Selleri Carmine, Maciejewski Jaroslaw P, Catalano Lucio, Ricci Patrizia, Andretta Claudia, Luciano Luigiana, Rotoli Bruno
Division of Hematology, Federico II University of Naples, Italy.
Cancer. 2002 Nov 1;95(9):1911-22. doi: 10.1002/cncr.10915.
Immunosuppression may benefit some patients with hypoplastic myelodysplasia (HMDS) and refractory anemia (RA), but its mechanism of action is still obscure.
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.
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.
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.
免疫抑制可能对一些低增生性骨髓增生异常综合征（HMDS）和难治性贫血（RA）患者有益，但其作用机制仍不清楚。
我们使用流式细胞术研究了从11例HMDS患者和20例RA患者获得的CD34(+)细胞和淋巴细胞中Fas受体（Fas-R）、Fas配体（Fas-L）和干扰素-γ（IFN-γ）的表达。在集落测定和长期培养中，确定了Fas触发、IFN-γ阻断或环孢素（CsA）对造血祖细胞（集落形成细胞[CFC]）生长的影响。还研究了CsA以每日1-3mg/kg的剂量给药至少3个月对HMDS患者的影响。
在基础条件下，骨髓增生异常综合征（MDS）患者中定向和未成熟祖细胞减少。未检测到HMDS患者和RA患者之间的显著差异。HMDS患者中表达IFN-γ的CD4(+)细胞显著增加，而CD3(+)MDS细胞中细胞质Fas-L表达仅略有升高。在HMDS和RA患者中发现表达Fas-R的CD34(+)细胞数量增加。CFC和二级CFC对Fas-L介导的抑制更敏感，IFN-γ阻断改善了骨髓一级CFC的生长，但未改善二级CFC的生长。体外向患者淋巴细胞中添加CsA显著降低了表达IFN-γ的CD4(+)细胞数量，但未降低Fas-L的产生。这些作用与集落形成增加有关。与IFN-γ阻断相似，CsA未增强二级CFC的产生。对患者给予CsA导致11例HMDS患者中的8例出现部分血液学改善延长。
产生IFN-γ的CD4(+)细胞频率增加支持淋巴细胞介导的造血抑制参与MDS患者血细胞减少的发生发展。CsA降低体外IFN-γ产生的能力可能改善造血功能，解释了该药物对HMDS患者的有益作用。
