No abstract

The bcl-2 oncoprotein, which is involved in the t(14,18) translocation, protects cells against apoptosis. We examined the effects of interferon-alpha (IFN-alpha) on bcl-2 protein expression and apoptosis in B-chronic lymphocytic leukaemia (B-CLL) cells. None of 12 patients with B-CLL examined expressed the t(14,18) translocation; however, all these, and seven other patients, expressed significant levels of bcl-2 protein. In vitro, IFN-alpha (500 U/ml over 18 h) increased bcl-2 expression on CLL cells (to 200 +/- 23% of control MCF, as determined by indirect immunofluorescence and flow cytometry, n = 10, P < 0.001). All of eight patients who received IFN-alpha (3 megaunits subcutaneously three times a week) demonstrated an increase in bcl-2 expression on circulating malignant cells. CLL cells undergo apoptotic cell death when cultured in vitro (35.6 +/- 10.3% DNA fragmentation after 18 h, n = 10). In the presence of IFN-alpha, however, DNA fragmentation was reduced to 6.6 +/- 5.8% (n = 10, P < 0.001). IFN-alpha also protected CLL cells against apoptosis induced by hydrocortisone and gamma irradiation (reducing DNA fragmentation from 63.9 +/- 12.6% to 10.8 +/- 4.5% and from 80 +/- 2.9% to 5.4 +/- 1.6%, respectively, P < 0.001 for both). The protective effect of IFN-alpha was dose dependent, and maintained for up to 24 h. Our data demonstrate that bcl-2 expression and apoptosis of CLL cells can be influenced by cytokines. In addition, it seems unlikely that the observed clinical responses to IFN-alpha in patients with CLL are due to a direct effect on the malignant cells.

We have examined the frequencies of T gamma delta cells in blood, synovial fluids, and synovial membranes of patients with rheumatoid arthritis (RA) and in blood from age-matched controls. Immunocytochemical and immunohistochemical techniques were used with monoclonal antibodies BB3 and A13 to define a major and minor blood subset of T gamma delta cells respectively. Together, these antibodies identify the majority (if not all) of the peripheral blood T gamma delta cells. Significantly lower levels of T gamma delta cells were found in the blood of RA patients compared with controls, whilst higher but not significant numbers were found in the synovial fluids of paired samples. Scattered T gamma delta cells were found only in some synovial membranes with a distribution similar to the T alpha beta cells. Analysis of the two different T gamma delta-cell subsets indicated a ratio of BB3 to A13 of about 5:1 in control and RA blood. However, this ratio was less than 1:1 in the RA synovial fluids and membranes. The migratory nature of the A13+ cells could account for their predominance in these sites. The possible pathological significance of these cells in the rheumatoid synovial fluid and synovial membranes is discussed.

No abstract

Seventeen patients with hairy-cell leukaemia (HCL) and peripheral cytopenias were given human lymphoblastoid interferon (Wellferon), 3 megaunits daily or 6 megaunits on alternate days intramuscularly, for 4-24 weeks. Twelve of the patients had undergone splenectomy, three had no palpable spleen and had therefore not been offered surgery, and two patients with substantial splenomegaly were given interferon (IFN) as treatment of first choice. Toxic effects were minor except in one patient who experienced a severe form of somnolence syndrome. In all patients hairy cells (HCs) were cleared from the blood and platelet and Hb levels improved in 2-14 weeks. Neutrophils were improved in 14/17 of the patients. In the two patients with splenomegaly, the spleen became impalpable after 5-8 weeks therapy, and haematological improvement occurred at 12-14 weeks. HC infiltration of the marrow was reduced in all patients, but was complete (less than 5%) in only two, both of whom had impalpable spleens. Immunological surface-marker studies confirmed that light-chain-restricted B cells disappeared from the blood in parallel with the clearance of morphological HCs. There was no evidence of HC maturation and no increase in phenotypic NK cells. T cells were moderately reduced and the relatively greater reduction of Leu 2a+ suppressor cells resulted in increased Leu 3a+/2a+ helper/suppressor ratios in 11/17 of the patients. Early experience in the six patients who have stopped IFN suggests that, after an initial further increase in Hb and neutrophil levels, HCs gradually return with slow deterioration of haematological parameters. Interferon is now the treatment of choice for patients becoming cytopenic post-splenectomy or for patients without splenomegaly. IFN is effective first-line therapy in patients with splenomegaly, but further work is needed to establish whether the agent should replace splenectomy in such patients. Some form of maintenance or re-treatment therapy will probably be necessary.