Effects of cyclosporine on hematopoietic and immune functions in patients with hypoplastic myelodysplasia

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Abstract
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-γ (IFN-γ) 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-γ 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-γ–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-γ improved marrow primary, but not secondary, CFC growth. CsA added in vitro to patient's lymphocytes significantly decreased the number of IFN-γ–expressing CD4+ cells, but not Fas-L production. These effects were associated with increased colony formation. Similar to IFN-γblockade, 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-γ 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-γ production may improve hematopoietic function, explaining the beneficial effect of this agent in HMDS patients. Cancer 2002;95:1911–22. © 2002 American Cancer Society. DOI 10.1002/cncr.10915