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

心脏移植对许多患者来说是治疗终末性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，比如钙调神经磷酸酶抑制剂。然而，发生在移植后几个月或几年内的慢性排斥反应对治疗相当抗拒。这些疾病的特点是血管病变、间质纤维化和心肌功能障碍。移植纤维化的发展机制在很大程度上是未知的。在以前的研究中，我们可以证明嗜碱性粒细胞渗透到移植物中，并对移植心脏的纤维化重塑起重要作用。嗜碱性粒细胞的耗竭和IL-4缺乏的受体或IL-4R缺乏的移植物的使用表明，嗜碱性粒细胞通过释放IL-4而导致纤维化和血管病变。然而，目前尚不清楚嗜碱性粒细胞是如何被招募到移植物中的，它们是如何被激活的(上游通路)，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(下游通路)。我们想要回答这两个问题，并分析嗜碱性粒细胞在一种新建立的基于停用环孢素A的移植纤维化模型中的作用。此外，我们想分析患者中是否存在慢性排斥移植中的嗜碱性粒细胞，以及在急性排斥反应期间是否也招募了嗜碱性粒细胞。

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.