A regulatory dendritic cell signature correlates with the clinical efficacy of allergen-specific sublingual immunotherapy

• Published in: Journal of allergy and clinical immunology Vol. 129; no. 4; pp. 1020 - 1030
• Main Authors: Zimmer, Aline, PhD, Bouley, Julien, PhD, Le Mignon, Maxime, PhD, Pliquet, Elodie, MSc, Horiot, Stéphane, Turfkruyer, Mathilde, MSc, Baron-Bodo, Véronique, PhD, Horak, Friedrich, MD, Nony, Emmanuel, MSc, Louise, Anne, PhD, Moussu, Hélène, MSc, Mascarell, Laurent, PhD, Moingeon, Philippe, PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.04.2012; Elsevier; Elsevier Limited
• Subjects: Administration, Sublingual; Allergens; Allergy and Immunology; Biological and medical sciences; Biomarker; biomarkers; Biomarkers - metabolism; Clinical trials; Complement component C1q; Cytokines; dendritic cell; Dendritic cells; Dendritic Cells - classification; Dendritic Cells - immunology; Dendritic Cells - metabolism; Desensitization, Immunologic - methods; efficacy; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gel electrophoresis; Genotype & phenotype; Grasses; Humans; Hypersensitivity; Hypersensitivity - immunology; Hypersensitivity - metabolism; Hypersensitivity - therapy; Immune system; Immune Tolerance - immunology; Immunological tolerance; Immunopathology; Immunotherapy; Interferon regulatory factor 4; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - metabolism; Lymphocytes; Lymphocytes T; Mass spectroscopy; Medical sciences; Monocytes; Oral administration; Polarization; Pollen; Polymerase chain reaction; Proteome - metabolism; proteomics; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Software; Studies; sublingual immunotherapy; Tablets; tolerance; Treatment Outcome; PR; Differential gel electrophoresis; Factor 13A; Annexin-1; ILT; DC2; moDC; DC1; IDO; PNR; STAB1; Stabilin-1; Regulatory T; Tripeptidyl peptidase 1; DCs driving the differentiation of regulatory T cells; qPCR; tolerance; TNF receptor-associated factor 1; Cytometric beads array; ANXA1; MS; ROC; 1,25 dihydroxyvitamin D3; Rapamycin; TRAF1; AIT; Glucocorticoid-induced leucine zipper; Quantitative PCR; AR; Peptidoglycan; IRF4; PGN; Retinaldehyde dehydrogenase; FSCN1; Active nonresponder; Placebo nonresponder; Monocyte-derived dendritic cell; Mass spectrometry; dendritic cell; Average Rhinoconjunctivitis Total Symptom Score; FKBP5; Biomarker; C1Q; CBA; ANR; RAPA; FK506 binding protein 5; NMES1; DCs driving the differentiation of T H1 cells; Fascin 1; GILZ; CATC; FDR; Immunoglobulin-like transcript; Normal mucosa of esophagus-specific gene 1 protein; Antigen-presenting cell; ARTSS; Cathepsin C; Myxovirus resistance 1; VitD3; ASP; Dexamethasone; DiGE; RALDH; proteomics; CD71; MX1; Treg; Complement component 1; Placebo responder; DCreg; Indoleamine 2,3-dehydrogenase; efficacy; APC; Aspergillus oryzae; DCs driving the differentiation of T H2 cells; Receiver operating characteristic; Interferon regulatory factor 4; DEX; Active group, responder patients; False discovery rate; Transferrin receptor protein 1; F13A; DC17; TPP1; sublingual immunotherapy; Allergen immunotherapy; DCs driving the differentiation of T H17 cells; DC; Dendritic cell; Immunopathology; Desensitization; Treatment efficiency; Sublingual administration; Biological marker; Tolerance; Immunology; Treatment; Antigen presenting cell; Immunotherapy; Proteomics; Regulatory cell
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2012.02.014

Background Given their pivotal role in the polarization of T-cell responses, molecular changes at the level of dendritic cells (DCs) could represent an early signature indicative of the subsequent orientation of adaptive immune responses during immunotherapy. Objective We sought to investigate whether markers of effector and regulatory DCs are affected during allergen immunotherapy in relationship with clinical benefit. Methods Differential gel electrophoresis and label-free mass spectrometry approaches were used to compare whole proteomes from human monocyte-derived DCs differentiated toward either regulatory or effector functions. The expression of those markers was assessed by using quantitative PCR in PBMCs from 79 patients with grass pollen allergy enrolled in a double-blind, placebo-controlled clinical study evaluating the efficacy of sublingual tablets in an allergen exposure chamber over a 4-month period. Results We identified several markers associated with DC1 and/or DC17 effector DCs, including CD71, FSCN1, IRF4, NMES1, MX1, TRAF1. A substantial phenotypic heterogeneity was observed among various types of tolerogenic DCs, with ANXA1, Complement component 1 (C1Q), CATC, GILZ, F13A, FKBP5, Stabilin-1 (STAB1), and TPP1 molecules established as shared or restricted regulatory DC markers. The expression of 2 of those DCs markers, C1Q and STAB1, was increased in PBMCs from clinical responders in contrast to that seen in nonresponders or placebo-treated patients. Conclusion C1Q and STAB1 represent candidate biomarkers of early efficacy of allergen immunotherapy as the hallmark of a regulatory innate immune response predictive of clinical tolerance.