PubMed · 2047271
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A Heenan. Passing the test.. https://pubmed.ncbi.nlm.nih.gov/2047271/
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Flow cytometric screening of sera using pooled chronic lymphocytic leukaemia (CLL) cells has previously been reported as a quick method for detecting HLA antibodies of the IgG class. In this study we investigated the sensitivity of this method in the detection of IgG and IgM alloantibodies, and its performance in serum screening when compared to conventional microlymphocytotoxic screening. Results indicate that flow cytometric screening is more sensitive in the measurement of IgG alloantibodies by up to five doubling dilutions, whereas the converse is true for IgM. IgM autoantibodies were found not to be detectable by flow cytometry. By testing a large number of sera by both methods in parallel, we have found that a significant proportion of sera exhibiting no activity of IgM activity alone on cytotoxic screening contain IgG antibodies detectable with a pool of CLL cells on the flow cytometer.
Monocytes, recovered by centrifugal elutriation, effectively inhibit functions of human NK cells in vitro. Histamine, acting via monocyte H2-type histamine receptors, abrogates the inhibitory signal. The aim of this study was to define the histamine-reversible mechanism by which monocytes inhibit NK cells with special reference to the respiratory burst activity of monocytes. Monocytes recovered from patients with chronic granulomatous disease did not suppress NK cell function, indicating the requirement of intact nicotinamide-adenine dinucleotide phosphate (NAPDH) oxidase activity of monocytes to inhibit NK cells. Furthermore, catalase, a scavenger of hydrogen peroxide (H2O2), was found to potently reverse the monocyte-induced inhibition of NK cell function; on the other hand, superoxide dismutase (a scavenger of superoxide anion), hydroxyl radical scavengers such as mannitol and deferoxamine, the hypochlorous acid scavenger taurin, or the nitric oxide synthetase inhibitor NG-monomethyl-L-arginine (L-NMMA) did not affect the monocyte-derived, suppressive signal. H2O2, at micromolar concentrations, reconstituted the inhibitory effects of monocytes on NK cell function. Histamine had no scavenger activity but effectively suppressed the generation of H2O2 in isolated monocytes. This effect of histamine was transduced by H2-type histamine receptors. We conclude that the histamine-reversible, inhibitory effect of elutriated monocytes on NK cells is dependent on the formation of reactive oxygen metabolites by monocytes and that H2O2 is a pivotal mediator of the suppressive signal.
BACKGROUND: Interleukin-2 (IL-2)-based immunotherapy has been shown to effect clinical responses in 15-35% of patients with metastatic renal cell carcinoma or melanoma. Despite its clinical efficacy, many clinicians refrain from using IL-2 because of the associated toxicity. This toxicity is believed to be mediated by such secondary cytokines as IL-1, tumor necrosis factor (TNF), and interferon (IFN)-gamma, which are produced by the patient's IL-2-stimulated peripheral blood mononuclear cells (PBMCs). METHODS: Human PBMCs were stimulated with 1 nM wild-type recombinant IL-2 (rIL-2) or IL-2 analogs (R38A or F42K) that preferentially bind to the intermediate affinity IL-2 receptor (IL-2R). PBMCs were activated for lymphokine-activated killer (LAK) activity in 4-h 51Cr-release assays, using Daudi target cells. Cytokine content in the culture supernatants was determined by enzyme-linked immunosorbent assay. RESULTS: Both R38A and F42K were capable of generating substantial LAK activity. Maximal specific lysis was 54% for PBMCs activated by R38A and 52% for F42K-stimulated cells, in contrast to 64% for rIL-2. In addition, analog-stimulated PBMCs secreted 59% of the IL-1 beta, 25% of the TNF-alpha, and only 8% of the IFN-gamma produced in response to rIL-2 (all p < 0.01 compared with rIL-2-stimulated secretion; one-way ANOVA). CONCLUSIONS: IL-2 analogs that preferentially bind the intermediate-affinity IL-2R retain the capacity to induce substantial LAK activity despite a greatly reduced secondary cytokine production. Therefore, such IL-2 analogs may provide an effective, yet less toxic means of cancer immunotherapy.