Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

C3H/HeH or C57BL/6 mice were injected with resting or Escherichia coli lipopolysaccharide (LPS)-stimulated splenic B cells from adult B10.BR mice. Animals were grafted with tail skin grafts from B10.BR mice 36 hr later. Spleen cells were removed from these mice 7 days after grafting and challenged in tissue culture with irradiated B10.BR spleen cells or BALB/c cells. LPS blasts, but not naive B cells, induced an antigen-specific reduction in proliferation and IL-2 production from stimulated C3H/HeJ cells. The response obtained from C57BL/6 spleen responder cells was increased by this treatment. IL-4 production was either unchanged (C57BL/6) or enhanced (C3H/HeJ). Modification of the C3H/HeJ anti-B10.BR response by B blasts was not blocked by CTLA-4 Ig, although the increased response seen using MHC-incompatible (C57BL/6) spleen cells was inhibited by CTLA-4 Ig. B10.BR, but not BALB/c, skin graft survival in vivo was enhanced in C3H/HeJ recipients of B10.BR B blasts. In addition, in lymph nodes draining the graft site of C3H/HeJ mice injected with B10.BR LPS blasts, mRNA for IL-4 was detected by polymerase chain reaction. When similar studies were performed with B10.BR immune C3H/HeJ or C57BL/6 mice, no enhancement of graft survival in vivo, or decrease in proliferation/IL-2 production in vitro, was seen following prechallenge with B10.BR LPS blasts.
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PMID:Tolerance induction to multiple minor histoincompatible cells by activated B cells is associated with preferential activation of Th2 cells. 803 8

T cell hybridomas were generated from a LEW rat T cell line specific for the uveitogenic peptide bov-B1 of bovine retinal S-antigen. Using these autoreactive hybridomas, IL-2 production and activation-induced cell death (AICD) were dissociated as outcomes of activation. The self-reactive hybridomas secrete IL-2 and undergo AICD in response to antigen presented by non-irradiated syngeneic splenocytes, whereas antigen presentation by irradiated splenocytes induced only AICD. IL-2 production by a non-self reactive hybridoma was unaffected by irradiation of the APC. Pretreatment of the APC with phorbol ester or lipopolysaccharide and IL-4 protected their ability to induce IL-2 secretion after gamma-irradiation. Although the co-stimulation-blocking reagent CTLA-4-Ig mimicked the effect of gamma-irradiation by preventing IL-2 secretion but not AICD, B7 expression on the APC was not radiosensitive, nor did co-stimulation, provided 'in trans' with a B7-expressing third-party cell, reconstitute antigen-specific hybridoma IL-2 secretion in response to irradiated APC. In summary, the data show that IL-2 secretion and AICD of a self-reactive T cell hybridoma can be dissociated as consequences of TCR occupancy in the presence of a functional co-stimulatory signal. It is proposed that the signals producing these events are transduced through the TCR-CD3 complex alone and reflect the differential outcomes of high- and low-affinity interactions.
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PMID:A radiosensitive APC activity dissociates IL-2 secretion and activation-induced cell death by autoreactive T cell hybridomas. 858 77

To investigate the mechanisms underlying T-cell responses during superantigen (SAg) stimulation, we analysed the effects of SAg on CD27 expression with or without lipopolysaccharide (LPS) as a novel regulator of T-cell function. CD27 is expressed on the majority of resting peripheral blood T cells (CD27low). Activation of T cells by SAg induces high levels of CD27 surface expression (CD27high) accompanied with simultaneous CD30 receptor expression. After prolonged activation in vitro, the level of CD27 expression became intermediate. The effects of LPS on down-regulation of CD27high expression on CD30+ T cells were dose-dependent. Separating LPS-stimulated monocytes from T cells by mechanical dispersion abolished its inhibitory effect, indicating the requirement for direct interactions between monocytes and T cells. We also found that SAg up-regulated CD80 expression on CD14+ monocytes and LPS inhibited SAg-induced CD80 expression after 24 hr of stimulation. Up-regulation of CD152 (CTLA-4) was selective, since it was found to be preferentially expressed on the CD30+ population. Competitive experiments using soluble blocking peptides showed that addition of CD28 or CD80 peptide recovered LPS-induced down-regulation of CD27high expression on CD30+ T cells. These observations suggested that the presence of low levels of CD80 on monocytes may partially inhibit CD27 expression due to inefficient delivery of positive signals via CD28/CD80 interaction, and that the increased levels of CD80 enhance the inhibition through interactions with CD152 which is expressed at the highest levels after 48 hr of activation.
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PMID:Lipopolysaccharide-dependent down-regulation of CD27 expression on T cells activated with superantigen. 1054 Feb 29

Acute and chronic graft versus host disease (GVHD) remain the major barriers to successful hematopoietic cell transplantation. The induction of GVHD may be divided into three phases: recipient conditioning;donor T-cell activation; andeffector cells mediating GVHD. This review examines GVHD prevention and treatment using this conceptual model as framework. The various pharmacological agents discussed impact on different phases of the GVHD cascade. For example, keratinocyte growth factor and interleukin (IL)-11 are cytokines that may be useful in disrupting phase I of the GVHD cascade by blocking gastrointestinal tract damage, and lowering serum levels of lipopolysaccharide and tumour necrosis factor (TNF)-alpha. Cyclosporin, tacrolimus (FK-506) and sirolimus (rapamycin) are some of the main agents that disrupt phase II (donor T-cell activation). Mycophenolate mofetil and tresperimus probably act on this phase as well. Other novel drugs that affect phase II are tolerance-induction agents such as CTLA-4 and anti-CD40-ligand monoclonal antibodies, and preliminary results using CTLA-4 monoclonal antibody in GVHD prevention are encouraging. Examples of agents that disrupt phase III are the IL-2 receptor antagonist daclizumab and the anti-TNFalpha monoclonal antibody infliximab. These anti-cytokine antibodies have shown promising results in early studies. The most effective approach to GVHD prevention will probably be a combination regimen where the three phases of the GVHD cascade are disrupted. Once GVHD has occurred, all three phases of the cascade are activated. Developments of combination therapy for treatment of both acute and chronic GVHD are likely to yield better results than monotherapy. The numerous new treatment modalities presented should improve the outlook for patients with acute and chronic GVHD.
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PMID:Novel pharmacotherapeutic approaches to prevention and treatment of GVHD. 1192 36

Acute graft-versus-host disease (GVHD) and chronic GVHD remain the major barriers to successful haematopoietic cell transplantation. The induction of GVHD may be divided into three phases: recipient conditioning, donor T cell activation and effector cells mediating GVHD. This review examines GVHD prevention and treatment using this conceptual model as framework. The various pharmacological agents discussed impact on different phases of the GVHD cascade. For example, keratinocyte growth factor and IL-11 are cytokines that may be useful in disrupting Phase I of the GVHD cascade by blocking gastrointestinal tract damage and lowering serum levels of lipopolysaccharide and TNF-alpha. Cyclosporin, FK506 and sirolimus are some of the main agents that disrupt Phase II (donor T cell activation). Mycophenolate mofetil likely acts on this phase as well. Other novel drugs that affect Phase II are tolerance-induction agents such as cytotoxic T lymphocyte antigen (CTLA)-4 Ig and anti-CD40 ligand, and preliminary results using CTLA-4 Ig in GVHD prevention are encouraging. Two exciting agents that appear to affect only activated lymphocytes are ABX-CBL and visilizumab. Examples of agents that disrupt Phase III are the IL-2 receptor antagonist daclizumab and the anti-TNF-alpha monoclonal antibody infliximab. These anticytokine antibodies have shown promising results in early studies. The most effective approach to GVHD prevention will likely be a combination regimen where the three phases of the GVHD cascade are disrupted. Once GVHD has occurred, all three phases of the cascade are activated. Developments of combination therapy for treatment of both acute and chronic GVHD will likely yield better results than monotherapy. The numerous new treatment modalities presented should improve the outlook for acute and chronic GVHD.
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PMID:Novel therapeutics for the treatment of graft-versus-host disease. 1222 48

We have recently described an impaired proliferative response of CD4(+) T-cells to primary antigens in patients with insulin-dependent diabetes mellitus (IDDM) [Clin. Immunol. 103 (2002) 249]. In order to further investigate possible mechanisms underlying this impairment, several factors known to be involved in the down-regulation of the immune response both at the level of APCs and CD4(+) T-cells were investigated: Monocyte-derived dendritic cells (MDDC) from IDDM patients were shown to express elevated amounts of CD86 (B7.2) (p=0.003) and reduced amounts of the adhesion molecule CD54 (ICAM-1) (p=0.03) on their cell surface compared to age-matched healthy controls and patients with non-insulin-dependent diabetes mellitus (NIDDM) as well as decreased SDS-PAGE stability of HLA-DQ and -DR peptide complexes directly isolated from the IDDM patients' peripheral blood mononuclear cells (PBMCs). Expression of CTLA-4 (CD152), known to be involved in the down-regulation of the immune response, was shown to be increased on CD4(+) T-cells from IDDM patients after exposure to the primary antigen KLH (keyhole limpet hemocyanin) presented by MDDC (p=0.0047). Likewise, purified CD4(+) T-cells from IDDM patients produced elevated levels of the cytokine TGF-beta1 after stimulation with immobilized monoclonal antibodies directed against CD3 and CD28 (p=0.014). When monocytes from IDDM patients were stimulated with lipopolysaccharide (LPS), an increased tendency to produce the inhibitory cytokine interleukin (IL)-10 (p=0.007) and the acute phase cytokine IL-6 (p=0.044) was observed, whereas the concentrations of tumor necrosis factor (TNF)-alpha, IL-1beta, and IL-12 were comparable to controls. Taken together, our data suggest that a deviation in the expression of certain molecules known to be involved in the peripheral control of the immune response is present in IDDM patients and is underlying the observed impairment of the primary immune response.
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PMID:Impaired primary immune response in type-1 diabetes. Functional impairment at the level of APCs and T-cells. 1274 78

Allogeneic cord blood (CB) transplantation is associated with less severe graft-versus-host disease (GvHD), thought to be due to the immaturity of CB T cells, but how T cells interact with host and donor-derived dendritic cells (DCs) to initiate GvHD has not been elucidated. We therefore investigated the responses of CB and adult blood CD4(+) T cells co-cultured with adult host DCs of different maturities. Primed by adult host DCs, CB and adult blood CD4(+) T cells underwent similar changes in the expression of CD45RA/45RO, CD25, CD40L and CTLA-4. However, CB CD4(+) T cells, when primed by either immature or Bacillus Calmette-Guerin mycobacteria-treated adult host DCs, produced lower interferon-gamma (IFN-gamma) and higher interleukin-10 (IL-10), which is a regulatory T cell-like cytokine profile, as compared with adult blood CD4(+) T cells. In contrast, lipopolysaccharide (LPS)-treated adult host DCs significantly up-regulated IFN-gamma and down-regulated IL-10 production levels from CB CD4(+) T cells to that from adult blood CD4(+) T cells. The sustained low IFN-gamma and high IL-10 production from CB CD4(+) T cells co-cultured with adult blood DCs might account for the less severe GvHD occurrence after CB transplantation, which could be reversed by LPS-treated adult blood DCs.
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PMID:Tolerance associated with cord blood transplantation may depend on the state of host dendritic cells. 1528 45

Dendritic cells (DC), as initiators and orchestrators of immune responses, control both naive and primed T cell responses. Depending on their maturation stage, DC promote immunity or tolerance. Here we investigated (1) the phenotype and cytokine secretion patterns of IL-10-modulated immature DC (IL-10-DC) and lipopolysaccharide (LPS)-driven mature DC (LPS-DC) in comparison with unmodulated immature DC (imDC) and (2) the effects of IL-10-DC, and of LPS-DC, vs. imDC on autologous T cell responses in patients with myasthenia gravis (MG) compared with healthy controls (HC). All three types of DC derived from MG significantly increased the levels of CD4+CD25+ T cells and of their subfraction expressing CD69, when compared to DC derived from HC. IL-10-DC induced production of IL-10 and IL-4 by T cells from MG patients, but only IL-10 production from HC. LPS-DC activated autologous T cells as reflected by augmented CD25, CD69 and CTLA-4 expression on CD4+ T cells, without differences between MG and HC. This was associated with increased production of both Th1 (IFN-gamma) and Th2 (IL-10 and IL-4) cytokines by T cells. These results indicate that DC-induced activation of autologous T cells is more pronounced in MG than in HC. In addition, DC-induced T cell responses in MG vs. HC are more Th2-prone.
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PMID:Dendritic cells activate autologous T cells and induce IL-4 and IL-10 production in myasthenia gravis. 1546 7

Class switching consists in the substitution of the heavy-chain constant region of immunoglobulin M (IgM) with that of IgG, IgA, or IgE. This enables antibodies to acquire new effector functions that are crucial to combat invading pathogens. Class switching usually requires engagement of CD40 on B cells by CD40 ligand (CD40L) on antigen-activated CD4(+) T cells and the production of cytokines. The process must be regulated tightly because abnormal IgG and IgA production favors the onset of autoimmunity, whereas increased switching to IgE leads to atopy. These inflammatory disorders can be triggered or exacerbated by costimulatory signals. Although thoroughly investigated on T cells, the roles of the inhibitory receptors CD85j, LAIR-1, and CD152 on B-cell functions have not been fully elucidated. In this study we show that cross-linking of the B-cell inhibitory receptors by specific monoclonal antibodies inhibits IgG and IgE production, reduces the percentage of IgG- and IgE-expressing B cells, and down-regulates interleukin 8 (IL-8), IL-10, and tumor necrosis factor alpha production. These effects were demonstrated using different B-cell stimulatory pathways (recall antigens, CD40L-transfected cells plus IL-4, and lipopolysaccharide plus IL-4). It thus appears that CD85j, LAIR-1, and CD152 play a central role for the control of IL-4-driven isotype switching.
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PMID:Inhibitory receptors CD85j, LAIR-1, and CD152 down-regulate immunoglobulin and cytokine production by human B lymphocytes. 1593 44

Overexpression of HER-2/neu (c-erbB2) is associated with increased risk of recurrent disease in ductal carcinoma in situ (DCIS) and a poorer prognosis in node-positive breast cancer. We therefore examined the early immunotherapeutic targeting of HER-2/neu in DCIS. Before surgical resection, HER-2/neu(pos) DCIS patients (n = 13) received 4 weekly vaccinations of dendritic cells pulsed with HER-2/neu HLA class I and II peptides. The vaccine dendritic cells were activated in vitro with IFN-gamma and bacterial lipopolysaccharide to become highly polarized DC1-type dendritic cells that secrete high levels of interleukin-12p70 (IL-12p70). Intranodal delivery of dendritic cells supplied both antigenic stimulation and a synchronized preconditioned burst of IL-12p70 production directly to the anatomic site of T-cell sensitization. Before vaccination, many subjects possessed HER-2/neu-HLA-A2 tetramer-staining CD8(pos) T cells that expressed low levels of CD28 and high levels of the inhibitory B7 ligand CTLA-4, but this ratio inverted after vaccination. The vaccinated subjects also showed high rates of peptide-specific sensitization for both IFN-gamma-secreting CD4(pos) (85%) and CD8(pos) (80%) T cells, with recognition of antigenically relevant breast cancer lines, accumulation of T and B lymphocytes in the breast, and induction of complement-dependent, tumor-lytic antibodies. Seven of 11 evaluable patients also showed markedly decreased HER-2/neu expression in surgical tumor specimens, often with measurable decreases in residual DCIS, suggesting an active process of "immunoediting" for HER-2/neu-expressing tumor cells following vaccination. DC1 vaccination strategies may therefore have potential for both the prevention and the treatment of early breast cancer.
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PMID:Targeting HER-2/neu in early breast cancer development using dendritic cells with staged interleukin-12 burst secretion. 1729 84


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