RRC ID 55781
Author Balam S, Schiechl-Brachner G, Buchtler S, Halbritter D, Schmidbauer K, Talke Y, Neumayer S, Salewski JN, Winter F, Karasuyama H, Yamanishi Y, Renner K, Geissler EK, Mack M.
Title IL-3 Triggers Chronic Rejection of Cardiac Allografts by Activation of Infiltrating Basophils.
Journal J Immunol
Abstract Chronic rejection is a major problem in transplantation medicine, largely resistant to therapy, and poorly understood. We have shown previously that basophil-derived IL-4 contributes to fibrosis and vasculopathy in a model of heart transplantation with depletion of CD4+ T cells. However, it is unknown how basophils are activated in the allografts and whether they play a role when cyclosporin A (CsA) immunosuppression is applied. BALB/c donor hearts were heterotopically transplanted into fully MHC-mismatched C57BL/6 recipients and acute rejection was prevented by depletion of CD4+ T cells or treatment with CsA. We found that IL-3 is significantly upregulated in chronically rejecting allografts and is the major activator of basophils in allografts. Using IL-3-deficient mice and depletion of basophils, we show that IL-3 contributes to allograft fibrosis and organ failure in a basophil-dependent manner. Also, in the model of chronic rejection involving CsA, IL-3 and basophils substantially contribute to organ remodeling, despite the almost complete suppression of IL-4 by CsA. In this study, basophil-derived IL-6 that is resistant to suppression by CsA, was largely responsible for allograft fibrosis and limited transplant survival. Our data show that IL-3 induces allograft fibrosis and chronic rejection of heart transplants, and exerts its profibrotic effects by activation of infiltrating basophils. Blockade of IL-3 or basophil-derived cytokines may provide new strategies to prevent or delay the development of chronic allograft rejection.
Volume 202(12)
Pages 3514-3523
Published 2019-6-15
DOI 10.4049/jimmunol.1801269
PII jimmunol.1801269
PMID 31068389
MeSH Animals Basophils / immunology* Cell Movement Cells, Cultured Chronic Disease Disease Models, Animal Graft Rejection / immunology* Heart Transplantation* Humans Interleukin-3 / genetics Interleukin-3 / metabolism* Interleukin-6 / genetics Interleukin-6 / metabolism Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Transplantation, Homologous Up-Regulation
IF 4.718
Times Cited 2
Mice RBRC02298