Immunologic findings in workers formerly exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin and its congeners.

One hundred ninety-two workers in a German pesticide factory who were exposed to polychlorinated dibenzodioxins and -furans (PCDD/PCDF) were investigated for former and present diseases and laboratory changes of the immune system. Moreover, in a subgroup of 29 highly exposed and 28 control persons, proliferation studies were performed. In addition to assays such as blood count, immunoglobulins, serum electrophoresis, monoclonal bands, surface markers, autoantibodies, and lymphocyte proliferation, two new methods, the rise of tetanus antibody concentration after vaccination and the in vitro resistance of lymphocytes to chromate, were used to diagnose the morphologic and functional state of the immune system. There was no stringent correlation of actual PCDD/PCDF concentrations with the occurrence of infections or with one of the immune parameters. In addition, outcomes of the tetanus vaccination and the chromate resistance test were not correlated with PCDD/PCDF. However, the chromate resistance of lymphocytes stimulated by phytohemagglutinin of highly exposed persons was significantly lower than that for the control group. These findings indicate that the function of lymphocytes can be stressed and possibly impaired by high exposure to PCDD/PCDF.

Regulation of immunomodulatory functions by granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor in vivo.

The present study was designed to investigate in vivo immunomodulatory properties of hematopoietic growth factors. The influence on the activation of cytokine synthesis and on the expression of surface antigens associated with cellular activation of G-CSF or GM-CSF was investigated in cancer patients receiving these factors. One single dose of growth factor was administered to patients with bladder cancer (G-CSF group) or small cell lung cancer (GM-CSF group) before chemotherapy. After cytoreductive chemotherapy patients received supportive therapy with G-CSF or GM-CSF. Peripheral blood mononuclear cells and plasma samples were obtained for flow cytometry, Northern blot analysis, and assessment of cytokine protein levels after single-dose as well as after continuous cytokine administration. Our results demonstrate differences in the induction of biological activities by GM-CSF and G-CSF in vivo which correlate well with in vitro findings. Among mature hematopoietic cells the effect of G-CSF is restricted to the granulocyte lineage. With GM-CSF moderate but unequivocal modulation of monocyte function was observed. On peripheral blood monocytes expression of MHC class-II molecules and CD44 was markedly stimulated. After one single dose of GM-CSF, plasma levels of sCD25 and IL-1RA were significantly induced (p < 0.0001, p = 0.032, respectively) and a trend to increased IL-8 levels was observed. The changes in plasma proteins were not correlated with shifts of mRNA expression for IL-8 and IL-1RA. T-cell activation was not observed with either cytokine. These results suggest that immunomodulatory features are differentially regulated by G-CSF and GM-CSF. The clinical relevance of a selective use of both hematopoietic growth factors in various disease settings remains to be determined.

Computer-assisted interpretation of flow cytometry data in hematology.

A computer program has been developed for computer-assisted diagnosis (including subclassification) of flow cytometry data of acute leukaemias and non-Hodgkin lymphomas by means of artificial intelligence. The knowledge base for the system has been formulated as semantic networks that describe physiological hematopoiesis as well as the pathological situation (e.g., aberrant antigen expression) of hematological disorders. The semantic networks reflect the hierarchy of cells and their occurrence in diseases, the normal and pathological antigen expression patterns of cells, cell maturation, and the frequency of cell populations in normal blood and bone marrow. Using these semantic networks, the diagnosis algorithm compares the characteristic antigen expression pattern of a disease with the actual findings in the blood or bone marrow sample. The algorithm can separate mixed populations by taking double staining findings into account. Finally, a diagnosis text is generated that describes all identified cell populations and the resulting diagnosis. The validation of the program showed a correct diagnosis (disease group and subclassification) in 97% of the cases (n = 633) with slight differences between the disease groups (e.g., B-NHL: 99%, B-cell ALL: 84%).

Low-dose gamma-interferon therapy is ineffective in renal cell carcinoma patients with large tumour burden.

The efficacy and immunomodulatory effects of low-dose gamma-interferon (gamma IFN) were investigated in an unselected population of patients with metastasising renal cell carcinoma. 36 patients suffering from metastasising renal cell carcinoma with a performance status exceeding Karnofsky index of 50 were entered into the open phase I/II trial. The majority of the patients recruited displayed a large tumour burden, and 28 patients (78%) had metastases involving two to six organ sites. Treatment was started with a 2-week cycle of either daily or weekly subcutaneous administration of either 100, 200 or 400 micrograms gamma IFN. After a therapy-free interval of 2 weeks treatment was switched to the alternate mode of administration. Subsequently, treatment was continued with the same dose applied once a week for a minimum of 3 months. Serum levels of neopterin and beta-2-microglobulin, as well as flow cytometric analyses of peripheral blood mononuclear cells, were used for the assessment of biological response. Minimal antitumour activity was observed in this high-risk patient group and only 1 patient experienced a partial response (PR) lasting 36 + months. Comparison of the patients' characteristics to those of other low-dose gamma IFN trials revealed a highly significant difference in the tumour burden and clinical response. We conclude that patient selection is a decisive parameter for the outcome of treatment with low-dose gamma IFN, and that patients with poor prognostic features and a large tumour burden are not likely to respond to this almost atoxic treatment.