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

慢性移植物血管病(CAV)，或通过肠腔扩张的移植物动脉腔闭塞，是主要的 晚期心脏移植失败的原因和患者发病率/死亡率。CAV病因学是多因素的，包括 干扰素-7促进Th1细胞的迁移/增殖 肌细胞(SMC)进入动脉腔。使用雷帕霉素(RapA)作为免疫抑制剂是 与CAV减少有关，部分是通过直接抑制SMC，但RAPA 改变宿主/移植物的免疫环境以限制CAV尚不清楚。我们已经把这部小说写成了 观察到，树突状细胞(DC)长期暴露于RAPA可使DC对促炎反应产生抵抗力 通过上调IL-1R家族成员ST2(ST2L)的跨膜形式来刺激。除了……之外 ST2L负向调节TLR和CD40信号，是IL-33的受体，IL-33是一种促进Th细胞的细胞因子 2型(Th2)反应。IL-33可由多种细胞产生，包括内皮细胞(EC)和 SMC，并可能具有心脏保护特性。当IL-33的功能被阻断或ST2L缺失时， 在动脉粥样硬化和心肌肥厚模型中，病理都会加剧。然而，如果IL-33劝告 目前尚不清楚Th极化能力是否能通过直接影响直流，抑或抑制CAV。我们的中央 假说是IL-33促进DC。尤其是表达RAPA-DC的ST2L、Th2细胞数量增加 极化能力和将防止CAV BV既诱导T细胞群Th2偏斜又直接 同种异体心脏移植的心脏保护作用。在AIM I中，我们假设IL-33诱导基因表达和 在体外和体内介导DC能力以促进Th2反应的信号通路。在AIM II中，我们 假设术后IL-33和RAPA单独或与治疗性DC给药相结合， 通过调节宿主免疫系统导致无排斥反应的同种异体心脏移植存活并预防CAV Th2和调节性T细胞反应。在AIM III中，我们假设IL-33通过ST2L在两者上起作用 免疫细胞和同种异体心脏移植细胞在急性和慢性排斥反应期间保护同种异体心脏移植。

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 Th 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 Th 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.