title: HLA Class II Antibody Activation of Endothelial Cells Promotes Th17 and Disrupts Regulatory T Lymphocyte Expansion.
abstract: Kidney transplantation is the most successful treatment option for patients with end-stage renal disease, and chronic antibody-mediated rejection is the principal cause of allograft loss. Predictive factors for chronic rejection include high levels of HLA alloantibodies (particularly HLA class II) and activation of graft endothelial cells (ECs). The mechanistic basis for this association is unresolved. We used an experimental model of HLA-DR antibody stimulation of microvascular ECs to examine the mechanisms underlying the association between HLA class II antibodies, EC activation and allograft damage. Activation of ECs with the F(Ab')2 fragment of HLA-DR antibody led to phosphorylation of Akt, ERK and MEK and increased IL-6 production by ECs cocultured with allogeneic peripheral blood mononuclear cells (PBMCs) in an Akt-dependent manner. We previously showed that HLA-DR-expressing ECs induce polarization of Th17 and FoxP3(bright) regulatory T cell (Treg) subsets. Preactivation of ECs with anti-HLA-DR antibody redirected EC allogenicity toward a proinflammatory response by decreasing amplification of functional Treg and by further increasing IL-6-dependent Th17 expansion. Alloimmunized patient serum containing relevant HLA-DR alloantibodies selectively bound and increased EC secretion of IL-6 in cocultures with PBMCs. These data contribute to understanding of potential mechanisms of antibody-mediated endothelial damage independent of complement activation and FcR-expressing effector cells.
authors.affiliation: Inserm, UMRs 1160, Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Lion
authors.affiliation: Inserm, UMRs 1160, Paris, France.|Service de Néphrologie et Transplantation, Hôpital Saint-Louis, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Taflin
authors.affiliation: Inserm, UMRs 1160, Paris, France.
authors.forename: A R
authors.initials: AR
authors.lastname: Cross
authors.affiliation: Inserm, UMRs 1160, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Robledo-Sarmiento
authors.affiliation: Inserm, UMRs 1160, Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Mariotto
authors.affiliation: Inserm, UMRs 1160, Paris, France.|Laboratoire de Histocompatibilité, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Savenay
authors.affiliation: Inserm, UMRs 1160, Paris, France.|Laboratoire de Histocompatibilité, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Carmagnat
authors.affiliation: Inserm, UMRs 1160, Paris, France.|Laboratoire de Histocompatibilité, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Suberbielle
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Paris, France.|LabEx Transplantex, AP-HP, Hôpital Saint-Louis, Paris, France.
authors.forename: D
authors.initials: D
authors.lastname: Charron
authors.affiliation: Inserm, UMRs 1160, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Haziot
authors.affiliation: Inserm, UMRs 1160, Paris, France.|Service de Néphrologie et Transplantation, Hôpital Saint-Louis, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Paris, France.|LabEx Transplantex, AP-HP, Hôpital Saint-Louis, Paris, France.
authors.forename: D
authors.initials: D
authors.lastname: Glotz
authors.affiliation: Inserm, UMRs 1160, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Paris, France.|LabEx Transplantex, AP-HP, Hôpital Saint-Louis, Paris, France.
authors.forename: N
authors.initials: N
authors.lastname: Mooney
mesh_terms: D002478:Cells, Cultured; D018920:Coculture Techniques; D004730:Endothelium, Vascular / Q000276:immunology*; D006684:HLA-DR Antigens / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007518:Isoantibodies / Q000276:immunology*; D016030:Kidney Transplantation; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D006684:HLA-DR Antigens; D015850:Interleukin-6; D007518:Isoantibodies; D007371:Interferon-gamma