Recruitment, activation and effector pathways of basophils in chronic allograft remodeling

心脏移植是许多患者晚期心力衰竭的最佳治疗方法。急性移植排斥反应可以有效地预防免疫抑制药物，如钙调神经磷酸酶抑制剂。然而，在移植后数月或数年内发生的慢性排斥反应对治疗具有相当大的抗性。其特征在于血管病变、间质纤维化和心肌功能障碍。移植物纤维化发展的机制在很大程度上是未知的。在以前的研究中，我们发现嗜碱性粒细胞浸润同种异体移植物，并对移植心脏的纤维化重塑起重要作用。嗜碱性粒细胞的消耗和使用IL-4缺陷受体或IL-4 R缺陷移植物揭示了嗜碱性粒细胞通过释放IL-4诱导纤维化和血管病变。然而，目前尚不清楚嗜碱性粒细胞如何被招募到移植物中，它们如何被激活（上游途径）以及嗜碱性粒细胞和IL-4如何诱导同种异体移植物的纤维化重塑（下游途径）。我们想回答这两个问题，并分析嗜碱性粒细胞在一个新建立的移植纤维化模型中的作用，该模型是基于环孢素A的停药。此外，我们还想分析患者中是否有嗜碱性粒细胞存在于慢性排斥的移植物中，以及它们是否也在急性排斥中被招募。

Heart transplantation is for many patients the best treatment for terminal heart failure. Acute transplant rejections can efficiently be prevented by immunosuppressive drugs, like calcineurin inhibitors. Chronic rejections however, occurring within months or years after transplantation, are rather resistant to therapy. These are characterized by vasculopathy, interstitial fibrosis and myocardial dysfunction. The mechanisms how transplant fibrosis develops are largely unknown. In previous studies we could show that basophils infiltrate the allografts and importantly contribute to fibrotic remodeling of transplanted hearts. Depletion of basophils and the use of IL-4 deficient recipients or IL-4R-deficient grafts revealed that basophils induce fibrosis and vasculopathy by the release of IL-4. However, it is still unclear how basophils are recruited into the transplants, how they are activated (upstream pathways) and how basophils and IL-4 induce fibrotic remodeling of allografts (downstream pathways). We would like to answer both questions and to also analyze the role of basophils in a newly established model of transplant fibrosis that is based on the withdrawal of cyclosporin A. In addition, we would like to analyze in patients whether basophils are present in chronically rejected transplants and whether they are also recruited during acute rejections.