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P Life

Publications and source records attributed to P Life.

12 recordsLinked to original sources
PubMed1995

Thiols decrease human interleukin (IL) 4 production and IL-4-induced immunoglobulin synthesis.

N-Acetyl-L-cysteine (NAC) is an antioxidant precursor of intracellular glutathione (GSH), usually given in human as a mucolytic agent. In vitro, NAC and GSH have been shown to act on T cells by increasing interleukin (IL) 2 production, synthesis and turnover of IL-2 receptors, proliferation, cytotoxic properties, and resistance to apoptosis. We report here that NAC and GSH decrease in a dose-dependent manner human IL-4 production by stimulated peripheral blood T cells and by T helper (Th) 0- and Th2-like T cell clones. This effect was associated with a decrease in IL-4 messenger RNA transcription. In contrast, NAC and GSH had no effect on interferon gamma and increased IL-2 production and T cell proliferation. A functional consequence was the capacity of NAC and GSH to selectively decrease in a dose-dependent manner IL-4-induced immunoglobulin (Ig) E and IgG4 production by human peripheral blood mononuclear cells. Interestingly, NAC and GSH also acted directly on purified tonsillar B cells by decreasing the mature epsilon messenger RNA, hence decreasing IgE production. In contrast, IgA and IgM production were not affected. At the same time, B cell proliferation was increased in a dose-dependent manner. Not all antioxidants tested but only SH-bearing molecules mimicked these properties. Finally, when given orally to mice, NAC decreased both IgE and IgG1 antibody responses to ovalbumin. These results demonstrate that NAC, GSH, and other thiols may control the production of both the Th2-derived cytokine IL-4 and IL-4-induced Ig in vitro and in vivo.

Acetylcysteine↗
PubMed1995

CD28 functions as an adhesion molecule and is involved in the regulation of human IgE synthesis.

Activated T cells induce IgE switching in B cells via a combination of lymphokines and direct T:B cell contact. As CD28-deficient mice have reduced basal levels of IgG1 and IgG2a and diminished Ig class switching, we investigated whether the CD28/B7.1 (CD80) ligand pairing might also be involved in human IgE regulation. Co-incubation of an allergen-specific, human T cell clone with tonsillar B cells caused a marked up-regulation of CD28 expression, whereas, in contrast, CD45 RB expression was unaffected. To test whether blocking the CD28: B7.1 interaction affected IgE synthesis, a dialyzed anti-CD28 monoclonal antibody (mAb) was added to cultures containing tonsillar B cells, pre-activated T cell clones and interleukin-4. Anti-CD28 treatment caused a reproducible, dose-dependent inhibition of IgE, but not IgG synthesis that was accompanied by a visible decrease in cell aggregate formation. Conversely, an anti-B7.1 mAb had no effect in this system. The effect of blocking CD28-ligand interactions on lymphocyte adhesion was formally assessed on human T cell clones and B cell lines using dual intracellular staining and flow cytometry. Co-incubation with an anti-CD28 mAb, but not control IgG or anti-B7.1 mAb, resulted in a marked impairment of conjugate formation that correlated well with T cell surface expression of CD28. Using this system we found that an anti-CTLA-4 mAb but not an anti-B7.2 mAb inhibited T:B cell conjugate formation. Lastly, in addition to a direct effect of anti-CD28 mAb on conjugate formation, 14-day culture of T and B cells in the presence of anti-CD28 caused a marked decrease of ICAM-1 (CD54) expression on aggregated lymphocytes. In contrast, LFA-1 (CD18) expression was unaffected. We, therefore, conclude that the T cell co-stimulatory molecule CD28 is involved in the regulation of IgE synthesis in vitro. CD28 may act to a limited extent as an adhesion molecule, though apparently not by pairing with B7.1 or B7.2. It is more likely that ligation of CD28 under certain conditions modulates the expression of other T and B cell surface molecules.

Abatacept↗
PubMed1995

Interleukin-12 increases interleukin-4 production by established human Th0 and Th2-like T cell clones.

Interleukin (IL)-12 is a potent inducer of cell-mediated immunity: it favors the generation of interferon (IFN)-gamma-producing T cells, increases IFN-gamma production by T cells and natural killer cells and prevents the generation of a Th2 response in murine in vivo models. Nevertheless, the effects of IL-12 on an established Th2 response remain poorly documented. In the present paper, we analyzed the effect of IL-12 on the profile of lymphokines produced by established IL-4-producing Th0 and Th2-like human T cell clones (TCC) and by polyclonal T cells. We found that IL-12 (i) enhances, as previously reported, IFN-gamma production by Th0 TCC and, to a smaller extent, by Th2-like TCC, (ii) increases the proliferation of Th0 and Th2-like TCC and (iii) unexpectedly, synergizes with T cell receptor-associated or nonspecific stimuli in increasing IL-4 production by these TCC. Thus, IL-12 potentiates the production of IFN-gamma and also of IL-4 by established IL-4 producing TCC. Although IL-12 has been widely reported to induce a Th1 response and to prevent the development of a Th2 response in vivo, IL-12 may on the contrary potentiate an established Th2 response in humans.

CD4-Positive T-Lymphocytes↗
PubMed1995

CD23 regulates monocyte activation through a novel interaction with the adhesion molecules CD11b-CD18 and CD11c-CD18.

CD23 is expressed on a variety of haemopoietic cells and displays pleiotropic activities in vitro. We report that in addition to CD21 and IgE, CD23 interacts specifically with the CD11b and CD11c, the alpha chains of the beta 2 integrin adhesion molecule complexes CD11b-CD18 and CD11c-CD18, on monocytes. Full-length recombinant CD23 incorporated into fluorescent liposomes was shown to bind to COS cells transfected with cDNA encoding either CD11b-CD18 or CD11c-CD18 but not with CD11a-CD18. The interaction was specifically inhibited by anti-CD11b or anti-CD11c, respectively, and by anti-CD23 MAbs. The functional significance of this ligand pairing was demonstrated by triggering CD11b and CD11c on monocytes with either recombinant CD23 or anti-CD11b and anti-CD11c MAbs to cause a marked increase in nitrite-oxidative products and pro-inflammatory cytokines (IL-1 beta, IL-6, and TNF alpha). These CD23-mediated activities were decreased by Fab fragments of MAbs to CD11b, CD11c, and CD23. These results demonstrate that CD11b and CD11c are receptors for CD23 and that this novel ligand pairing regulates important activities of monocytes.

CD11 Antigens↗
PubMed1993

Induction of human IgE synthesis in B cells by mast cells and basophils.

Immunoglobulin E (IgE) is central to the induction of allergic diseases through its binding to the high-affinity receptor (Fc epsilon R1) on mast cells and basophils. Crosslinking by allergens of the bound IgE leads to the release of various inflammatory mediators. IgE production by B cells requires a physical interaction with T cells, involving a number of surface adhesion molecules, as well as the soluble factors interleukin-4 (IL-4) and IL-13 (ref. 5) produced by T cells, basophils and mast cells. Here we report that, in the presence of IL-4, mast and basophilic cell lines can provide the cell contact signals that are required for IgE synthesis. The human cell lines HMC-1 (mast) and KU812 (basophilic) both express the ligand for CD40 (CD40L) which is shown to be responsible for the IgE production. Moreover, freshly isolated purified human lung mast cells and blood basophils are also shown to express CD40L and to induce IgE production. This evidence suggests that mast cells and basophils may therefore play a key role in allergy not only by producing inflammatory mediators, but also by directly regulating IgE production independently of T cells.

Animals↗
PubMed1993

Human CD40-ligand: molecular cloning, cellular distribution and regulation of expression by factors controlling IgE production.

Here we report the cloning of the cDNA for human CD40-Ligand (CD40-L) from a CD4-positive T cell clone. The deduced amino acid sequence predicts a type II membrane protein of 261 amino acids. Northern blot and FACS analysis of PBMNC revealed that the human CD40-L can be detected on T cells and is absent from B cells and monocytes. The human CD40-L is expressed on both CD4- and CD8-positive T cells, (CD45R0+) and (CD45RA+) subsets. We observed that IL-4, an inducer of IgE production, upregulated CD40-L mRNA level while IFN gamma, an inhibitor of IgE synthesis, reduced the expression of CD40-L mRNA. These data suggest a the correlation between human CD40-L expression and IgE production.

Amino Acid Sequence↗
PubMed1993

Responses to gram negative enteric bacterial antigens by synovial T cells from patients with juvenile chronic arthritis: recognition of heat shock protein HSP60.

OBJECTIVE: To investigate the antigenic specificity of synovial T cells in juvenile chronic arthritis (JCA). METHODS: Synovial fluid and peripheral blood mononuclear cells from 24 patients with JCA were tested for their proliferative responses to recall antigens, enteric organisms associated with reactive arthritis, influenza A and a recombinant preparation of a mycobacterial heat shock protein, HSP65. To investigate further recognition of this last antigen, synovial T cells from one B27+ patient with pauciarticular disease were cloned using HSP65. The specificity of the resultant clones was then examined. RESULTS: Marked synovial T cell responses to enteric organisms and to HSP65 were noted, particularly in HLA-B27+, pauciarticular patients; these were similar to those seen in a B27+ patient with reactive arthritis. Responses to enteric organisms and to HSP65 were significantly correlated, suggesting recognition of an epitope common to these antigen preparations. However, all of the T cell clones obtained using HSP65 proved to recognize E. coli derived antigens contaminating the recombinant HSP65 rather than the mycobacterial antigen; these contaminants included the 60 kDa E. coli HSP, GroEL. The GroEL specific T cells did not respond to heat shocked human cells; this suggests (but does not prove) that they do not crossreact with human HSP60. CONCLUSION: Synovial T cell recognition of antigens from enteric organisms associated with reactive arthritis is a common feature in pauciarticular JCA. Among the target antigens is the GroEL HSP, but T cells recognizing this antigen do not necessarily crossreact with the homologous human HSP60.

Antigens, Bacterial↗
PubMed1992

Mucosal cell-mediated immunity to mycobacterial, enterobacterial and other microbial antigens in inflammatory bowel disease.

Culture studies have suggested that Mycobacterium paratuberculosis may play a role in the aetiology of Crohn's disease. However, evidence of sensitization to mycobacterial antigens amongst patients with Crohn's disease has not yet been adequately demonstrated. Previous studies of cell-mediated immunity (CMI) in Crohn's disease were restricted to responses of peripheral blood mononuclear cells (PBMC) to mycobacterial antigens. In this study we have investigated the proliferative responses of both PBMC and mesenteric lymph node mononuclear cells (MLNMC) to a range of mycobacterial and non-mycobacterial antigens. There was no evidence of specific sensitization in the responses of MLNMC and PBMC from patients with inflammatory bowel disease (IBD) to the mycobacterial antigens. However, anergy to M. paratuberculosis could not be excluded. IBD MLNMC responses to most antigens were generally greater than those of PBMC, which were often undetectable. When compared with controls, there was evidence of increased CMI to a range of non-mycobacterial antigens, especially Yersinia enterocolitica, amongst both MLNMC and PBMC from patients with Crohn's disease and ulcerative colitis (UC). These results do not provide support to the proposed role of mycobacteria in the pathogenesis of Crohn's disease, but indicate that further investigation may determine a role for bacterial-specific T cell-mediated responses in the pathogenesis of IBD.

Antigens, Bacterial↗
PubMed1987

Immunoadsorbent purification of carcinoembryonic antigen using a monoclonal antibody: a direct comparison with a conventional method.

Carcinoembryonic antigen (CEA) has been extracted and purified by two different methods from a single aqueous homogenate of liver metastases from a primary adenocarcinoma of the colon, thus enabling direct comparison to be made between a conventional technique using gel filtration and a monoclonal antibody immunoadsorbent method. Yield, immunoreactivity and purity have been determined in both cases by direct weighing, enzyme-linked immunoadsorbent assay, radioimmunoassay and SDS-polyacrylamide gel electrophoresis. Reactivity of the antigen with monoclonal and polyclonal anti-CEA antibodies recognising different epitopes was analysed by Western blotting. There appears to be no significant difference in immunoreactivity or purity by these criteria, but the immunoadsorbent method gave a higher yield of CEA for far less expenditure of time and effort. A variant of CEA with a lower molecular weight was also identified in both preparations.

Antibodies, Monoclonal↗
PubMed1986

In vivo studies on the uptake of radiolabelled antibodies by colorectal and gastric carcinoma xenografts.

A number of criteria have been investigated to try to improve the uptake of radiolabelled antibodies by colorectal carcinoma xenografts. The in vivo behaviour of four antibodies was compared and found to vary. Two antibodies, 11-285-14 and 14-95-55, demonstrated specific uptake by the tumours. 11-357-5 was lost from the tumour after 72 h and the fourth antibody could not be iodinated without loss of activity. Neither increased time nor increased dose were shown to increase the uptake of antibody by tumours although the clearance of antibody from blood was shown to be more rapid than from tumour resulting in clearer backgrounds. Increased tumour:blood ratios were demonstrated by particular combinations of antibodies but the extent to which this occurred varied with the epitopes recognised. High carcinoembryonic antigen expressing xenografts did not show significantly higher uptake of antibody. This was shown to be due to the smaller size of these tumours and associated decreased vascularity.

Animals↗
PubMedDate not supplied

Regulation of IgE synthesis by CD23/CD21 interaction.

At least two cell-derived signals have been shown to be necessary for the induction of immunoglobulin isotype switching in B cells. The first signal is given by either of the soluble lymphokines interleukin (IL)-4 or IL-13 which induce germline epsilon transcript expression, but alone is insufficient to trigger secretion of IgE. The second signal is provided by a physical interaction between B cells and activated T cells, basophils and mast cells, and it has been shown that the CD40/CD40L pairing is crucial for mediating IgE synthesis. In HIGM1 syndrome, which is characterized by greatly decreased levels of IgG, IgA and IgE, there are mutations in CD40L resulting in a completely non-functional extracellular domain. CD40L is therefore playing a central role in Ig switching. Amongst the numerous pairs of surface adhesion molecules, the CD23/CD21 pair seems to play a key role in the generation of IgE. The CD23 molecule is positively and negatively regulated by factors which increase or decrease IgE production, respectively. Antibodies to CD23 have been shown to inhibit IL-4-induced human IgE production in vitro and to inhibit antigen-specific IgE responses in a rat model, in an isotype-selective manner. CD23 interacts with CD21 on B cells, preferentially driving IgE production. CD23 recognises two main epitopes on the CD21 molecule. One region consists of short consensus repeat sequences (SCRs) 1-2 and the other of SCRs 5-8. In the latter region ASn370 and Asn295 are critical in the interaction with the lectin CD23. Therefore, a restricted number of cytokines and surface molecules seems to selectively regulate human IgE synthesis.

Animals↗