IFN-gamma, smooth muscle cells and graft arteriosclerosis

慢性排斥反应是心脏移植的主要限制因素，其特点是病理性重构。 和冠状动脉功能障碍，称为移植物动脉硬化(GA)。遗传性关节炎的发病机制较差 可以理解，但可能是免疫介导的，可能是慢性迟发性超敏反应所致 受体T细胞通过分泌细胞因子对供体血管抗原的反应，如 干扰素-γ(干扰素-γ)。矛盾的是，干扰素-γ通常被认为对血管平滑肌细胞(VSMCs)具有抑制增殖的作用，并被认为是一种前动脉硬化剂，仅仅是因为 其对内皮细胞和浸润性白细胞的免疫调节作用。但是我们发现， 在没有白细胞的情况下，干扰素-γ会引起动脉硬化。我们之前的观察和目前的初步调查 研究使我们假设，干扰素-γ诱导VSMC增殖依赖于mTOR/p70S6K 途径，通过上调XAF1和NOXA使VSMCs对凋亡敏感，并启动VSMCs 通过诱导RIG-I和MDA5对碎片核酸的先天免疫反应。这些完全不同的 干扰素-γ对VSMC存活和炎症相互作用引起内膜扩张、外向血管形成的影响 管状冠状动脉的重塑和血管功能障碍最终决定管腔大小和 血液流动。我们进一步假设，干扰素-γ对VSMC的这些直接作用将被 过氧化物酶体增殖物激活受体(PPAR)γ配体。用实验来检验我们的假设 在这个项目中，我们已经与该项目的其他研究人员形成了富有成效的合作 应用，我们共同开发了新的GA模型，其中人的冠状动脉 通过腺病毒载体插入产生人干扰素-γ的严重免疫缺陷小鼠宿主中 感染。我们的方法是通过小鼠动脉移植模型和细胞和 人血管平滑肌细胞的分子研究。我们将使用这些方法来阐明干扰素-γ对 体内和体外的动脉组织。这些研究的结果将提供相当多的新信息 关于干扰素-γ在GA中的作用，可能会发现新的治疗靶点来治疗和成像GA，并研究 现有药物抑制赤霉素A的机制。

Chronic rejection, the major limitation of cardiac transplantation, is characterized by pathological remodeling and dysfunction of coronary arteries, termed graft arteriosclerosis (GA). The pathogenesis of GA is poorly understood, but is likely immune-mediated and may result from chronic delayed-type hypersensitivity responses by recipient T cells to donor vascular antigens through the secretion of cytokines, such as interferon-gamma (IFN-gamma). Paradoxically, IFN-gamma is generally thought to have an antiproliferative effect on vascular smooth muscle cells (VSMCs) and was considered to function as a proarteriosclerotic agent solely because of its immunomodulatory effects on endothelial cells and infiltrating leukocytes. However, we have found that IFN-gamma elicits arteriosclerosis in the absence of leukocytes. Our prior observations and current preliminary studies have led us to hypothesize that IFN-gamma induces VSMC proliferation that depends on a mTOR/p70S6K pathway, sensitizes VSMCs to apoptosis through upregulation of XAF1 and Noxa, and primes VSMCs for innate immune responses to fragmented nucleic acids by induction of RIG-I and MDA5. These disparate effects of IFN-gamma on VSMC survival and inflammation interact and cause intimal expansion, outward vascular remodeling, and vasodysfunction of conduit coronary arteries which ultimately determine lumen size and blood flow. We further hypothesize that these direct actions of IFN-gamma on VSMCs will be inhibited by peroxisome proliferator-activated receptor (PPAR)gamma ligands. To test our hypotheses with the experiments planned in this project, we have formed productive collaborations with other investigators of the program application and together we have developed novel models of GA in which human coronary arteries are interposed in severely immunodeficient mouse hosts that produce human IFN-gamma by adenoviral vector infection. Our methods are supplemented by mouse artery transplantation models and by cellular and molecular studies of human VSMCs. We will use these approaches to elucidate the effects of IFN-gamma on arterial tissue in vivo and in vitro. The outcomes of these studies will provide considerable new information about the role of IFN-gamma in GA, may identify novel therapeutic targets to treat and image GA, and investigate mechanisms of inhibiting GA by existing pharmacological agents.