IL-3 Triggers Chronic Rejection of Cardiac Allografts by Activation of Infiltrating Basophils
| Autor: | Kerstin Renner, Yoshinori Yamanishi, Edward K. Geissler, Dagmar Halbritter, Jan-Niklas Salewski, Saidou Balam, Hajime Karasuyama, Yvonne Talke, Kathrin Schmidbauer, Matthias Mack, Sophia Neumayer, Gabriela Schiechl-Brachner, Simone Buchtler, Frederike Winter |
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| Přispěvatelé: | Publica |
| Rok vydání: | 2019 |
| Předmět: |
Graft Rejection
medicine.medical_treatment Immunology chemical and pharmacologic phenomena Mice 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Cell Movement Fibrosis Cyclosporin a parasitic diseases medicine Animals Humans Transplantation Homologous Immunology and Allergy Cells Cultured Mice Knockout Heart transplantation Mice Inbred BALB C Interleukin-6 business.industry Activator (genetics) hemic and immune systems Immunosuppression medicine.disease Basophils Up-Regulation Blockade Mice Inbred C57BL Transplantation Disease Models Animal surgical procedures operative Chronic Disease Heart Transplantation Interleukin-3 business 030215 immunology |
| Zdroj: | The Journal of Immunology. 202:3514-3523 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1801269 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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