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B M Chain

Publications and source records attributed to B M Chain.

At least 55 records · Page 3Linked to original sources
PubMed1993

The effects of auranofin on activation and interleukin-2 release from human peripheral blood mononuclear cells.

Auranofin, 30-300 nM causes a concentration-dependent potentiation of phytohaemagglutinin (PHA)-induced interleukin-2 (IL-2) release from human peripheral blood mononuclear cells in culture. At concentrations of auranofin between 1 and 3 microM, PHA-stimulated IL-2 release was inhibited, and the drug is cytotoxic at these concentrations. At concentrations of auranofin which potentiated PHA-induced IL-2 release, it had no effect on [3H]-thymidine incorporation. Auranofin, 3 to 300 nM caused a concentration-dependent increase in the population of peripheral blood mononuclear cells bearing the IL-2 receptor (Tac positive cells). Auranofin, 300 nM caused an increase of approximately 100% in the glutathione level within the resting cells, and also increased the glutathione level in PHA-stimulated cells. We conclude that auranofin acts early in the cell cycle, selectively to increase the release of IL-2 and the expression of Tac. The action of auranofin on cellular glutathione levels may alter the redox state of the cell which is known to be important in the control of transcription factor activation.

Antibodies, Monoclonal↗
PubMed1993

Characterization and functional analysis of the expression of intercellular adhesion molecule-1 in human papillomavirus-related disease of cervical keratinocytes.

We have investigated the expression of intercellular adhesion molecule-1 (ICAM-1) in squamous neoplasia of the cervix and have noted a significant induction of the molecule in high-grade intra-epithelial lesions. Using monolayer and organotypic in vitro tissue culture systems, we have shown that there is no constitutive ICAM-1 expression on cervical keratinocytes immortalized but not transformed by human papillomavirus type 16, whereas two human papillomaviruses type 16 containing and fully transformed cervical keratinocyte lines do constitutively express the molecule. All cell types, including human papillomavirus-negative normal cervical keratinocytes, can be induced to up-regulate their expression of ICAM-1 by pro-inflammatory cytokines such as interferon-gamma. In addition, we have used an in vitro adhesion assay to show that ICAM-1:lymphocyte function antigen-1 interaction is functionally important in lymphocyte binding to cervical keratinocytes, suggesting a role for ICAM-1 in retaining and enabling functional activity of lymphocytes in the cervix in intraepithelial neoplasia.

Carcinoma in Situ↗
PubMed1993

Differential regulation of cytokine production by nitric oxide.

Nitric oxide (NO) has recently been identified as a potent and pleiotropic intracellular mediator produced by and acting on many cells of the body. Although considerable attention has been devoted to the regulation of NO by inflammatory cytokines, and also to the role of NO as an important effector molecule in immune function, there is very little information on the role of this mediator in modulating T-cell-dependent cytokine production. In this study we show that physiological levels of NO (either produced by activated macrophages or by the addition of exogenous NO donors) can selectively down-regulate interleukin-3 (IL-3) production by spleen cells from contact-sensitized mice, while leaving IL-2 activity unaffected. Thus NO may have an important role as an immunomodulatory as well as effector molecule in the immune system.

Animals↗
PubMed1992

Endocytosis by antigen presenting cells: dendritic cells are as endocytically active as other antigen presenting cells.

Although dendritic cells are the most potent of all antigen presenting cells, they have paradoxically been regarded as having only a minimal capacity for endocytosis, which is a crucial step in antigen processing prior to presentation. Previous studies of dendritic cells, which are only available in small numbers, have been restricted to measurement of long-term endocytosis and so have stressed lysosomal accumulation. Measurement of traffic through late endosomes, which are closely related to the organelle in which antigen processing occurs, has, to date, required large numbers of cells and therefore has not been possible for dendritic cells. To resolve the paradox for dendritic cells, we have developed a flow cytometric assay of fluid-phase endocytosis that assesses late endosomal traffic by kinetic analysis of exocytosis in small numbers of cells. Using this assay, we show that fluid-phase endocytosis--in particular, traffic through late endosomes--is as active in dendritic cells as in other antigen presenting cells.

Animals↗
PubMed1992

Antigen processing for presentation by class II major histocompatibility complex requires cleavage by cathepsin E.

Proteolytic degradation (processing) of antigen by antigen-presenting cells is a major regulatory step in the activation of a T lymphocyte immune response. However, the enzymes responsible for antigen processing remain largely undefined. In this study we show that cathepsin E, and not the ubiquitous lysosomal cathepsin D, is the major aspartic proteinase in a murine antigen-presenting cell line, A20. This enzyme is localized to a non-lysosomal compartment of the endosomal system in these cells. Functional studies using a highly specific inhibitor of cathepsin E show that this enzyme is essential for the processing of ovalbumin by this cell line. Thus, cathepsin E, whose function was hitherto unknown, may play a major role in antigen processing.

Animals↗
PubMed1992

Sensitization of allo-specific T lymphocytes in vivo: role of antigen-presenting cells.

The migratory behavior of antigen-presenting cells was investigated in vivo. Purified murine splenic dendritic cells and splenic and peritoneal macrophages were labelled and injected subcutaneously in the hind foot-pads of mice and monitored for seven days. In the first 24 h, a small quantity of label was recovered from popliteal but not inguinal lymph nodes with radioactive (111In-oxine and 3H-uridine) but not fluorescent (1,1'-dioctadecyl 3,3,3'3'-tetramethylindocarbocyanine perchlorate and fluorescein isothiocyanate) labelling of the antigen-presenting cells. Chemical fixation of the injected antigen-presenting cells had no effect on the detection of label in the popliteal lymph nodes, suggesting that it was unlikely to be due to active cellular migration. Label recovery from hind feet declined with time over the seven day period and was independent of the label type. Essentially the same observations were made whether the antigen-presenting cells were syngeneic or allogeneic to the injected mice and irrespective of the type of antigen-presenting cell used. However, allogeneic antigen-presenting cells, which did not migrate to the draining lymph nodes, successfully primed T lymphocytes in these lymph nodes as shown by a secondary in vitro mixed leukocyte reaction. Again, chemical fixation of the injected antigen-presenting cells had no effect on their ability to prime allogeneic T lymphocytes in the draining lymph nodes. These experiments suggest that, during experimental allo-sensitization via the subcutaneous route, indirect priming of allogeneic T lymphocytes may be a dominant pathway.

Animals↗
PubMed1992

Adjuvant composition determines the induction of type II collagen-induced arthritis.

In this study we have investigated the influence of adjuvant composition on the development of collagen-induced arthritis and of anti-collagen type II specific B- and T-cell responses following immunization with type II collagen. DBA/l mice immunized with bovine collagen type II emulsified in complete Freund's adjuvant (CFA) containing Mycobacterium tuberculosis strain H37Ra developed footpad swelling indicative of arthritis. Animals immunized with collagen type II plus CFA containing Mycobacterium butyricum, or incomplete Freund's adjuvant showed no significant increase in footpad width. Induction of anti-CII specific T-cell proliferation was also dependent upon immunization with CII plus CFA containing M. tb H37RA. In contrast, ovalbumin-reactive T-cell proliferation was unaffected by the species of mycobacteria, indicating that the difference in adjuvant activity of the mycobacterial species is specific for anti-collagen type II T-cell responses. Antibody response to collagen type II, unlike T-cell responses, was not significantly different using the two adjuvants. This study therefore demonstrates that murine collagen-induced arthritis requires immunization with collagen type II together with complete Freund's adjuvant containing Mycobacterium tuberculosis H37RA. Since only this combination of antigen and adjuvant induces detectable arthritis and T-cell responses against collagen type II, while antibody synthesis does not have such stringent adjuvant requirements, this suggests that the development of the full pattern of the collagen-induced arthritis disease requires synergistic activation of both humoral and cell-mediated responses.

Adjuvants, Immunologic↗
PubMed1992

Prostaglandin E2 (PGE2) differentially regulates the production of IL-2 and IL-3 by murine immune T-cells.

Eicosanoids are important mediators of inflammation, and have been shown to have potent, and usually suppressive immunoregulatory activities. In the paper, we have examined the role of prostaglandin (PGE2) production in the regulation of two cytokines, IL-2 and IL-3, which both play a key role in contact sensitivity and delayed type hypersensitivity reactions. In agreement with previous studies, we demonstrate that prostaglandins down-regulate IL-2 production in the system. Unexpectedly, however, IL-3 levels are enhanced in the presence of the prostaglandin PGE2 and conversely, are inhibited by treatment with aspirin, a potent inhibitor of prostaglandin metabolism. The implications of this result in terms of the immunoregulatory role of PGs will be discussed.

Animals↗
PubMed1991

Chemically modified antigen-presenting cells induce T lymphocyte allospecific hyporesponsiveness.

We have investigated the interaction between murine T lymphocytes and allogeneic APC in an in vitro proliferative mixed leukocyte reaction. Our results demonstrate that freshly isolated potentially alloreactive murine splenic T lymphocytes, in primary culture, can be induced to develop a state of allospecific proliferative hyporesponsiveness in vitro by exposure to 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide-modified allogeneic APC, a method similar to that previously used to induce nonresponsiveness in murine Ag-specific self-MHC-restricted T lymphocyte clones. This hyporesponsiveness was: specific for the allohaplotype of inducing APC, maintained for 96 h in vitro, not due to cellular inhibitory mechanisms, and associated with reduced ability to secrete IL-2 but not IL-3. Induction of this hyporesponsiveness was not due to altered expression of class II MHC gene products on the APC but was associated with markedly reduced T lymphocyte-APC adhesive interactions despite the lack of a detectable immunophenotypic change in lymphocyte function-associated Ag 1 (LFA-1) and intercellular adhesion molecule 1 (ICAM-1) expression on the modified APC. Therefore, we propose that TCR occupancy in the absence of normal T lymphocyte-APC adhesive clustering may induce T lymphocyte tolerance.

Animals↗
PubMed1991

Temperature-induced stress abrogates co-stimulatory function in antigen-presenting cells.

This study examines the effect of heat-induced stress on the function of splenic antigen-presenting cells. Heat shock (at 41 degrees C, 45 degrees C) profoundly inhibits the ability of this population to stimulate antigen-specific proliferation in ex vivo, or short-term cultures of T cells. This inhibition is not due to the release of suppressor factors from the antigen-presenting cells, nor to a lack of interleukin 1. Comparison of the effect of heat shock on presentation to a T cell hybridoma suggest that heat shock may affect the ability of antigen-presenting cells to deliver a co-stimulatory signal to the T cell. The implication of these findings in terms of the regulation of autoimmune phenomena is discussed.

Animals↗
PubMed1991

Antigen presentation by dendritic cells provides optimal stimulation for the production of interleukin (IL) 2, IL 4 and interferon-gamma by allogeneic T cells.

Previous studies have shown that dendritic cells are the most potent inducers of T cell proliferation in vitro and that this is reflected in the release of interleukin (IL) 2 into culture supernatants during dendritic cell-T cell interaction. However, the role of the dendritic cells, and, indeed, of the antigen-presenting step, has not yet been explored with respect to other T cell-derived cytokines, in either a qualitative or relative fashion. In this study, therefore, we have examined the comparative role of different antigen-presenting cells (APC) as inducers of T cell cytokine release in allogeneic responses. We have confirmed that dendritic cells are the most effective inducers for IL2 and have shown that this is true not only in primary alloresponses, but also in alloresponder T cells maintained for extended periods and then rechallenged. Dendritic cells were also the most potent inducers of IL3 and interferon-gamma (IFN-gamma) in primary cultures. No IL4 was demonstrable irrespective of the type of presenting cells used, and both tissue macrophages and dendritic cells can induce synthesis of IL6. Likewise, in secondary alloresponses both dendritic cells and to a lesser extent tissue macrophages induce release of IL3, no IL4 is detectable, and activated macrophages and B cells raise IFN-gamma levels in the supernatants albeit to a lower concentration than that seen when dendritic cells are used as stimulators. The results were similar in the tertiary alloresponse except that (a) IL4 was now detectable in the supernatants but only where dendritic cells had been used as APC, and (b) both resting and activated macrophages induced IL2 and IFN-gamma. By the eighth cycle of allostimulation there is negligible IL2. Dendritic cells, tissue macrophages and activated B cells constitute a hierarchy of APC for IL3, IFN-gamma and IL4. These findings therefore demonstrate the role of dendritic cells as potent in vitro inducers of IL3, IL4 and IFN-gamma synthesis as well as of IL2.

Animals↗
PubMed1991

Suppression of lymphokine production in anti-minor histocompatibility antigen responses.

Allogeneic immunizations between mice strains that differ at multiple loci coding for minor histocompatibility antigens (mha) result in a variety of immune responses, including the induction of cytotoxic T cells, helper T cells, and delayed hypersensitivity reactions. However, high-dose intravenous immunization induces a population of cells that can suppress these responses. In this paper, we show that the transfer of this suppressor population in vivo is accompanied by a reduced ability of immune cells to produce the two lymphokines interleukin-2 (IL-2) and interleukin-3 (IL-3). In a different assay of suppressor function, suppressor cells were co-cultured with responder cells in vitro. Under these conditions, the presence of suppressor cells resulted in a lowered net production of IL-2, but not IL-3. Possible mechanisms for this phenomenon are discussed.

Animals↗
PubMed1991

The cell biology of antigen processing.

T lymphocytes recognize antigen only after a series of intracellular events known as antigen processing. The result of antigen processing is the production of short segments of the primary peptide sequence bound to a polypeptide-binding groove on major histocompatibility complex (MHC) molecules. Antigen originates from one of two sites: intracellular or extracellular. There are two corresponding pathways for antigen processing and two corresponding classes of MHC molecule. Analysis of each pathway has demonstrated that their separation is not purely anatomical, but is maintained by molecular interactions with other molecules. Antigen processing has been shown to regulate the overall immune response, but the mechanisms involved remain obscure.

Animals↗