title: Intrarenal B Cell Cytokines Promote Transplant Fibrosis and Tubular Atrophy.
abstract: Renal transplantation is the optimum treatment for end-stage renal failure. B cells have been identified in chronic allograft damage (CAD) and associated with the development of tertiary lymphoid tissue within the human renal allograft. We performed renal transplantation in mice to model CAD and identified B cells forming tertiary lymphoid tissue with germinal centers. Intra-allograft B220(+) B cells comprised of IgM(high) CD23(-) B cells, IgM(lo) CD23(+) B cells, and IgM(lo) CD23(-) B cells with elevated expression of CD86. Depletion of B cells with anti-CD20 was associated with an improvement in CAD but only when administered after transplantation and not before. Isolated intra-allograft B cells were cultured and shown to synthesize multiple cytokines, the most abundant of these were GRO-α (CXCL1), RANTES (CCL5), IL-6 and MCP-1 (CCL2). Tubular loss was observed with T cell accumulation within the allograft and development of interstitial fibrosis, whilst type III collagen deposition was observed in areas of F4/80(+) macrophages and PDGFR-β(+) and transgelin(+) fibroblasts, all of which were reduced by B cell depletion. We have shown that intra-allograft B cells are key mediators of CAD. B cells possibly contribute to CAD by intra-allograft secretion of cytokines and chemokines.
authors.affiliation: Medical Research Council/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: G H
authors.initials: GH
authors.lastname: Tse
authors.affiliation: Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: C J C
authors.initials: CJ
authors.lastname: Johnston
authors.affiliation: Medical Research Council/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: D
authors.initials: D
authors.lastname: Kluth
authors.affiliation: Medical Research Council/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: M
authors.initials: M
authors.lastname: Gray
authors.affiliation: Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: D
authors.initials: D
authors.lastname: Gray
authors.affiliation: Medical Research Council/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: J
authors.initials: J
authors.lastname: Hughes
authors.affiliation: Medical Research Council/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: L P
authors.initials: LP
authors.lastname: Marson
mesh_terms: D064591:Allografts; D000818:Animals; D001284:Atrophy; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D016207:Cytokines / Q000633:toxicity*; D005434:Flow Cytometry; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007676:Kidney Failure, Chronic / Q000601:surgery; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D007684:Kidney Tubules / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009395:Nephritis, Interstitial / Q000473:pathology*; D011183:Postoperative Complications
chemical_list: D016207:Cytokines
keywords: Animal models: murine; B cell biology; atrophy; interstitial fibrosis and tubular; kidney (allograft) function/dysfunction; rejection: chronic