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IL-3 triggers chronic rejection of cardiac allografts by activation of infiltrating basophils

 
: Balam, Saidou; Schiechl-Brachner, Gabriela; Buchtler, Simone; Halbritter, Dagmar; Schmidbauer, Kathrin; Talke, Yvonne; Neumayer, Sophia; Salewski, Jan-Niklas; Winter, Frederike; Karasuyama, Hajime; Yamanishi, Yoshinori; Renner, Kerstin; Geissler, Edward K.; Mack, Matthias

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The Journal of immunology 202 (2019), Nr.12, S.3514-3523
ISSN: 0022-1767
ISSN: 1048-3233
ISSN: 1047-7381
ISSN: 1550-6606
Englisch
Zeitschriftenaufsatz
Fraunhofer ITEM ()

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.

: http://publica.fraunhofer.de/dokumente/N-582818.html