by immunological pathophysiology. In particular, aplastic anemia may follow on viral infections, especially non-A non-B hepatitis. Patients have evidence of activation of their immune system similar to that observed in many viral infections, such as activation of cytotoxic lymphocytes, excessive lymphokine production, and decreased natural killer cells. With the recent discovery of hepatitis C virus, the agent for non-A non-B hepatitis, we have tested the hypothesis that aplastic anemia may be incited by hepatitis C infection. However, using several different experimental approaches, we have excluded hepatitis C as an etiologic agent in hepatitis/aplasia syndrome and in aplastic anemia in general, although we have established hepatitis C infection as frequent following transfusion in this patient population. Based on these studies and those of patients with fulminant hepatitis, we suggest the existence of a novel hepatitis agent, hepatitis F, as responsible for aplastic anemia and fulminant hepatitis. We have investigated a member of the herpesvirus family, cytolomegalovirus, which is implicated in marrow graft failure following transplantation. We have established that cytomegalovirus can be propagated in human macrophages and monocytes and in hematopoietic progenitor cells without affecting their number or function. Recombinant cytomegalovirus may be useful efficiently for gene transfer for therapy. In clinical studies, we have investigated a variety of hematopoietic growth factors for their efficacy in the treatment of marrow states. Most successfully, we have shown that interleukin-3 can lead to complete remissions in patients with congenital pure red cell aplasia (Diamond-- Blackfan anemia). In myelodysplasia, G-CSF appears to be superior to either GM-CSF or IL-3 in a controlled study. Interleukin-1 has not been effective in patients with refractory aplastic anemia, although these patients lack interleukin-1 production as measured in vitro. Finally, we have instigated studies of intensive immunosuppression for severe aplastic anemia utilizing anti-thymocyte globulin in combination with cyklosporine; this regimen appears to be a significant advance over ATG treatment alone.

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National Heart, Lung, and Blood Institute (NHLBI)
Intramural Research (Z01)
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