Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The APC-derived cytokine interleukin (IL)-12 polarizes CD4 T cells towards the pro-inflammatory Th1 phenotype and has been shown to be crucial for the development of EAE in rodents. In this study we demonstrate that production of IL-12 by human adult CNS-derived microglial cells can be triggered by cell contact with activated T cells. Microglial activation and IL-12 production can be blocked by anti-CD154 mAbs. IL-12 production could also be induced by direct engagement of CD40 on microglia using a CD40 agonist. IL-12 secretion by microglia is significantly reduced by TNF and IFN-gamma antagonists showing that the IL-12 production is subject to regulation by auto- and paracrine stimuli.
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PMID:CD40 engagement stimulates IL-12 p70 production by human microglial cells: basis for Th1 polarization in the CNS. 1062 65

Pulmonary immunity reflects a balance between proinflammatory and immunosuppressive factors in the lung. To determine the immune activities of exudate macrophages in the pulmonary immune response, Lewis rats were injected intratracheally with heat-killed Listeria (HKL), labeled ex vivo with the lipophilic dye PKH-26. At 24 h, macrophages from bronchoalveolar lavage fluid were purified on the basis of their surface membrane expression of RMA, a macrophage-specific antigen, which is brightly expressed by resident alveolar macrophages but dimly expressed by monocytes. Pulmonary macrophages were analyzed for uptake of PKH-26-HKL, and RMA(bright/dim) macrophages sorted by FACS were compared for cytokine expression, nitric oxide (NO) release, and APC activities. RMA(bright) macrophages were OX-62(-), B7(-), and factor XIIIa(-); they were the dominant mediators of phagocytosis when low doses of HKL were administered intratracheally but did not support the proliferation of T lymphocytes. RMA(dim) exudate macrophages were OX-62(+), B7(+), and factor XIIIa(+). They expressed more IL-1 and TNF, but less nitric oxide, than did RMA(bright) macrophages; they were excellent APCs for T cell responses. We conclude that a subset of RMA(dim) exudate macrophages shows phenotypic and functional evidence of dendritic cell differentiation.
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PMID:Accumulation of macrophages with dendritic cell characteristics in the pulmonary response to Listeria. 1067 97

In vivo and in vitro studies have demonstrated the selective regulatory effect that TH1 and TH2 cytokines reciprocally exert in the regulation of the polarization of precursor cells into TH1 or TH2 types. The study of the network relationships between TH1 and TH2 (TH1/TH2) cytokines in healthy subjects could lead to a better understanding of how the physiological network of cytokines regulates the immune response. Such study could lead to gain suggestions for follow-up experiments to create prognostic and diagnostic indices for biotherapeutic treatments of patients. Hence we determined serum levels (environment network) and PBMC production (cellular network) of IL2, IFN gamma, IL4, IL6 and IL10 in the peripheral blood of healthy subjects; these cytokines made up our networks under basic conditions. Both men and women were studied as hormones can influence the polarization of TH1 and TH2 cells. Cytokines within the physiological network function simultaneously so multivariate statistical methods were used to study TH1/TH2 relationships. The use of mathematical modelling is the only effective way of studying the immune system as a whole. The physiological TH1/TH2 network under activation conditions was evaluated by incorporating: sIL2R and sIL6R into the basic environment network model and the production levels of cytokines by PBMC after PHA stimulus, into the basic cellular network model. The influence of APC was evaluated by adding: serum levels of TNF alpha and IL1 beta to the environment network model, and production levels of IFN gamma, IL10 and IL6, after stimulus with LPS, to the cellular network model. Our results led us to hypothesize that the physiological network of TH1/TH2 cytokines regulates TH polarization by means of specific relationships between TH1 and TH2 cytokines, which may be different in men and women. These relationships could be studied experimentally to create prognostic and diagnostic indices for more efficient prevention programs and biotherapeutic treatments of patients.
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PMID:The TH1 and TH2 cytokine network in healthy subjects: suggestions for experimental studies to create prognostic and diagnostic indices for biotherapeutic treatments. 1094 34

Growing evidence has demonstrated that members of TNF superfamily transduce signals after engagement with their receptors. TNF-related activation-induced cytokine (TRANCE), a member of TNF superfamily, is preferentially expressed on the surface of activated CD4(+) Th1 cells. The soluble receptor activator of NF-kappaB (RANK).Fc fusion protein suppresses IFN-gamma secretion by activated Th1 cells, but does not affect IL-4 secretion by Th2 cells. The suppressive effect on IFN-gamma secretion is observed when Th1 cells are activated by APCs, but not by immobilized anti-TCR beta mAb. In contrast, immobilized RANK.Fc fusion protein augments IFN-gamma secretion by Th1 cells, indicating the occurrence of reverse signaling through TRANCE during T cell/APC interaction. The enhanced secretion of IFN-gamma mediated via TRANCE correlates with the activation of p38 mitogen-activated protein kinase and is blocked by SB203580, a p38 mitogen-activated protein kinase-specific inhibitor. Thus, in addition to its role in activating dendritic cells by binding to the receptor RANK, TRANCE itself can signal the augmentation of IFN-gamma secretion via a p38-dependent pathway, and this provides yet another example of reverse signaling by a member of TNF superfamily.
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PMID:Enhanced secretion of IFN-gamma by activated Th1 cells occurs via reverse signaling through TNF-related activation-induced cytokine. 1112 2

The unique glycerolipids of Archaea can be formulated into vesicles (archaeosomes) with potent adjuvant activity. We studied the effect of archaeosomes on APCs to elucidate the mechanism(s) of adjuvant action. Exposure of J774A.1 macrophages to archaeosomes in vitro resulted in up-regulation of B7.1, B7.2, and MHC class II molecules to an extent comparable to that achieved with LPS. Similarly, incubation of bone marrow-derived DCs with archaeosomes resulted in enhanced expression of MHC class II and B7.2 molecules. In contrast, conventional liposomes made from ester phospholipids failed to modulate the expression of these activation markers. APCs treated with archaeosomes exhibited increased TNF production and functional ability to stimulate allogenic T cell proliferation. More interestingly, archaeosomes enhanced APC recruitment and activation in vivo. Intraperitoneal injection of archaeosomes into mice led to recruitment of Mac1alpha(+), F4/80(+) and CD11c(+) cells. The expression of MHC class II on the surface of peritoneal cells was also enhanced. Furthermore, peritoneal cells from archaeosome-injected mice strongly enhanced allo-T cell proliferation and cytokine production. The ability of archaeosome-treated APCs to stimulate T cells was restricted to Mac1alpha(high), B220(-) cells in the peritoneum. These Mac1alpha(high) cells in the presence of GM-CSF gave rise to both F4/80(+) (macrophage) and CD11c(+) (dendritic) populations. Overall, the activation of APCs correlated to the ability of archaeosomes to induce strong humoral, T helper, and CTL responses to entrapped Ag. Thus, the recruitment and activation of professional APCs by archaeosomes constitutes an efficient self-adjuvanting process for induction of Ag-specific responses to encapsulated Ags.
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PMID:The potent adjuvant activity of archaeosomes correlates to the recruitment and activation of macrophages and dendritic cells in vivo. 1116 Feb 36

Autoreactive thymocytes can be deleted at an immature stage of their development by Ag-induced apoptosis or negative selection. In addition to Ag, negative selection also requires costimulatory signals from APC. We recently used a fetal thymus organ culture system to show that CD5, CD28, and TNF cooperatively regulate deletion of autoreactive thymocytes. Although these experiments provided strong evidence for the action of several costimulators in negative selection, we wished to demonstrate a role for these molecules in a physiologically natural model where thymocytes are deleted in vivo by endogenously expressed AGS: Accordingly, we examined thymocyte deletion in costimulator-null mice in three models of autoantigen-induced negative selection. We compared CD5(-/-) CD28(-/-) mice to CD40L(-/-) mice, which exhibited a profound block in negative selection in all three systems. Surprisingly, only one of the three models revealed a requirement for the CD5 and CD28 costimulators in autoantigen-induced deletion. These results suggest that an extraordinarily complex array of costimulators is involved in negative selection. We predict that different sets of costimulators will be required depending on the timing of negative selection, the Ag, the signal strength, the APC, and whether Ag presentation occurs on class I or class II MHC molecules.
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PMID:Requirement for a complex array of costimulators in the negative selection of autoreactive thymocytes in vivo. 1134 22

It is becoming increasingly clear that coagulation augments inflammation and that anticoagulants, particularly natural anticoagulants, can limit the coagulation induced increases in the inflammatory response. The latter control mechanisms appear to involve not only the inhibition of the coagulation proteases, but interactions with the cells that either generate anti-inflammatory substances, such as prostacyclin, or limit cell activation. Recent studies have demonstrated a variety of mechanisms by which coagulation, particularly the generation of thrombin, factor Xa and the tissue factor-factor VIIa complex, can augment acute inflammatory responses. Many of these responses are due to the activation of one or more of the protease activated receptors. Activation of these receptors on endothelium can lead to the expression of adhesion molecules and platelet activating factor, thereby facilitating leukocyte activation. Therefore, anticoagulants that inhibit any of these factors would be expected to dampen the inflammatory response. The three major natural anticoagulant mechanisms seem to exert a further inhibition of these processes by impacting cellular responses. Antithrombin has been shown in vitro to increase prostacyclin responses and activated protein C has been shown to inhibit a variety of cellular responses including endotoxin induced calcium fluxes in monocytes and the nuclear translocation of NFKB, a key step in the generation of the inflammatory response. In some, but not all, in vivo models, these natural anticoagulants have been able to inhibit endotoxin/E. coli-mediated leukocyte activation and to diminish cytokine elaboration (TNF, IL-6 and IL-8). Phase III clinical studies for treatment of patients with severe sepsis have been completed for APC, which was successful (1), and for antithrombin, which was not (2). A phase III trial with tissue factor pathway inhibitor is in progress. In this review, the mechanisms by which the different natural anticoagulants are thought to function will be reviewed.
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PMID:Role of coagulation inhibitors in inflammation. 1148 41

OX40 ligand (OX40L) expressed on APCs, and its receptor, OX40 present on activated T cells, are members of the TNF/TNFR family, respectively, and have been located at the sites of inflammatory conditions. We have observed in OX40L-deficient mice (OX40L(-/-)) an impaired APC capacity and in our recently constructed transgenic mice expressing OX40L (OX40L-Tg), a markedly enhanced T cell response to protein Ags. Using these mice, we demonstrate here the critical involvement of the OX40L-OX40 interaction during the T cell priming events in the occurrence of experimental autoimmune encephalomyelitis (EAE). In OX40L(-/-) mice, abortive T cell priming greatly reduced the clinical manifestations of actively induced EAE, coupled with a reduction in IFN-gamma, IL-2, and IL-6 production in vitro. Adoptive transfer experiments however revealed an efficient transfer of disease to OX40L(-/-) mice using wild-type donor T cells, indicating an intact capacity of OX40L(-/-) mice to initiate effector responses. On the other hand, OX40L(-/-) donor T cells failed to transfer disease to wild-type recipient mice. Furthermore, OX40L-Tg mice developed a greater severity of EAE despite a delayed onset, while both OX40L-Tg/CD28(-/-) and OX40L-Tg/CD40(-/-) mice failed to develop EAE demonstrating a requisite for these molecules. These findings indicate a pivotal role played by OX40L in the pathogenesis of EAE.
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PMID:Critical involvement of OX40 ligand signals in the T cell priming events during experimental autoimmune encephalomyelitis. 1150 50

In vivo priming of CD8(+) T lymphocytes against exogenously processed model Ags requires CD4(+) T cell help, specifically interactions between CD40 ligand (CD40L) expressed by activated CD4(+) T cells and CD40, which is present on professional APC such as dendritic cells (DCs). To address this issue in the context of bacterial infection, we examined CD40L-CD40 interactions in CD8(+) T cell priming against an exogenously processed, nonsecreted bacterial Ag. CD40L interactions were blocked by in vivo treatment with anti-CD40L mAb MR-1, which inhibited germinal center formation and CD8(+) T cell cross-priming against an exogenous model Ag, OVA. In contrast, MR-1 treatment did not interfere with CD8(+) T cell priming against a nonsecreted or secreted recombinant Ag expressed by Listeria monocytogenes. Memory and secondary responses of CD8(+) T cells against nonsecreted and secreted bacterial Ags were also largely unimpaired by transient MR-1 treatment. When MR-1-treated mice were concurrently immunized with L. monocytogenes and OVA-loaded splenocytes, cross-priming of OVA-specific naive CD8(+) T cells occurred. No significant decline in cross-priming against OVA was measured when either TNF or IFN-gamma was neutralized in L. monocytogenes-infected animals, demonstrating that multiple signals exist to overcome CD40L blockade of CD8(+) T cell cross-priming during bacterial infection. These data support a model in which DCs can be stimulated in vivo through signals other than CD40, becoming APC that can effectively stimulate CD8(+) T cell responses against exogenous Ags during infection.
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PMID:Listeria monocytogenes infection overcomes the requirement for CD40 ligand in exogenous antigen presentation to CD8(+) T cells. 1169 31

TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, induces apoptosis in susceptible cells, which can be both malignant and nontransformed. Despite homologies among the death ligands, there are great differences between the TRAIL system on the one hand and the TNF and CD95 systems on the other hand. In particular, TRAIL-induced apoptosis differs between rodents and man. Studies on animal models of autoimmune diseases suggested an influence of TRAIL on T cell growth and effector functions. Because we previously demonstrated that TRAIL does not induce apoptosis in human (auto)antigen-specific T cells, we now asked whether TRAIL exhibits other immunoregulatory properties in these cells. Active TRAIL inhibited calcium influx through store-operated calcium release-activated calcium channels, IFN-gamma/IL-4 production, and proliferation. These effects were independent of APC, Ag specificity, and Th differentiation, and no differences were detected between healthy donors and multiple sclerosis patients. TRAIL affected neither the expression of the cell cycling inhibitor p27(Kip1) nor the capacity of T cells to produce IL-2 upon Ag rechallenge, indicating that signaling via TRAIL receptor does not induce T cell anergy. Instead, the TRAIL-induced hypoproliferation could be attributed to the down-regulation of the cyclin-dependent kinase 4, indicating a G(1) arrest of the cell cycle. Thus, although it does not contribute to mechanisms of peripheral T cell tolerance such as clonal anergy or deletion by apoptosis, TRAIL can directly inhibit activation of human T cells via blockade of calcium influx.
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PMID:Death ligand TRAIL induces no apoptosis but inhibits activation of human (auto)antigen-specific T cells. 1199 37


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