S. Cinieri

Biochemical and immunological responses of hairy cell leukemia patients to interferonβ

SummaryTen hairy-cell leukemia patients were treated with interferon β (IFN-β) at a dose rate of 2 × 106 IU/m2 × 5 days for 4 weeks (induction therapy) and, thereafter, at the same dose three times a week for 11 months (maintenance therapy). The effect of this treatment on serum neopterin, β2-microglobulin, (2′–5′)oligoadenylate [(2′–5′)An] levels, intracellular (2′–5′)An values and human Mx protein synthesis was analysed. There were significant rises in serum neopterin and (2′–5′)An levels during both induction and maintenance, whereas β2-microglobulin levels rose only during induction. Rises in intracellular (2′–5′)An were documented mainly during induction, but they were not significantly higher than pretherapy values. IFNβ provoked an increase in human Mx protein synthesis over the entire induction — maintenance period, but was only significantly higher than baseline during induction. All markers proved useful for monitoring the effects of IFNβ dose schedules, but were not predictive of clinical outcome. Natural killer activity and IFNγ production, which were initially defective, followed a different trend from that of the other factors studied, in that increases were documented only late in the course of therapy when the disease was already in remission.

Modulation of NK activity by thymic hormones:in vitro effects of thymostimulin

Plastic-adherent depleted or not depleted peripheral mononuclear blood cells (PMBC) from healthy donors showed enhanced lytic activity against51Cr-labelled K562 target cells when exposed to thymostimulin (TS), 1 μg ml-1, for 3 h, washed and incubated in TS-free medium before testing for natural killer (NK) cytotoxicity. No modification of NK cell activity was seen when effector cells were treated with placebo (splenic extract). The NK boosting activity of TS was lost when effector cells were treated for 3 h immediately before the performance of the cytotoxic test or when this thymic extract was added directly to the mixture of effector and target cells during the lytic phase of51Cr release assay.

Natural-killer-stimulatory effect of combined low-dose interleukin-2 and interferon β in hairy-cell leukemia patients

The association of low doses of interleukin-2 (IL-2; 5 IU/ml) and interferon β (IFNβ; 10 IU/ml) induced an additive or synergic stimulatory effect on natural killer (NK) activity (32%) in peripheral blood samples from hairy-cell leukemia patients, both those with active disease and those in remission. The synergic NK stimulatory effect was more commonly found in samples from patients with active disease, while the additive effect was more frequent in the patients in remission. The IL-2/IFNβ combination provoked a nonadditive nonsynergic NK-stimulatory effect in a further 19.8% samples. The targets of the IL-2/IFNβ combination were typical NK cells, as shown by the fact that there was increased cytotoxicity (synergic, additive or nonadditive nonsynergic) against the K562, but not the Daudi cell line in peripheral blood mononuclear cell samples treated with the combination of the two cytokines. When CD16+/CD56+ or CD57+/CD16+/CD56+ cells were removed, the NK-stimulatory effect was lost. The fact that the NK-cell-enhancing activity of the IL-2/IFNβ combination was reduced when Percoll fractions 2 and 3 were used, but still persisted in 66% of tests, may have been due to cytotoxicity being higher in the untreated fractions 2 and 3 than in the untreated unfractionated samples. One of the factors responsible for the NK-stimulatory effect appears to be the capacity of the IL-2/IFNβ combination to trigger an increase in IFNγ synthesis. If similar experiments give like results in samples from patients suffering from other B-cell lymphoproliferative, or HIV-associated disorders, all of which are characterized by a deficiency in NK activity, it should be possible to use low-dose IL-2/IFNβ to treat these disorders and, perhaps, residual neoplastic disease without exposing the patient to undue toxicity. Further, by testing other combinations one should be able to identify the lowest IL-2 and IFNβ doses that would effectively boost the additive or synergic effect in a greater number of cases.