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)

Theiler's murine encephalomyelitis virus induces immune-mediated demyelination in susceptible mice after intracerebral inoculation. A naturally occurring, low pathogenic Theiler's murine encephalomyelitis virus variant showed a single amino acid change within a predominant Th epitope from lysine to arginine at position 244 of VP1. This substitution is the only one present in the entire viral capsid proteins. In this paper, we demonstrate that the majority of T cells specific for VP1(233-250) and VP2(74-86) from wild-type virus-infected mice are Th1 type and these VP1-specific cells poorly recognize the variant VP1 epitope (VP1(K244R)) containing the substituted arginine. In contrast, the Th2-type T cell population specific for these epitopes predominates in variant virus-infected mice. Immunization with UV-inactivated virus or VP1 epitope peptides could not duplicate the preferential Th1/Th2 responses following viral infection. Interestingly, the major APC populations, such as dendritic cells and macrophages, produce IL-12 on exposure to the pathogenic wild-type virus, whereas they preferentially produce IL-10 in response to the low pathogenic variant virus. Thus, such a spontaneous mutant virus may have a profoundly different capability to induce Th-type responses via selective production of cytokines involved in T cell differentiation and the consequent pathogenicity of virally induced immune-mediated inflammatory diseases.
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PMID:Preferential induction of IL-10 in APC correlates with a switch from Th1 to Th2 response following infection with a low pathogenic variant of Theiler's virus. 1193 84

Th1-mediated cellular responses are important for protection in tuberculosis. However, the mechanisms and APC types responsible for initiating Th1 responses are not well understood. These studies show that macrophages and dendritic cells, albeit both being APC, respond differently following Mycobacterium tuberculosis infection and thereby have different consequences for the development of naive T cells. We report that M. tuberculosis-infected dendritic cells bias the polarization of OVA peptide-specific naive transgenic T cells to the Th1 phenotype, and, in contrast, in the presence of infected macrophages naive T cells do not develop a Th1 phenotype. Comparison of the cytokine profile expressed by the infected dendritic cells and macrophages revealed several differences, the most striking being that infected macrophages did not express the Th1-promoting cytokine IL-12. These studies also show that IL-10 is responsible for the failure of IL-12 production by M. tuberculosis-infected macrophages, and that the effects of IL-10 can be overcome by IFN-gamma priming. We speculate that the observed difference in response of the two APC types to M. tuberculosis infection may be a reflection of their respective roles in immune initiation and granuloma regulation.
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PMID:Mycobacterium tuberculosis induces differential cytokine production from dendritic cells and macrophages with divergent effects on naive T cell polarization. 1197 Oct 12

We showed previously that cecal bacterial Ag (CBA)-specific CD4(+) T cells induce colitis when transferred into SCID mice. The purpose of this study was to generate and characterize CBA-specific regulatory T cells in C3H/HeJBir (Bir) mice. CD4(+) T cells were stimulated with CBA-pulsed APC in the presence of IL-10 every 10-14 days. After four or more cycles, these T cells produced high levels of IL-10, low levels of IL-4 and IFN-gamma, and no IL-2, consistent with the phenotype of T regulatory-1 (Tr1) cells. Bir Tr1 cells proliferated poorly, but their proliferation was dependent on CD28-B7 interactions and was MHC class II-restricted. Transfer of Bir Tr1 cells into SCID mice did not result in colitis, and cotransfer of Bir Tr1 T cells with pathogenic Bir CD4(+) Th1 cells prevented colitis. Bir Tr1 cells inhibited proliferation and IFN-gamma production of a CBA-specific Th1 cell line in vitro. Such inhibition was partly due to IL-10 and TGFbeta1, but cognate interactions with either APCs or Th1 cells were also involved. Normal intestinal lamina propria CD4(+) T cells had Tr1-like activity when stimulated with CBA-pulsed APCs. We conclude that CD4(+) T cells with the properties of Tr1 cells are present in the intestinal lamina propria and hypothesize that these cells maintain intestinal immune homeostasis to the enteric flora.
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PMID:Bacterial-reactive T regulatory cells inhibit pathogenic immune responses to the enteric flora. 1244 13

Both in vivo skin immune responses and the skin's reaction to sun exposure integrate a complex interplay of biologic responses. The complexity and multiplicity of events that occur in the skin during an immune response make it a sensitive indication of both UVB and UVA-induced changes in the skin by sun damage, as well as those changes that are prevented by various sunscreens. Sunscreens are the most effective and widely available intervention for sun damage, other than sun avoidance or clothing. However, sunscreens vary widely in their relative ability to screen various UV waveband components, and their testing has been variably applied to outcomes other than for erythema to determine the sunburn protection factor (SPF), a measure primarily of UVB filtration only. Determination of an immune protection factor (IPF) has been proposed as an alternative or adjunctive measure to SPF, and recent studies show IPF can indeed detect added in vivo functionality of sunscreens, such as high levels of UVA protection, that SPF cannot. Clarification of the definition of IPF, however, is required. Excellent data are available on quantification of the IPF for restoring the afferent or induction arm of contact sensitivity, but other immune parameters have also been measured. Proposed here is nomenclature for whether the IPF is measured using contact sensitivity induction (IPF-CS-I), contact sensitivity elicitation (IPF-CS-E), delayed-type hypersensitivity elicitation (IPF-DTH-E), antigen-presenting cell function (IPF-APC-FXN) or numbers (IPF-APC-#), and cytokine modification such as IL-10 (i.e. IPF-cyto-IL-10). Similar nomenclatures could be used for other measures of skin function protection (i.e. DNA damage, p53 induction, oxidation products, etc.). A review of in vivo human studies, in which sunscreens are used to intervene in a UV-induced modulation of immune response, cells or cytokines, highlights the technical variables and statistical approaches which must also be standardized in the context of an IPF for regulatory or product claim purposes. Development of such IPF standards would allow the integration of both UVB and nonUVB (UVA, blue and possible IR) solar waveband effect-reversals, could be applied to integrate effects of other ingredients with protective function (i.e. antioxidants, retinoids, or other novel products), and would spur development of more advanced and complete protection products.
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PMID:Protection against UV-induced suppression of contact hypersensitivity responses by sunscreens in humans. 1244 55

Adenovirus vectors are increasingly being used for genetic vaccination and may prove highly suitable for intervention in different pathological conditions due to their capacity to generate high level, transient gene expression. In this study, we report the use of a recombinant adenovirus vector to induce regulatory responses for the prevention of autoimmune diseases through transient expression of a TCR beta-chain. Immunization of B10.PL mice with a recombinant adenovirus expressing the TCR Vbeta8.2 chain (Ad5E1 mVbeta8.2), resulted in induction of regulatory type 1 CD4 T cells, directed against the framework region 3 determinant within the B5 peptide (aa 76-101) of the Vbeta8.2 chain. This determinant is readily processed and displayed in an I-A(u) context, on ambient APC. Transient genetic delivery of the TCR Vbeta8.2 chain protected mice from Ag-induced experimental autoimmune encephalomyelitis. However, when the Ad5E1 mVbeta8.2 vector was coadministered with either an IL-4- or IL-10-expressing vector, regulation was disrupted and disease was exacerbated. These results highlight the importance of the Th1-like cytokine requirement necessary for the generation and activity of effective regulatory T cells in this model of experimental autoimmune encephalomyelitis.
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PMID:Protection against experimental autoimmune encephalomyelitis generated by a recombinant adenovirus vector expressing the V beta 8.2 TCR is disrupted by coadministration with vectors expressing either IL-4 or -10. 1251 39

Programmed death-1 ligand (PD-L)1 and PD-L2 are ligands for programmed death-1 (PD-1), a member of the CD28/CTLA4 family expressed on activated lymphoid cells. PD-1 contains an immunoreceptor tyrosine-based inhibitory motif and mice deficient in PD-1 develop autoimmune disorders suggesting a defect in peripheral tolerance. Human PD-L1 and PD-L2 are expressed on immature dendritic cells (iDC) and mature dendritic cells (mDC), IFN-gamma-treated monocytes, and follicular dendritic cells. Using mAbs, we show that blockade of PD-L2 on dendritic cells results in enhanced T cell proliferation and cytokine production, including that of IFN-gamma and IL-10, while blockade of PD-L1 results in similar, more modest, effects. Blockade of both PD-L1 and PD-L2 showed an additive effect. Both whole mAb and Fab enhanced T cell activation, showing that PD-L1 and PD-L2 function to inhibit T cell activation. Enhancement of T cell activation was most pronounced with weak APC, such as iDCs and IL-10-pretreated mDCs, and less pronounced with strong APC such as mDCs. These data are consistent with the hypothesis that iDC have a balance of stimulatory vs inhibitory molecules that favors inhibition, and indicate that PD-L1 and PD-L2 contribute to the poor stimulatory capacity of iDC. PD-L1 expression differs from PD-L2 in that PD-L1 is expressed on activated T cells, placental trophoblasts, myocardial endothelium, and cortical thymic epithelial cells. In contrast, PD-L2 is expressed on placental endothelium and medullary thymic epithelial cells. PD-L1 is also highly expressed on most carcinomas but minimally expressed on adjacent normal tissue suggesting a role in attenuating antitumor immune responses.
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PMID:Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. 1253 84

APC infection and dysfunction may contribute to the immunopathogenesis of HIV disease. In this study, we examined immunologic function of highly enriched populations of HIV-infected monocyte-derived dendritic cells (DC). Compared with uninfected DC, HIV-infected DC markedly down-regulated surface expression of CD4. HIV p24(+) DC were then enriched by negative selection of CD4(+)HIV p24(-) DC and assessed for cytokine secretion and immunologic function. Although enriched populations of HIV-infected DC secreted increased IL-12p70 and decreased IL-10, these cells were poor stimulators of allogeneic CD4(+) T cell proliferation and IL-2 production. Interestingly, HIV-infected DC secreted HIV gp120 and the addition of soluble (s) CD4 (a known ligand for HIV gp120) to DC-CD4(+) T cell cocultures restored T cell proliferation in a dose-dependent manner. By contrast, addition of antiretroviral drugs did not affect CD4(+) T cell proliferation. Furthermore, recombinant HIV gp120 inhibited proliferation in uninfected cocultures of allogeneic DC and CD4(+) T cells, an effect that was also reversed by addition of sCD4. In summary, we show that HIV gp120 produced by DC infected by HIV in vitro impairs normal CD4(+) T cell function and that sCD4 completely reverses HIV gp120-mediated immunosuppression. We hypothesize that HIV-infected DC may contribute to impaired CD4(+) T cell-mediated immune responses in vivo and that agents that block this particular immunosuppression may be potential immune adjuvants in HIV-infected individuals.
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PMID:Decreased stimulation of CD4+ T cell proliferation and IL-2 production by highly enriched populations of HIV-infected dendritic cells. 1268 60

Glatiramer acetate (GA; copolymer-1, Copaxone) suppresses the induction of experimental autoimmune encephalomyelitis and reduces the relapse frequency in relapsing-remitting multiple sclerosis. Although it has become clear that GA induces protective degenerate Th2/IL-10 responses, its precise mode of action remains elusive. Because the cytokine profile of Th cells is often regulated by dendritic cells (DC), we studied the modulatory effects of GA on the T cell regulatory function of human DC. This study shows the novel selective inhibitory effect of GA on the production of DC-derived inflammatory mediators without affecting DC maturation or DC immunostimulatory potential. DC exposed to GA have an impaired capacity to secrete the major Th1 polarizing factor IL-12p70 in response to LPS and CD40 ligand triggering. DC exposed to GA induce effector IL-4-secreting Th2 cells and enhanced levels of the anti-inflammatory cytokine IL-10. The anti-inflammatory effect of GA is mediated via DC as GA does not affect the polarization patterns of naive Th cells activated in an APC-free system. Together, these results reveal that APC are essential for the GA-mediated shift in the Th cell profiles and indicate that DC are a prime target for the immunomodulatory effects of GA.
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PMID:Glatiramer acetate (copolymer-1, copaxone) promotes Th2 cell development and increased IL-10 production through modulation of dendritic cells. 1270 24

Following trauma, increased inflammatory monokine activation and depressed APC function can occur simultaneously. These contradictory monocyte (Mphi) dysfunctions could result if postinjury Mphi differentiation preferentially favored inflammatory macrophage (Mac) differentiation over development into the most potent APC, dendritic cells (DC). In this report, Mphi of trauma patients with a depressed MLR induction capacity are, for the first time, shown to be unable to differentiate in vitro to immature CD1a(+) DC under the influence of GM-CSF and IL-4. Trauma patient Mphi that retained MLR-inducing capacity had a nonsignificant reduction in DC differentiation capacity. Only patient Mphi populations with depressed differentiation to immature DC (iDC) demonstrated depressed IL-12 and IL-15 production and a continued reduced MLR induction capacity. Neither increased IL-10 production nor decreased CD11c(+) DC precursor numbers correlated with depressed Mphi-to-DC differentiation. Instead, these patients' APC-dysfunctional Mphi populations had increased expression of inflammatory Mac phenotypes (CD64(+), CD86(low), HLA-DR(low)) and up-regulated secretion of M-CSF. M-CSF combined with IL-6 inhibits Mphi-to-iDC differentiation and promotes Mphi-to-Mac differentiation by down-regulating GM-CSFR expression and increasing DC apoptosis. Both depressed GM-CSFR expression and increased Mphi iDC apoptosis, as well as increased expression of CD126 (IL-6R) and CD115 (M-CSFR), were detected in APC-defective patient Mphi. In vitro addition of anti-M-CSF enhanced the IL-4 plus GM-CSF-induced Mphi-to-DC differentiation of these patients. This suggests that, in trauma patients, enhanced Mphi-to-Mac differentiation with concomitant inhibited iDC development is partially due to increased circulating Mphi sensitivity to and production of M-CSF and contributes to postinjury immunoaberrations.
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PMID:Failure of monocytes of trauma patients to convert to immature dendritic cells is related to preferential macrophage-colony-stimulating factor-driven macrophage differentiation. 1279 69

NK cells not only respond rapidly to infection, shaping subsequent adaptive immunity, but also play a role in regulating autoimmune disease. The ability of NK cells to influence adaptive immunity before Ag exposure was examined in a gender-dependent model of preferential Th1 and Th2 activation. The inability of young adult male SJL mice to activate Th1 cells was reversed via depletion of NK1.1(+) cells, whereas the presence or the absence of NK1.1(+) cells did not alter responses in age-matched females. Consistent with a gender-dependent role in regulating adaptive immunity, significantly more NK1.1(+) cells were present in males compared with females, and this difference was reversed by castration. In contrast to NK1.1(+) cells derived from C57BL/6 mice, no spontaneous cytokine secretion was detected in NK1.1(+) cells derived from either male or female SJL mice, although an increased frequency of IL-10-secreting NK1.1(+) cells was observed in males vs females following in vitro stimulation. Direct evidence that NK1.1(+) cells in males influence CD4(+) T cell activation before Ag exposure was demonstrated via the adoptive transfer of APC from control and NK1.1-depleted males. The absence of a functional NK T cell population in SJL mice suggests that NK cells influence adaptive immunity before Ag exposure via alterations in APC activity.
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PMID:NK cells regulate CD4 responses prior to antigen encounter. 1281 3


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