Alessandro Rambaldi

THERAPY WITH HUMAN RECOMBINANT ERYTHROPOIETIN IN PATIENTS WITH MYELODYSPLASTIC SYNDROMES

We welcome the opportunity to comment on the letter of Drs Snowden and Bhavnani about granular T lymphocyte proliferation and B-cell dysfunction. As they and other researchers (Loughran & Starkebaum, 1987; Semenzatoet al, 1987; Bassanet al, 1989)pointedout. granular lymphocyte-proliferative disorders (GLPD) (Oshimi, 1988) are frequently associated with B-cell dysfunctions including polyclonal hypergammaglobulinaemia, autoantibody production, autoimmune diseases, M-proteinaemia and B-cell neoplasms. The fundamental question to be answered is whether GLPD induce B-cell dysfunction or B-cell dysfunction induces GLPD. Both possibilities are likely. When GLPD cells do not possess suppressor function, or when GLPD cells have contrasuppressor function (Saito et al. 1991). gammaglobulin level may be elevated, though the function of GLPD cells does not always correlate with the serum immunoglobulin level (Semenzato et al, 1987; Saito et al, 1991). B-cell neoplasms may induce GLPD. T-lineage GLPD cells are considered to be in vivo-primed cytotoxic T lymphocytes (CTL) (Kaneko et al. 1992). and therefore these CTL may have been primed in vivo by tumour antigens, or CTL that have been generated in vivo by other stimulants, such as viruses, may have been expanded by cytokines produced by B-cell neoplasms.

Constitutive expression of IL-1β, M-CSF and c-fms during the myeloid blastic phase of chronic myelogenous leukaemia

During the myeloid blast crisis (BC) of chronic myelogenous leukaemia (CML) non‐random additional chromosome abnormalities occur in over 80% of patients. However, these cytogenetic changes have been reported to precede the clinical signs of CML‐BC by several months to years suggesting that other biological events may participate in the multistep process of acute transformation of CML. The autocrine production of growth factors has been recently shown to occur in several haematological malignancies and particularly in acute myeloblastic leukaemia (AML). In the present report we demonstrate that IL‐1β gene is expressed in almost all cases of CML in myeloid blast crisis. The secretion of IL‐1 from CML blasts in culture supernatants was confirmed in all five of the patients we studied. A high proportion of cases showed constitutive expression of the M‐CSF gene and many of the same patients often had a simultaneous co‐expression of the proto‐oncogene c‐fms which encodes for the M‐CSF receptor. After exposure of leukaemic cells to phorbol myristate acetate (PMA), release of M‐CSF protein was documented in three of five patients studied. No significant interleukin‐3 (IL‐3), granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) or granulocyte colony‐stimulating factor (G‐CSF), was detected in these patients demonstrating that a different pattern of growth factors secretion exist in AML and CML, where distinct molecular events are likely involved in the control of leukaemic proliferation.

Interleukin-1 and glomerular mesangial cells.

Our previous in vitro study demonstrated that interleukin-1 (IL-1) stimulates gene expression and production of leukocyte chemotactic factors, colony-stimulating factors and interleukin-6 in human mesangial cells in culture. Here we investigated whether IL-1 regulates its own gene expression in human mesangial cells. Northern blot experiments showed that IL-1 induced IL-1 mRNA expression in a dose-dependent manner. The action of IL-1 on mesangial cells was mediated through the IL-1 receptor type I, which is constitutively expressed by mesangial cells. Recombinant IL-1 receptor antagonist blocked the IL-1 mRNA as well as interleukin-6 and interleukin-8 gene expression induced by IL-1. These data support the crucial role played by IL-1 in regulating mesangial cell cytokine genes within the glomerulus during immunological or inflammatory processes.