title: Neutralizing IL-6 reduces human arterial allograft rejection by allowing emergence of CD161+ CD4+ regulatory T cells.
abstract: Perioperative injuries to an allograft exacerbate graft rejection, which in humans is primarily mediated by effector memory T cells. IL-6 transcripts in human coronary artery segments rapidly increase posttransplantation into immunodeficient mouse hosts compared with those of pretransplant specimens and fall dramatically by 30 d. Adoptive transfer of human PBMCs allogeneic to the artery 2 d postoperatively results in T cell infiltrates and intimal expansion 4 wk later. Ab neutralization of human IL-6 reduces the magnitude of intimal expansion and total T cell infiltration but increases the relative expression of CD161 while decreasing other Th17 markers. Coculture of MHC class II-expressing human endothelial cells (ECs) with allogeneic CD4(+) memory T cells results in T cell activation and EC secretion of IL-6. Neutralizing IL-6 in primary allogeneic T cell-EC cocultures results in enhanced T cell proliferation of CD161(+) CD4(+) T cells, reduces total T cell proliferation upon restimulation in secondary cultures (an effect dependent on CD161(+) T cells), increases expression of FOXP3 in CD161(+) T cells, and generates T cells that suppress proliferation of freshly isolated T cells. These data suggest that IL-6 released from injured allograft vessels enhances allogeneic T cell infiltration and intimal expansion in a model of human allograft rejection by inhibiting an increase in CD161(+) regulatory T cells.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Birgit
authors.initials: B
authors.lastname: Fogal
authors.forename: Tai
authors.initials: T
authors.lastname: Yi
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.forename: Deepak A
authors.initials: DA
authors.lastname: Rao
authors.forename: Amir
authors.initials: A
authors.lastname: Lebastchi
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kulkarni
authors.forename: George
authors.initials: G
authors.lastname: Tellides
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Pober
mesh_terms: D000328:Adult; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D018920:Coculture Techniques; D003331:Coronary Vessels / Q000293:injuries / Q000473:pathology / Q000637:transplantation*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D032389:Myocytes, Smooth Muscle / Q000276:immunology / Q000473:pathology; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000096:biosynthesis*; D009500:Neutralization Tests / Q000379:methods; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D000093242:Interleukin-6 Inhibitors
chemical_list: D015850:Interleukin-6; D055651:NK Cell Lectin-Like Receptor Subfamily B; D000093242:Interleukin-6 Inhibitors; C508600:IL6 protein, human
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