Lymphokine research最新文献

Six patient with malignant effusions (five with ascites and one with malignant pleural effusion) due to refractory ovarian carcinomatosis, received intracavitary injections of ovarian viral oncolysate (VO). Measurements were made of the intracavitary activities of T cell growth factor (TCGF-IL-2) and B cell growth factor 12-kD (BCGF) and these were correlated with the clinical activity and cytologic changes in the malignant effusions. Both BCGF and IL-2 activities were demonstrated in malignant effusions prior to therapy although these were relatively higher for BCGF. Increases in the activities of both lymphokines were observed in the post VO treatment samples ranging from 4.1% to 45.0% for BCGF and 4.8% - 33.9% for IL-2. One patient who exhibited marked clinical improvement accompanied by mononuclear cell infiltrates and diminution of ascitic fluid malignant cells, also had elevation of lymphokine activities after repeated VO injections. These data provide further support for the role of VO as inducers of regional immunity.

We investigated the effects of N-glycosidase treatment on the interferon-gamma (IFN-gamma) induced HLA-DR expression of Colo 205 cells. N-glycosidase treatment resulted in a significant decrease of IFN-gamma induced HLA-DR specific immunofluorescence intensity ranging from complete reduction to approximately 30% of that of untreated control cells depending on the IFN-gamma dose. IFN-gamma binding studies showed that this was due to a severe reduction in IFN-gamma binding capacity of N-glycosidase treated cells. Since the number of cell membrane IFN-gamma receptors (IFN-gamma-Rs) was virtually unchanged as revealed by immunofluorescence analysis with a hIFN-gamma-R specific monoclonal antibody this indicates that N-linked carbohydrates play an important role in signal transduction and ligand binding capacity of the hIFN-gamma-R and strengthens the view that carbohydrate moieties of receptor proteins are of greater functional significance than originally anticipated.

IL-1 induces its own gene expression in cultured smooth muscle and endothelial cells and in human PBMC. IL-1-induced IL-1 may be part of a self-amplification or autocrine event in inflammation. In the present study IFN gamma consistently increased LPS-induced IL-1, but reduced the total amount of IL-1-induced IL-1 from PBMC. On a molar basis, IFN gamma and IFN alpha 2 were equally effective. IL-6 also reduced IL-1 induced IL-1 but was approximately 300-fold less potent than the two interferons. The augmentation of LPS-stimulated IL-1 by IFN gamma was observed only when added at the same time as LPS, but IFN gamma could be added several hours after stimulation with IL-1 and still suppress IL-1 production. LPS-induced mRNA for IL-1 beta at 4 hours was enhanced by IFN gamma whereas IL-1-induced IL-1 beta mRNA was reduced by 70% in the presence of IFN gamma and this reduction was not due to increase degradation of IL-1 beta mRNA. These results suggest that in inflammatory tissues where IL-1 self amplification of its own gene expression is part of the pathological process, interferons may act to inhibit this cycle.

Cellular immune response to localized upper respiratory viral infection was studied in two groups of healthy volunteers infected with an unnumbered rhinovirus serotype (Hanks). In the first group of 18 volunteers, serum levels of thymosin alpha 1 rose on day 5 following rhinovirus challenge. This observation was confirmed in a second group of 20 normal volunteers inoculated with the same rhinovirus strain; there was a slight increase in thymosin alpha 1 levels on day 3 and a significant rise on day 5 (p less than .001). There was also a significant rise in serum thymosin beta 4 levels on day 5 (p less than .001). Serum cortisol rose in parallel with thymosin alpha 1 on day 5 after rhinovirus inoculation, but there was no direct relationship between individual changes in cortisol and thymosin alpha 1 levels. Enumeration of peripheral blood mononuclear cell subpopulations during rhinovirus infection revealed a significant increase in total lymphocytes on day 5 (p less than .01), but not on day 3. The rise in total lymphocyte count was attributable to an increase in T lymphocytes (CD3+) (p less than .05), cytotoxic/suppressor (CD8+) cells (p less than .01) and natural killer (CD16+ cells) (p less than .05). This is the first report of thymic hormone modulation by a virus, and suggests that local rhinovirus infection of the upper respiratory tract has systemic effects and induces cellular immune responses.

The cytokine interleukin-1 plays an important role in the induction of IL-2 secretion and IL-2 receptor expression. The events that follow binding of IL-1 to its receptor are not known. We found that in a purified T cell population (comprising the Lyt2- and L3T4- T cells) IL-1 in the absence of antigen or mitogen induced strong proliferation and de novo expression of IL-2R light chain mRNA. This was accompanied by high affinity IL-2 binding. Production of IL-2 or IL-2 mRNA was not detected under these conditions. As a model system for IL-1 action two EL4 subclones were isolated. EL4 5D3 responded to IL-1 by augmentation of PMA induced IL-2 secretion and IL-2R expression. EL4D6/76 bound IL-1 with the same affinity but did not respond. We found that this line was unable to internalize surface bound IL-1. The finding suggests that in T cells internalization of IL-1 is required for its activity.

The effect of two quinolone derivatives, ciprofloxacin and ofloxacin, on the production of interleukin-2 (IL-2) was studied in human peripheral blood lymphocytes (PBL) and in a T-cell leukemia cell line (Jurkat) following phytohemagglutinin (PHA) stimulation. Both antimicrobial agents markedly increased IL-2 production in PHA-stimulated PBL cultures. No such effect was observed without PHA stimulation. The effect of the two quinolones on IL-2 production was both time and concentration dependent, reaching a 3-5 fold increase at a drug concentration of 50-100 micrograms/ml, following 24 h incubation. IL-2 synthesized in response to ciprofloxacin or ofloxacin stimulation, exhibited identical chromatographic properties and molecular weight to IL-2 synthesized at standard IL-2 inducing conditions. Only ciprofloxacin enhanced IL-2 production in PHA or in PHA and phorbol myristic acetate (PMA)-stimulated Jurkat cells. The stimulatory effect observed in Jurkat cells at optimal dose concentration (10-50 micrograms/ml), was at most 50% above control levels. In contrast to the effect of ciprofloxacin as a costimulator of IL-2 production in PHA-stimulated PBL, the drug excerted a prominent inhibitory effect on the incorporation of radioactive thymidine and amino acids into these cells. Ciprofloxacin, but not ofloxacin, enhanced interferon (IFN) production in PHA-induced PBL, whereas immunoglobulin M [IgM] production in a SKW6 cell line was enhanced only by ofloxacin.

In a previous study, we demonstrated that supernatants from human T cell clones stimulated by a pair of anti-CD2 monoclonal antibodies cause resting human B cells to become activated and to proliferate in the absence of any other signals. The activity responsible for these effects was shown to be different from already characterized lymphokines and in particular from IL-2 and IL-4, and was named B Cell Activating Factor or BCAF. In this paper, we describe the production of BCAF by a human T cell tumor line T687 after phorbol myristate acetate (PMA) stimulation; this production can be potentiated by phytohemagglutinin (PHA). We further show that the stimulatory phase can be separated from the secretory phase thereby avoiding contamination of BCAF-containing supernatant by PMA and PHA. Supernatants produced under these conditions do not contain either IL-4 or IFN but contain traces of lymphotoxin and 2 to 10 ng/ml of IL-2. The T687 cell line will allow us to obtain a large volume of supernatant for biochemical study and purification of the molecule(s) responsible for BCAF activity.

Tumour necrosis factor (TNF) has been implicated as a mediator of toxicity in a number of infectious diseases, including malaria. We have shown that human and rodent blood-stage parasites liberate heat-stable soluble antigens that induce the release of TNF by activated macrophages in vitro and in vivo, and are toxic to mice made hypersensitive to TNF by D-galactosamine. These antigens induce T-independent antibodies which specifically block their ability, but not that of bacterial lipopolysaccharide, to cause the secretion of TNF. Cytokine release in vitro may be a useful strategy for identifying potentially toxic molecules of infectious organisms and for investigating the nature of antibodies that can protect the host against their damaging effects.

Studies related to the functional activity of human endogenous pyrogen have emphasized its susceptibility to oxidative inactivation. Here we show that the specific activity of murine IL-1 beta polypeptides can be increased by reduction and subsequent alkylation. This treatment induces a change in the relative molecular weight from 20 kDa to 21 kDa of the molecule, suggesting that conformational changes may play a critical role in the functional maturation of IL-1 beta molecules.

Suppressor T-cell hybridomas specific for the synthetic polypeptide antigen L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT) release TsF spontaneously and are not dependent on exogenous sources of lymphokines for their growth. IL-2 has no effect on the cell growth of these hybridomas and little overall effect is observed on protein biosynthesis. Nevertheless, the addition of IL-2 to one of these hybridomas (762 B3.7), leads to a substantial increase in suppressor factor (TsF2) production as measured by both bioactivity and direct analysis of 35S-methionine incorporation into TsF2. Treatment of the TsF2 producing hybridoma with phorbol myristate acetate (PMA) causes an increase in the level of IL-2 receptor expression in this hybridoma and enhances the effects of IL-2 on the biosynthesis of TsF2. These data suggest that in addition to its growth promoting properties, IL-2 may provide a signal that triggers suppressor cells to produce antigen specific suppressor factors.