EFFECTS OF INTERLEUKIN-12 ON NATURAL-KILLER-CELL CYTOTOXICITY AND THEPRODUCTION OF INTERFERON-GAMMA AND TUMOR-NECROSIS-FACTOR-ALPHA IN PATIENTS WITH MYELODYSPLASTIC SYNDROMES

The effects of interleukin 12 (IL-12) on natural killer (NK) cell cyto toxicity and on the production of interferon-gamma (IFN-gamma) and tum our necrosis factor-alpha (TNF-alpha) were examined in 15 patients wit h myelodysplastic syndromes (MDS), which are well known to have immuno logic defects, and in 11 normal subjects. The NK cell cytotoxicity of all of the normal subjects was augmented by incubation with IL-12 alon e, and co-incubation with interleukin 2 (IL-2) further augmented it (t ype A response). The MDS patients showed varied responses to IL-12/IL- 2. Seven patients showed the type A response, resulting in augmented N K cell cytotoxicity which was similar to that in the normal subjects. In five other patients the cytotoxicity was not increased by IL-12 alo ne, but the combination of IL-12 and IL-2 did augment the cytotoxicity (type B response). The augmented cytotoxicity in these type B patient s was lower than that in the normal subjects. In the final three MDS p atients the cytotoxicity was low and not affected by IL-12 and/or IL-2 (type C response). All patients with refractory anaemia with excess b lasts (RAEB) and patients with RAEB in transformation showed a type B or C response. Conversely, six of eight refractory anaemia patients sh owed a type A response. In MDS patients there was a positive correlati on between the percentage of CD3(-)CD56(+) cells in pre-incubated cell s and the cytotoxicity of cells incubated with IL-12/IL-2. The combina tion of IL-12 and IL-2 augmented IFN-gamma and TNF-alpha production by nonadherent mononuclear cells in a synergistic or cumulative manner, respectively, in most patients. These results suggest that IL-12, alon e or with IL-2, may modulate these important immunologic functions in most MDS patients.