IL-3 Triggers Chronic Rejection of Cardiac Allografts by Activation of Infiltrating Basophils
IL-3 Triggers Chronic Rejection of Cardiac Allografts by Activation of Infiltrating Basophils
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DOI：
10.4049/jimmunol.1801269
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发表时间：
2019-06-15
影响因子：
4.4
通讯作者：
Mack, Matthias
中科院分区：
文献类型：
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作者：
Balam, Saidou;Schiechl-Brachner, Gabriela;Mack, Matthias
慢性排斥反应是移植医学中的一个主要问题，对治疗有很大的抵抗力，并且知之甚少。我们先前已经证明，嗜碱性粒细胞来源的IL-4有助于纤维化和血管病变的心脏移植模型中的CD 4（+）T细胞耗竭。然而，目前尚不清楚嗜碱性粒细胞是如何在同种异体移植物中被激活的，以及当应用环孢菌素A（CsA）免疫抑制剂时它们是否发挥作用。将BALB/c供体心脏异位移植到完全MHC不匹配的C57 BL/6受体中，通过清除CD 4（+）T细胞或CsA治疗来预防急性排斥反应。我们发现IL-3在慢性排斥的同种异体移植物中显著上调，并且是同种异体移植物中嗜碱性粒细胞的主要激活剂。使用IL-3缺陷小鼠和嗜碱性粒细胞耗竭，我们表明，IL-3有助于移植物纤维化和器官衰竭的嗜碱性粒细胞依赖性的方式。此外，在涉及CsA的慢性排斥反应模型中，IL-3和嗜碱性粒细胞实质上有助于器官重塑，尽管CsA几乎完全抑制IL-4。在这项研究中，嗜碱性粒细胞来源的IL-6对CsA的抑制有抵抗力，这在很大程度上是同种异体移植物纤维化和移植存活率有限的原因。我们的数据表明，IL-3诱导同种异体移植物纤维化和心脏移植的慢性排斥反应，并通过激活浸润的嗜碱性粒细胞发挥其促纤维化作用。阻断IL-3或嗜碱性粒细胞衍生的细胞因子可能为预防或延缓慢性同种异体移植排斥反应的发生提供新的策略。
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.