Inhibition of human allergic T-cell responses by IL-10–treated dendritic cells: Differences from hydrocortisone-treated dendritic cells

216

161

Although helminths induce a polarized Th2 response they have been shown, in clinical studies, to confer protection against allergies. To elucidate the basis for this paradox, we have examined the influence of an enteric helminth infection on a model of food allergy. Upon Ag challenge, mice fed peanut (PN) extract plus the mucosal adjuvant cholera toxin (CT) produced PN-specific IgE that correlated with systemic anaphylactic symptoms and elevated plasma histamine. PN-specific IgE was not induced in helminth-infected mice fed PN without CT. Moreover, when PN plus CT was fed to helminth-infected mice, both PN-specific IgE and anaphylactic symptoms were greatly diminished. The down-regulation of PN-specific IgE was associated with a marked reduction in the secretion of IL-13 by PN-specific T cells. When helminth-infected PN plus CT-sensitized mice were treated with neutralizing Abs to IL-10, the PN-specific IgE response and anaphylactic symptoms were similar to, or greater than, those seen in mice that receive PN and CT alone. Taken together, these results suggest that helminth-dependent protection against allergic disease involves immunoregulatory mechanisms that block production of allergen-specific IgE.

Section: Discussionmentioning

confidence: 99%

An Enteric Helminth Infection Protects Against an Allergic Response to Dietary Antigen

Bashir

Andersen

Fuss

et al. 2002

216

161

“…iDCs and IL-10-pretreated mDCs express lower levels of B7-1, B7-2, and class II MHC molecules than mDC. This lower level of stimulatory molecules has been proposed to account for their poor capacity to stimulate T cells (2,6,29); however, expression of comparably low amounts of MHC and B7 on transfectants is sufficient for efficient T cell activation (Ref. 31 and G. Freeman, unpublished data).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, because IL-10 reduces the capacity of mDC to stimulate T cells (6,28,29), we reasoned that the PD-1:PD-L pathway may play a role in mediating the effects of IL-10 on mDC. Therefore, IL-10-pretreated mDC were generated by adding IL-10 to the mixture of inflammatory cytokines used to effect DC maturation.…”

Section: Cell Surface Expression Of Pd-l1 and Pd-l2 On Monocytes Dcsmentioning

confidence: 99%

Blockade of Programmed Death-1 Ligands on Dendritic Cells Enhances T Cell Activation and Cytokine Production

Brown

Dorfman

et al. 2003

865

632

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-γ-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-γ 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.

“…DIG-labeled DNA was detected by enzyme-linked immunoassay using an Ab conjugate (anti-DIG alkaline phosphatase conjugate). The hybrids were detected by the chemiluminescent reagent disodium 3-{4-methoxyspiro(1,2-dioxetane-3,2Ј-(5Ј-chloro)tricyclo[3,1,1 3,7 ]decan}-4-yl-)phenylphosphate on an x-ray film.…”

Section: Southern Blotmentioning

confidence: 99%

“…Therefore, binding and cross-linking of Fc⑀RI by specific IgE-allergen complexes on circulating monocytes may suggest special functions and/or veto fundamental effector mechanisms of allergy responses. Histologically, AEDS is an eczematous reaction where T lymphocytes mediate profound pathophysiological outcome (7). The aggregation of Fc⑀RI on APCs may exert immunomodulatory signals on T cells, thus regulating T cell responsiveness.…”

mentioning

confidence: 99%

Kinetics of Gene Induction After FcεRI Ligation of Atopic Monocytes Identified by Suppression Subtractive Hybridization

Bubnoff

Matz

Cazenave

et al. 2002

The high-affinity receptor for IgE, FcεRI, on APCs plays an important role in the initiation and chronicity of inflammatory atopic diseases. To understand the molecular regulation of FcεRI-mediated processes, differentially expressed genes are of great interest to be identified. Suppression subtractive cDNA hybridization has been used to identify genes induced after FcεRI stimulation on atopic monocytes. Overexpression of the identified genes was determined by semiquantitative RT-PCR analysis of transcripts from the tester (stimulated) and driver (unstimulated) monocytes. Results were confirmed and kinetics of the transcripts established using blood cells from additional atopics at 4 and 24 h of FcεRI induction. The following sequences were identified: monocyte chemoattractant protein 1, macrophage-inflammatory protein 1β, IL-6, βA subunit of inhibin/activin, IFN-stimulated gene of 54 kDa, IL-1R antagonist, and kynurenine 3-monooxygenase. Chemokines are highly expressed during the early and late phase after FcεRI cross-linking, whereas proinflammatory and differentiation stimuli rapidly decline after an initial overexpression. Kynurenine 3-monooxygenase, an enzyme involved in the degradation of the amino acid tryptophan, is significantly up-regulated during the late phase after 24 h of FcεRI induction. These results demonstrate that the analysis of the profile of gene induction following activation of FcεRI on atopic monocytes may reveal how these cells might participate in the regulation of atopic disorders.