Background:
Immunosuppression may benefit some patients with hypoplastic myelodysplasia (hmds) and refractory anemia (ra), but its mechanism of action is still obscure.
Methods:
Using flow cytometry, we studied fas-receptor (fas-r), fas-ligand (fas-l), and interferon-gamma (ifn-gamma) expression in cd34(+) cells and lymphocytes obtained from 11 hmds and 20 ra patients. in colony assays and long-term cultures, the effects of fas triggering, ifn-gamma blockade, or cyclosporine(csa) on the growth of hematopoietic progenitors (colony-forming cells [cfc]) were determined. the effects of csa at daily doses of 1-3 mg/kg for at least 3 months in hmds patients were also studied.
Results:
In basal conditions, committed and immature progenitor cells were found decreased in myelodysplastic (mds) patients. no significant differences between hmds and ra patients were detected. ifn-gamma-expressing cd4(+) cells were significantly increased in hmds patients, whereas intracytoplasmic fas-l expression was only borderline elevated in cd3(+) mds cells. increased numbers of cd34(+) cells expressing fas-r were found in hmds and ra patients. cfc and secondary cfc showed higher susceptibility to fas-l-mediated inhibition and the blockade of ifn-gamma improved marrow primary, but not secondary, cfc growth. csa added in vitro to patient's lymphocytes significantly decreased the number of ifn-gamma-expressing cd4(+) cells, but not fas-l production. these effects were associated with increased colony formation. similar to ifn-gammablockade, production of secondary cfc was not enhanced by csa. administration of csa to patients resulted in prolonged partial hematologic improvement in 8 of 11 hmds patients.
Conclusions:
Increased frequency of ifn-gamma producing cd4(+) cells supports the involvement of lymphocyte-mediated suppression of hematopoiesis in the development of cytopenia in mds patients. the ability of csa to decrease in vitro ifn-gamma production may improve hematopoietic function, explaining the beneficial effect of this agent in hmds patients.