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

Abstract

BACKGROUNDImmunosuppression may benefit some patients with hypoplastic myelodysplasia (HMDS) and refractory anemia (RA), but its mechanism of action is still obscure.METHODSUsing 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.RESULTSIn 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.CONCLUSIONSIncreased 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

IFN-γ Negatively Modulates Self-Renewal of Repopulating Human Hemopoietic Stem Cells

“…Furthermore, IFN-␥ produced by human stromal microenvironment has been demonstrated to negatively affect hemopoiesis (16,47). In agreement with this, IFN-␥ inhibits the in vitro growth of hemopoietic progenitors, including primitive human CD34 ϩ…”

“…Clinical and experimental studies have strongly implicated IFN-␥ as a key mediator of BM failure in a number of diseases associated with inflammation, such as graft-vs-host disease, myelodysplasic syndromes, and aplastic anemia (10,11,21,47), and recent studies suggest that the ability of drugs, such as cyclosporine, to inhibit IFN-␥ production might explain their beneficial effects on hemopoiesis in patients with immune-mediated BM suppression (47). Furthermore, IFN-␥ produced by human stromal microenvironment has been demonstrated to negatively affect hemopoiesis (16,47).…”

Role of the p38 Mitogen-Activated Protein Kinase Pathway in Cytokine-Mediated Hematopoietic Suppression in Myelodysplastic Syndromes

“…Altogether, these studies showed that the p38 MAPK pathway is essential for the generation of the growth-inhibitory effects of IFN-a on leukemic progenitors, consistent with our previous observations in studies using SB203580 (11). TNF-a is overproduced in certain disease states and has been implicated in the pathogenesis of bone marrow failure syndromes and MDS (22)(23)(24)(25)(26)(27). We sought to examine the activation of the p38 MAPK pathway by TNF-a in hematopoietic cells and to identify downstream effectors of this signaling cascade that may be participating in the generation of TNF-a responses.…”

“…Several of these cytokines have been implicated in the pathophysiology of MDS and other bone marrow failure disorders, including ACD (22)(23)(24)(25)(26)(27). Therefore, we considered the possibility that pharmacologic inhibitors of the p38 MAPK pathway may reverse the suppressive effects of these cytokines in the bone marrows of patients with MDS and ACD, in which bone marrows there is abnormal cytokine overproduction.…”

“…22,23). Moreover, in addition to classic cytokine-mediated bone marrow failure syndromes, TNF-a, TGF-h, and IFN-g have been all implicated in the pathophysiology of certain subtypes of myelodysplastic syndromes (MDS), especially those with hypoplastic features (24)(25)(26)(27). As the p38 pathway is a common element in the signaling cascades of several myelosuppressive cytokines, we examined whether pharmacologic inhibition of its activation reverses the hematopoietic defects seen in MDS and ACD.…”