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B M Chain

Publications and source records attributed to B M Chain.

At least 37 records · Page 2Linked to original sources
PubMed1998

From sentinel to messenger: an extended phenotypic analysis of the monocyte to dendritic cell transition.

The transitional stages in the relationship between sentinel monocytes and messenger dendritic cells that are active in adaptive immunity, are, as yet, unclear. To explore these events, 2-hr adherent peripheral blood mononuclear cells were used either as monocytes, or cultured for 7 days with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) to generate dendritic cells, and the phenotypic features and relationship of the two cell populations was investigated using an extensive panel of monoclonal antibodies (mAbs). The features of the shift from monocyte to dendritic cell were also examined by daily phenotyping during the 7-day culture period. Twenty-five mAbs, most of which recognized known CD molecules, bound both monocytes and dendritic cells equally, whereas 19 mAbs exhibited differential staining. Four molecules not previously reported on dendritic cells were documented: CD87, CD98, CD147 and CD148. Seven cell-surface molecules (HLA-DQ, CD1a, CD13, CD30, CD43, CD63 and CD86) were expressed either at very low levels or not at all on monocytes, but had a strikingly increased expression on dendritic cells, suggesting a role in antigen presentation. The kinetics of monocyte to dendritic cell transition revealed a rapid activation phase within the first 24 hr, with a considerable increase in expression of the activation markers HLA-DR, CD13, CD14 and CD98; this was followed by a down-regulation of CD14 and a more gradual development of the other dendritic cell features over the remaining 6 days, with steady increases in CD1a, CD18, CD43, CD86, HLA-DR and HLA-DQ. Thus, these studies have demonstrated four novel components of the dendritic cell, and have documented the dynamic multistep nature of the process whereby an antigen-presenting dendritic cell phenotype may emerge from a monocyte precursor.

Animals↗
PubMed1998

Differential regulation of HLA-DQ expression by keratinocytes and Langerhans cells in normal and premalignant cervical epithelium.

Keratinocytes in normal ectocervix did not express major histocompatibility complex class II molecules. In low-grade intraepithelial lesions expression was confined to HLA-DR, while in high-grade disease there was expression of HLA-DR and occasional expression of HLA-DQ. HLA-DR was expressed constitutively on the majority of Langerhans cells. In contrast, few Langerhans cells expressed HLA-DQ in normal cervix, but there was a steady upregulation of the proportion expressing HLA-DQ which paralleled the severity of disease. There was no direct correlation between human papillomavirus 16 and the expression of major histocompatibility complex class II by keratinocytes and Langerhans cells. Significant upregulation of HLA-DQ by Langerhans cells is observed in high-grade intraepithelial cervical lesions, suggesting antigen-presenting cell activation in papillomavirus-related premalignant disease.

Female↗
PubMed1997

Mechanisms for variability in a member of the scavenger-receptor cysteine-rich superfamily.

This study reports a molecular analysis of pig WC1, a new member of the scavenger-receptor cysteine-rich (SRCR) superfamily. The pig WC1 contains up to six extra-cellular SRCR domains, highly homologous to other members of the family. However, the striking feature of the WC1 gene, as for its cattle and sheep homologues, is that it is present as a multigene family showing extensive sequence diversity, for both DNA and predicted protein sequence. The basis of this diversity was examined and was shown to be attributable to several different causes. These included single base-pair changes within SRCR domains, the optional usage of whole domains or exons, including a SRCR domain and the proximal "hinge" region, and alternative isoforms of the putative cytoplasmic tail. These results suggest that WC1 may code for a new, though more primitive type of antigen recognition structure specific for gamma/delta T cells.

Amino Acid Sequence↗
PubMed1997

Enhancement of CD4+ T-cell-dependent interleukin-2 production in vitro by murine alveolar macrophages: the role of leukotriene B4.

Local tissue macrophages are known to play a key role in regulation of adaptive immune responses, often by inhibition of T-cell activation and proliferation. In this study, we compare the influence of alveolar and peritoneal macrophages on T-cell-dependent interleukin-2 (IL-2) release. Alveolar macrophages, in contrast to peritoneal macrophages, enhance IL-2 release. Assay of a panel of potential macrophage-derived mediators indicated that activated alveolar macrophages stimulated greater release of IL-1 beta, tumour necrosis factor-alpha and, especially, leukotriene B4 (> 100 times) than activated peritoneal macrophages. Inhibition of prostaglandin synthesis by alveolar macrophages further enhanced the production of IL-2, while inhibition of leukotriene synthesis abolished the enhancement. The addition of exogenous prostaglandin E2 inhibited IL-2 release, while exogenous leukotriene B4 enhanced IL-2 release. When added simultaneously, the two compounds antagonized each other's activity. In conclusion, this study confirms that alveolar macrophages enhance IL-2 secretion, and suggests that this enhancement may be due at least in part to the very high rates of production of leukotriene B4. The overall influence of macrophage populations on T cells in vivo will reflect the complex balance between the multiple mediators produced within the local tissue microenvironment.

Animals↗
PubMed1997

Characterization of the T cell response to human rhinovirus in children: implications for understanding the immunopathology of the common cold.

Human rhinovirus (HRV) is a frequent respiratory pathogen, responsible for a large proportion of cases of the "common cold" and linked to acute asthma, especially in children. T cell responses to HRV and their contribution to HRV-associated pathology were investigated. T cells were obtained from tonsils removed from children at routine tonsillectomy. Proliferative and cytokine responses were measured after in vitro restimulation with purified HRV preparations of both major and minor serotypes. Most tonsils tested showed T cell proliferation, and responses to multiple serotypes in one tonsil were observed frequently. Responding T cells were CD4-positive and produced interleukin-2 and interferon-gamma but no interleukin-4. Thus, children respond to HRV, a proportion of the response is serotype-cross-reactive, and a Th1 reaction predominates. In addition to contributing to protection, this response may enhance expression of virus receptor and be implicated in the immunopathology of HRV infection.

Adolescent↗
PubMed1997

Cathepsin E expression by normal and premalignant cervical epithelium.

We have investigated the expression of the aspartic proteinase cathepsin E and HLA-DR and the presence of HPV16 in normal squamous epithelium (n = 8) and low-grade (n = 21) and high-grade (n = 14) intraepithelial squamous lesions of the uterine cervix. Immunohistochemistry of cervical biopsies revealed that up-regulation of cathepsin E expression was related to increasing severity of the cervical intraepithelial neoplasia (CIN). Up-regulation of protein was associated with increased message as assessed by in situ hybridization. Langerhans cells and the majority of koilocytes did not express detectable cathepsin E levels. Although there was also an up-regulation of HLA-DR expression by cervical keratinocytes in cervical intraepithelial neoplasia lesions, as determined by immunohistochemistry, no significant correlation was found between HLA-DR and cathepsin E expression in these lesions; neither was expression of cathepsin E correlated to the presence of HPV16, detected by polymerase chain reaction. The expression of cathepsin E, an aspartic proteinase that is reported to play a role in antigen processing for presentation by class II major histocompatibility complex molecules, is associated with cellular dedifferentiation in cervical intraepithelial neoplasia.

Adolescent↗
PubMed1996

Is there a role for nitric oxide in regulation of T cell secretion of IL-2?

Nitric oxide (NO) can have both effector (cytotoxic) and regulatory roles in immune function. In this study, we have re-examined the potential role of nitric oxide in mediating the macrophage-dependent suppression of IL-2 synthesis. In our model, TNP-specific CD4+ T cells are cocultured with Ag and either peritoneal or alveolar macrophages. Both populations of macrophages after in vitro stimulation with IFN-gamma can inhibit IL-2 release. In vitro stimulation also induces substantial levels of NO release by these macrophages, as well as high levels of prostaglandin E2 (PGE2). However, there was no correlation between NO levels and inhibitory activity. Furthermore, NG-monomethyl-L-arginine monoacetate, a specific inhibitor of NO release had no effect on IL-2 release, while indomethacin, which blocked prostaglandin synthesis, largely abrogated the suppressor activity of both macrophage populations. Although the addition of exogenous NO donors at high concentrations could inhibit IL-2 release by T cells, our data does not support the hypothesis that NO is a major macrophage mediator of suppression in this model.

Animals↗
PubMed1995

Tumor-associated E6 protein of human papillomavirus type 16 contains an unusual H-2Kb-restricted cytotoxic T cell epitope.

We previously showed that CTL from H-2b mice immunized against the E6 protein of human papilloma virus (HPV) type 16 recognized a 10-mer peptide corresponding to amino acids 131 to 140. We show in this study that the minimal epitope, 130 to 137, is a 8-mer peptide presented by H-2Kb class I molecules. At position P8, the 130 to 137 peptide contains a hydrophobic methionine anchor residue, but P3 and P5 do not contain the typical anchor residues that are frequently found in Kb-bound peptides. Analysis with alanine-substituted peptides indicates that the tryptophan at P3 acts as an alternative anchor mediating Kb binding, while an arginine at P2 is a TCR contact residue. Synthetic 9-mer peptides corresponding to residues 130 to 138 are as efficiently recognized by CTL as 130 to 137 peptides. Analysis of extracts of E6-expressing cells suggests that Ag processing may produce multiple peptides containing the minimal 130 to 137 epitope. In vitro binding studies indicate that Kb binding of peptide 130 to 137 is approximately five orders of magnitude less efficient than Kb binding of previously identified CTL epitopes. In contrast, the E6 protein contains another potential CTL epitope in the region of amino acids 41 to 50. A synthetic peptide spanning this region binds very strongly to Kb and is capable of stimulating a strong peptide-specific CTL response. In the context of the whole protein, however, this epitope remains cryptic.

Amino Acid Sequence↗
PubMed1995

The injured cell: the role of the dendritic cell system as a sentinel receptor pathway.

A major unresolved paradox in immunology remains: how do we avoid harm, despite the abundant opportunities for induction of immune responses against self-proteins? Here, Mohammad Ibrahim, Benjamin Chain and David Katz extend Janeway's proposed explanation, arguing that adaptive immune responses are initiated not only by conserved microbial products, but also by microenvironmental tissue injury. They suggest that the key step is local dendritic cell activation, followed by upregulation of T-cell costimulatory molecules on these cells, and migration, leading to antigen presentation.

Allergens↗
PubMed1994

The gold anti-rheumatic drug auranofin governs T cell activation by enhancing oxygen free radical production.

Gold-containing drugs continue to be used in the treatment of rheumatoid arthritis, but their mode of action remains unknown. One model to explain gold action is that gold-containing compounds can alter free radical production in cells of the immune system, but direct evidence for this hypothesis has been lacking. In this study we show that auranofin can enhance the rapid flux of reactive oxygen species (ROS), which accompanies phytohemagglutinin activation of peripheral blood T cells. Blocking this enhancement by the addition of antioxidants can reverse the functional effects of the drug on T cell responses, which we have previously demonstrated. These results provide strong experimental support for a model in which gold anti-rheumatics act by modulating ROS production. Furthermore, our experiments suggest that auranofin may be a useful tool to investigate the postulated role of ROS in the intra cellular T cell signaling pathway.

Auranofin↗
PubMed1994

The role of non-adhesive T-cell-accessory cell interactions in the induction of T-cell proliferative hyporesponsiveness.

We have suggested previously that induction of T-cell proliferative hyporesponsiveness is associated with a defective adhesive T-cell-antigen-presenting cell (APC) interaction. In the previous study, the hyporesponsiveness was allospecific, implying that a T-cell receptor-major histocompatibility complex (MHC) interaction had occurred. Therefore, we hypothesized that this type of non-adhesive T-cell-APC interaction might induce T-cell tolerance rather than activation. This hypothesis has now been tested further in the present study, using two experimental approaches. Firstly, L cells, which express a T-cell receptor ligand, i.e. MHC class II molecules, but lack the capacity to bind to T cells and do not express the crucial receptor/counter receptor lymphocyte function-associated antigen-1 (LFA-1)/intracellular adhesion molecule-1 (ICAM-1) pair, also induced non-allospecific T-cell proliferative hyporesponsiveness; this was not due to any direct inhibitory effect on the T cells. Secondly, monoclonal antibodies (mAb) directed to LFA-1 and ICAM-1 were used to disrupt T-cell-APC adhesion specifically, while allowing for T-cell receptor-MHC interaction to occur. The results of this new study suggest that the non-allospecific T-cell proliferative hyporesponsiveness induced was a function of direct T-cell inhibitory effects of these mAb. Taken together, these experiments add further evidence to support the notion that accessory cells which engage T-cell receptors without providing the necessary co-stimulatory signals induce T cells which are in a state of functional 'paralysis' with respect to the antigen which the T-cell receptor recognizes.

Animals↗
PubMed1993

Antigen processing and presentation of human rhinovirus to CD4 T cells is facilitated by binding to cellular receptors for virus.

Human rhinovirus serotypes (HRV) fall into two distinct groups, major and minor, by virtue of their cell receptor-binding ability. In this study minor receptor-binding group viruses are demonstrated to bind directly to cells of the murine immune system, including lymphoid dendritic cells which act as antigen-presenting cells, although they do not produce a productive infection in murine cells. This binding is specific and can be blocked by other serotypes of minor-group HRV. Pre-treatment of HRV 1A, a minor-group virus, with HRV 1A-specific antibodies inhibited the cellular proliferation of murine virus primed T helper cells, whereas antibody treatment of HRV 15, a non-binding major serotype, gave no inhibition. The cell binding ability of minor-group HRV played a role in the overall immunogenicity of this virus group, which was shown to be enhanced compared to the immunogenicity of major-group viruses in mice.

Adjuvants, Immunologic↗
PubMed1993

Epitope analysis of the T cell response to a complex antigen: proliferative responses to human rhinovirus capsids.

Understanding the factors which regulate the repertoire of a T cell response is important when selecting T helper cell epitopes for inclusion in synthetic viral vaccines. In this study we have examined the T cell response to human rhinovirus (HRV) type 1 A in a mouse model system, using a comprehensive set of synthetic peptides which span all four of the proteins which make up the HRV capsid. This constitutes the first study to use a set of peptides covering the entire sequence of all structural proteins of any virus. This study identifies the major proliferative (CD4) T cell epitopes within the minor receptor group HRV 1 A, and analyzes these epitopes with relation to their location within the three-dimensional structure of the virus. The proliferative response to HRV is highly selective, with strong responses to only a very small number of epitopes, many of which are grouped together within restricted areas of the primary structure of the HRV proteins. The repertoire of the response is almost entirely specific to the major histocompatibility complex haplotype of the host. The major T cell epitopes are spatially distinct from the sites of the major antibody recognition sites, and are buried within the viral capsid. In striking contrast to the antibody responses, the T cell responses are highly cross-reactive against a wide variety of viral serotypes.

Amino Acid Sequence↗
PubMed1993

Regulation of in vitro release of TH2 type cytokines (IL-4, IL-6) in the T cell response to the trinitrophenyl (TNP) hapten.

We have investigated in vitro the ability of T cells from mice primed for contact hypersensitivity to release cytokines of the TH2 subtype, in particular IL-4 and IL-6. We demonstrate that both these cytokines are indeed produced by T cells from the lymph node and spleen of mice immunized by topical application of picryl chloride and restimulated in vitro by TNP-coupled spleen cells. However, the release of IL-4 is limited by the activity of IFN-gamma, a TH1 cytokine which we have previously shown is also produced after contact sensitization. Finally, induction of tolerance to TNP, by intravenous administration of antigen, or transfer of cells from tolerant mice into naive donors prior to sensitization (which suppresses the contact sensitivity reaction in the recipients) leads to a fall in IL-4 production. Thus neither tolerance nor suppression in this system is mediated by the antagonistic activities of TH1- and TH2-type T cells. In contrast, IL-6 production is upregulated during both suppression and tolerance, suggesting that this cytokine may play a part in the negative regulation of contact sensitivity.

Animals↗
PubMed1993

Differential cytokine regulation by eicosanoids in T cells primed by contact sensitisation with TNP.

Eicosanoids are important mediators of inflammation, but also play a role in regulation of lymphocyte function. In this study we have examined the function of both prostaglandins (PGs) and leukotrienes in regulating the release of a set of cytokines produced by T cells from mice primed with the contact-sensitising agent picryl chloride. Various patterns of response by different cytokines in response to exogenous eicosanoids were observed. Both interleukin-2 (IL-2) and interferon-gamma (IFN-gamma), two cytokines involved in activating the cellular contact sensitivity reaction, were downregulated by prostaglandin E2 (PGE2) and to a lesser extent by 6-keto PGF2 alpha (PGI2). In contrast, both PGE2 and PGI2 potentiated the release of IL-3 and IL-6 which both play an important role in stimulating haemopoesis after inflammation. Unexpectedly, IL-4 release was strongly inhibited by exogenous PGI2, while remaining unaffected by PGE2. This inhibition, in contrast to the PG-mediated effects on IL-2, IL-3, IL-6, and IFN-gamma was not due to increased intracellular levels of cAMP. In contrast to the strong immunomodulatory effects of PGs, leukotrienes B4 and C4 had only small and rather variable effects on any cytokine release.

Animals↗
PubMed1993

The interaction of auranofin and buthionine sulfoximine blocks activation of human peripheral T lymphocytes.

We have previously demonstrated that auranofin, at nanomolar concentrations, enhances T cell activation, as measured by IL-2 release and Tac expression. However, it is not clear how enhanced T cell activation might be related to therapeutic value, since rheumatoid arthritis is widely believed to be associated with overactivation of the immune response. In this study, we show that the action of auranofin on T cell activation is dramatically influenced by the glutathione levels of the responding cells. Under conditions of very low intracellular glutathione where the synthesis of glutathione is blocked, the action of auranofin is converted from enhancement to a profound inhibition of T cell activation. Since glutathione levels in rheumatoid arthritis are known to be abnormally low, these results may explain how auranofin can act to suppress the immunological processes leading to rheumatoid arthritis. In addition, this study further demonstrated the close link which exists between auranofin action and glutathione metabolism in lymphocytes.

Auranofin↗