Effects of cyclosporine on hematopoietic and immune functions in patients with hypoplastic myelodysplasia: in vitro and in vivo studies.
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.
Selleri
Carmine
C
Division of Hematology, Federico II University of Naples, Italy. selleri@unina.it
Maciejewski
Jaroslaw P
JP
Catalano
Lucio
L
Ricci
Patrizia
P
Andretta
Claudia
C
Luciano
Luigiana
L
Rotoli
Bruno
B
D000328:Adult; D000368:Aged; D000753:Anemia, Refractory / Q000188:drug therapy; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018952:Antigens, CD34 / Q000032:analysis; D000954:Antigens, Surface / Q000378:metabolism; D015704:CD4 Antigens / Q000032:analysis; D002478:Cells, Cultured; D016572:Cyclosporine / Q000627:therapeutic use*; D053222:Fas Ligand Protein; D005260:Female; D005434:Flow Cytometry; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000502:physiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D016176:T-Lymphocyte Subsets; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism / Q000502:physiology
D000911:Antibodies, Monoclonal; D018952:Antigens, CD34; D000954:Antigens, Surface; D015704:CD4 Antigens; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007166:Immunosuppressive Agents; D008024:Ligands; D008562:Membrane Glycoproteins; D019014:fas Receptor; D007371:Interferon-gamma; D016572:Cyclosporine