title: Basophils Trigger Fibroblast Activation in Cardiac Allograft Fibrosis Development.
abstract: Fibrosis is a major component of chronic cardiac allograft rejection. Although several cell types are able to produce collagen, resident (donor-derived) fibroblasts are mainly responsible for excessive production of extracellular matrix proteins. It is currently unclear which cells regulate production of connective tissue elements in allograft fibrosis and how basophils, as potential producers of profibrotic cytokines, are involved this process. We studied this question in a fully MHC-mismatched model of heart transplantation with transient depletion of CD4(+) T cells to largely prevent acute rejection. The model is characterized by myocardial infiltration of leukocytes and development of interstitial fibrosis and allograft vasculopathy. Using depletion of basophils, IL-4-deficient recipients and IL-4 receptor-deficient grafts, we showed that basophils and IL-4 play crucial roles in activation of fibroblasts and development of fibrotic organ remodeling. In the absence of CD4(+) T cells, basophils are the predominant source of IL-4 in the graft and contribute to expansion of myofibroblasts, interstitial deposition of collagen and development of allograft vasculopathy. Our results indicated that basophils trigger the production of various connective tissue elements by myofibroblasts. Basophil-derived IL-4 may be an attractive target for treatment of chronic allograft rejection.
authors.affiliation: Department of Internal Medicine II, Nephrology, University Hospital Regensburg, Regensburg, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Schiechl
authors.affiliation: Department of Internal Medicine II, Nephrology, University Hospital Regensburg, Regensburg, Germany.
authors.forename: F J
authors.initials: FJ
authors.lastname: Hermann
authors.affiliation: Department of Internal Medicine II, Nephrology, University Hospital Regensburg, Regensburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Rodriguez Gomez
authors.affiliation: Department of Internal Medicine II, Nephrology, University Hospital Regensburg, Regensburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kutzi
authors.affiliation: Department of Internal Medicine II, Nephrology, University Hospital Regensburg, Regensburg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Schmidbauer
authors.affiliation: Department of Internal Medicine II, Nephrology, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Y
authors.initials: Y
authors.lastname: Talke
authors.affiliation: Department of Internal Medicine II, Nephrology, University Hospital Regensburg, Regensburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Neumayer
authors.affiliation: Department of Internal Medicine II, Nephrology, University Hospital Regensburg, Regensburg, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Goebel
authors.affiliation: Department of Internal Medicine II, Nephrology, University Hospital Regensburg, Regensburg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Renner
authors.affiliation: Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Brühl
authors.affiliation: Department of Immune Regulation, Tokyo Medical and Dental University Graduate School, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Karasuyama
authors.affiliation: Department of Immune Regulation, Tokyo Medical and Dental University Graduate School, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Obata-Ninomiya
authors.affiliation: Department of Pathology, University Hospital Regensburg, Regensburg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Utpatel
authors.affiliation: Department of Pathology, University Hospital Regensburg, Regensburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Evert
authors.affiliation: Department of Cardiothoracic Surgery, University Hospital Regensburg, Regensburg, Germany.
authors.forename: S W
authors.initials: SW
authors.lastname: Hirt
authors.affiliation: Department of Surgery, University Hospital Regensburg, Regensburg, Germany.
authors.forename: E K
authors.initials: EK
authors.lastname: Geissler
authors.affiliation: Department of Surgery, University Hospital Regensburg, Regensburg, Germany.|RCI Regensburg Center for Interventional Immunology, University of Regensburg, Regensburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Fichtner-Feigl
authors.affiliation: Department of Internal Medicine II, Nephrology, University Hospital Regensburg, Regensburg, Germany.|RCI Regensburg Center for Interventional Immunology, University of Regensburg, Regensburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Mack
mesh_terms: D064591:Allografts; D000818:Animals; D001491:Basophils / Q000276:immunology*; D005260:Female; D005355:Fibrosis / Q000209:etiology / Q000473:pathology; D006084:Graft Rejection / Q000209:etiology* / Q000473:pathology; D006085:Graft Survival; D006331:Heart Diseases / Q000209:etiology* / Q000473:pathology; D016027:Heart Transplantation / Q000009:adverse effects*; D015847:Interleukin-4 / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D015847:Interleukin-4
keywords: basic (laboratory) research/science; fibrosis; heart (allograft) function/dysfunction; heart transplantation/cardiology; immune regulation; immunobiology; immunosuppression/immune modulation; rejection: chronic; signaling/signaling pathways