title: Tolerogenic dendritic cells specific for β2-glycoprotein-I Domain-I, attenuate experimental antiphospholipid syndrome.
abstract: Tolerogenic dendritic cells (tDCs) have the potential to control the outcome of autoimmunity by modulating the immune response. The aim of this study was to uncover the tolerance efficacy attributed to beta-2-glycoprotein-I (β2GPI) tDCs or β2GPI domain-I (D-I) and domain-V (D-V)-tDCs in mice with antiphospholipid syndrome (APS). tDCs were pulsed with β2GPI or D-I or D-V derivatives. Our results revealed that β2GPI related tDCs phenotype includes CD80(high), CD86(high) CD40(high) MHC class II(high). The miRNA profiling encompass miRNA 23b(high), miRNA 142-3p(low) and miRNA 221(low). In addition the β2GPI related tDCs showed reduced secretion of IL-1β, IL-12 and IL-23. D-I tDCs treatment was more efficient than β2GPI tDCs in inducing of tolerance in APS mice, manifested by lowered titers of anti- β2GPI antibodies (Abs) and reduced percentage of fetal loss. Tolerance induction was accompanied by poor T cell response to β2GPI, high numbers of CD4 + CD25 + FOXP3 + T-regulatory cells (Treg), reduced levels of IFNγ, IL-17 and increased expression of IL-10 and TGFβ. Tolerance was successfully transferred by Treg cells from the tolerized mice to β2GPI immunized mice. We conclude that predominantly D-I-tDCs and β2GPI tDCs have the potential to attenuate experimental APS by induction of Treg cells, reduction of anti- β2GPI Abs titers and increased expression of anti-inflammatory cytokines. We suggest that β2-GPI-D-I-tDCs may offer a novel approach for developing therapy for APS patients.
authors: The Zabludowicz Center For Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Sackler Faculty of Medicine Tel-Aviv University, 52621, Israel; Department of Medicine C, Wolfson Medical Center, Sackler Faculty of Medicine Tel-Aviv University, Holon, Israel.
authors: Gisele
authors: G
authors: Zandman-Goddard
authors: Antiphospholipid Standardization Laboratory, Division of Rheumatology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA.
authors: Silvia S
authors: SS
authors: Pierangeli
authors: The Zabludowicz Center For Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Sackler Faculty of Medicine Tel-Aviv University, 52621, Israel.
authors: Smadar
authors: S
authors: Gertel
authors: The Zabludowicz Center For Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Sackler Faculty of Medicine Tel-Aviv University, 52621, Israel. Electronic address: mblank@post.tau.ac.il.
authors: Miri
authors: M
authors: Blank
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000276:immunology; D016736:Antiphospholipid Syndrome / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D007108:Immune Tolerance / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D009930:Organic Chemicals / Q000276:immunology / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology; D053482:beta 2-Glycoprotein I / Q000276:immunology / Q000494:pharmacology
chemical_list: D000943:Antigens, Differentiation; D016207:Cytokines; D009930:Organic Chemicals; C029248:Tolerogen; D053482:beta 2-Glycoprotein I
keywords: Antiphospholipid syndrome; Domain-I; Domain-V; Tolerogenic dendritic cells; β2-glycoprotein-I