Influence of ST2 and IL-33 on cardiac allograft vasculopathy and outcome

描述（由申请人提供）：慢性同种异体移植物血管病变（CAV），或通过耳廓扩张引起的移植物动脉腔阻塞，是晚期心脏移植衰竭和患者发病率/死亡率的主要原因。CAV的病因是多因素的，包括IFN-7分泌T辅助细胞（Th） 1型细胞（Th1）促进和平滑肌细胞（SMC）向动脉腔的迁移/增殖。使用雷帕霉素（RAPA）作为免疫抑制剂与减少CAV有关，部分是通过直接抑制SMC，但RAPA通过改变宿主/移植物免疫环境来限制CAV的机制尚不清楚。我们观察到树突状细胞（DC）长期暴露于RAPA，通过上调IL-1R家族成员ST2 （ST2L）的跨膜形式，赋予DC对促炎刺激的抗性。除了负调控TLR和CD40信号外，ST2L还是IL-33的受体，IL-33是一种促进2型（Th2）反应的细胞因子。IL-33可以由多种细胞产生，包括内皮细胞（EC）和SMC，并可能具有心脏保护特性。当IL-33功能被阻断或ST2L缺失时，动脉粥样硬化和心肌肥厚模型的病理都会加重。然而，IL-33是否通过直接影响DC的极化能力，或者是否能够抑制CAV尚不清楚。我们的中心假设是IL-33促进DC。特别是RAPA-DC表达增加ST2L， Th2细胞极化能力，并通过诱导T细胞群的Th2偏斜和对同种异体移植物的直接心脏保护作用来阻止CAV。在AIM I中，我们假设IL-33诱导基因表达和信号通路，介导DC能力，促进体外和体内Th2反应。在AIM II中，我们假设术后IL-33和RAPA单独使用或与治疗性DC联合使用，可导致无排斥的同种异体心脏移植存活，并通过调节宿主免疫系统对Th2和调节性T细胞反应来预防CAV。在AIM III中，我们假设IL-33通过ST2L作用于免疫细胞和心脏移植物细胞，在急性和慢性排斥反应中保护心脏移植物。

DESCRIPTION (provided by applicant): Chronic allograft vasculopathy (CAV), or graft arterial lumen occlusion through intinna expansion, is a major cause of late heart transplant failure and patient morbidity/mortality. CAV etiology is multi-factorial, including promotion by IFN-7 secreting T helper (Th) Type-1 cells (Th1) and the migration/proliferation of smooth muscle cells (SMC) into arterial lumen. The use of rapamycin (RAPA) as an immunosuppressant is associated with reduced CAV, in part through direct inhibition of SMC, but the mechanisms by which RAPA alters the host/graft immunological environment to limit CAV are unclear. We have made the novel observation that prolonged dendritic cell (DC) exposure to RAPA confers DC resistance to pro-inflammatory stimuli by upregulating the transmembrane form of the IL-1R family member ST2 (ST2L). In addition to negatively regulating TLR and CD40 signaling, ST2L is the receptor for IL-33, a cytokine that promotes The Type-2 (Th2) responses. IL-33 can be produced by a variety of cells, including endothelial cells (EC) and SMC, and may have cardioprotective properties. When the function of IL-33 is blocked, or ST2L is absent, pathology is exacerbated in both atherosclerosis and cardiac hypertrophy models. However, if IL-33 exhorts a The polarization capacity through direct influence on DC, or can inhibit CAV is not known. Our central hypothesis is that IL-33 promotes DC. especially RAPA-DC expressing increased ST2L, Th2 cell polarization capacity and will prevent CAV bv both inducing Th2 skewing of T cell populations and direct cardioprotective effects on the allograft. In AIM I, we hypothesize that IL-33 induces gene expression arid signaling pathways that mediate a DC capacity to promote Th2 response in vitro and in vivo. In AIM II, we hypothesize that post-operative IL-33 and RAPA alone or, combined with therapeutic DC administration, leads to rejection-free heart allograft survival and prevents CAV by modulating the host immune system towards Th2 and regulatory T cell responses. In AIM III we hypothesize that IL-33 acts via ST2L on both immune cells and cardiac allograft cells to protect cardiac allografts during acute and chronic rejection.