SUMMARYCongenital patients who lack natural killer (NK) cell activity experience repeated polymicrobial infections. NK cell activity varies significantly among normal people, but it is unknown whether this variation influences their ability to fight infections. This study examined this concern. NK cell activity and other variables, i.e. age, sex, performance status (PS), serum albumin value, lymphocyte and neutrophil counts, various lymphocyte subsets, etc. were determined for 108 immunologically normal elderly subjects who were in nursing homes due to an impaired PS. We analysed for correlations between these variables and the follow-up results of the subjects. Forty-eight subjects developed infection(s) during the first year of follow-up. A low NK cell activity was associated with the development of infection (P 0´0105, multivariate logistic regression analysis). The relative risk for the development of infection increased in accordance with the decrease in the NK cell activity. Eleven subjects died of infection during the study period. A low NK cell activity was associated with short survival due to infection (P 0´0056, multivariate Cox's proportional-hazards regression analysis). Our data indicate that low NK cell activity is associated with development of infections and death due to infection in immunologically normal elderly subjects with an impaired PS.

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We studied a male patient with cyclic thrombocytopenia whose bone marrow megakaryocyte count showed cyclic fluctuations in synchrony with cyclic changes of platelet count. He failed to respond to either prednisolone or bolus methylprednisolone therapy, but subsequently he was successfully treated with azathioprine. To investigate the underlying pathogenesis of the cyclic fluctuations in the platelet count, we studied the kinetics of megakaryocyte progenitor cells (CFU-Meg) and the effects of the patient's peripheral blood mononuclear cells on CFU-Meg. In one cycle of the platelet fluctuation, the increase in the CFU-Meg number preceded an increase in the bone marrow megakaryocyte count and then the platelet count. In the latter half of the cycle, CFU-Meg, bone marrow megakaryocytes and platelets began to decrease in that order. Peripheral blood mononuclear cells obtained from the patient in the thrombocytopenic phase suppressed megakaryocyte colony formation from normal bone marrow cells in a dose-dependent manner. In contrast, these cells obtained in the phase of a normal platelet count did not suppress megakaryocyte colony formation at all. These findings indicate that the cause of platelet fluctuation is periodic failure of megakaryocytopoiesis at the stage of CFU-Meg and that the patient's peripheral mononuclear cells are responsible for periodically suppressing the CFU-Meg.

The effects of interleukin 12 (IL-12) on natural killer (NK) cell cytotoxicity and on the production of interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) were examined in 15 patients with myelodysplastic syndromes (MDS), which are well known to have immunologic defects, and in 11 normal subjects. The NK cell cytotoxicity of all of the normal subjects was augmented by incubation with IL-12 alone, and co-incubation with interleukin 2 (IL-2) further augmented it (type A response). The MDS patients showed varied responses to IL-12/IL-2. Seven patients showed the type A response, resulting in augmented NK cell cytotoxicity which was similar to that in the normal subjects. In five other patients the cytotoxicity was not increased by IL-12 alone, but the combination of IL-12 and IL-2 did augment the cytotoxicity (type B response). The augmented cytotoxicity in these type B patients was lower than that in the normal subjects. In the final three MDS patients the cytotoxicity was low and not affected by IL-12 and/or IL-2 (type C response). All patients with refractory anaemia with excess blasts (RAEB) and patients with RAEB in transformation showed a type B or C response. Conversely, six of eight refractory anaemia patients showed a type A response. In MDS patients there was a positive correlation between the percentage of CD3- CD56+ cells in pre-incubated cells and the cytotoxicity of cells incubated with IL-12/IL-2. The combination 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, alone or with IL-2, may modulate these important immunologic functions in most MDS patients.

Bone marrow progenitor cell assays of three cell lineages, i.e., colony-forming unit megakaryocytes (CFU-Meg), burst-forming unit erythrocytes (BFU-E) and colony-forming unit granulocyte-macrophages (CFU-GM), were performed for 21 patients with myelodysplastic syndromes (MDS). Markedly reduced or absent colony formation was found in 67% of the patients for CFU-Meg and all patients except 2 with refractory anemia (RA) for BFU-E. Abnormal CFU-GM colony formation was found in only 5 of 12 patients with RA and RA with ring sideroblasts, in contrast to all of the RA patients with excess of blasts and excess of blasts in transformation. Defective colony formation of all three cell lineages was seen in 63% of the MDS patients. The colony number of CFU-Meg correlated significantly with the numbers of both BFU-E and CFU-GM. These findings indicate that hematopoiesis in MDS patients is disturbed due to a qualitative or quantitative defect at the multipotent stem cell level.