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

心脏移植是许多患者治疗晚期心力衰竭的最佳方法。急性移植排斥反应可以通过免疫抑制药物有效地预防，如钙调磷酸酶抑制剂。然而，在移植后几个月或几年内发生的慢性排斥反应对治疗相当有抵抗力。其特点是血管病变、间质纤维化和心肌功能障碍。移植纤维化发生的机制在很大程度上是未知的。在先前的研究中，我们可以发现嗜碱性细胞浸润同种异体移植物，并重要地促进移植心脏的纤维化重塑。嗜碱性粒细胞的消耗和使用IL-4缺陷受体或il - 4r缺陷移植物表明，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）。我们想要回答这两个问题，并分析嗜碱性粒细胞在基于环孢素a停药的新建立的移植纤维化模型中的作用。此外，我们想要分析患者中嗜碱性粒细胞是否存在于慢性排斥移植中，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.