The role of heme oxygenase-1 in the Immune Response

描述（由申请人提供）：血红素加氧酶-1（HO-1）系统由血红素加氧酶-1和血红素、一氧化碳、胆绿素和铁的降解产物组成。HO-1的过表达可保护细胞和组织免受免疫介导的损伤以及氧化损伤，表明HO-1及其产物是重要的免疫调节机制。这种调节的机制尚不清楚。我们已经表明，HO-1的缺乏强烈影响居民树突状细胞（DC）亚群在体内的分化和废除调节性T细胞介导的抑制T细胞活化的DC在体外。这些发现支持了这样的概念，即免疫应答的调节以及因此同种异体移植物排斥是通过HO- 1对DC的分化和功能的影响。为了支持我们的总体目标，识别独特的分子靶点调节免疫反应，我们建议确定宿主HO-1的表达如何影响居民DC亚群的分化，以及HO-1的表达如何通过DC调节体内慢性排斥反应的肾移植模型中的炎症反应。将使用PI开发的独特工具来实现这一目标，包括i）通过与适当的cre重组体杂交，允许选择性表达HO-1的转基因floxed HO-1小鼠品系; CD 11 c-DC特异性HO-1过表达品系; ii）GFP+ HO-1-/-小鼠品系;和iii）具有类似于人CAN的特征的慢性同种异体移植肾病（CAN）的原位鼠肾移植模型。本研究的主要目的是：1）验证HO-1调节DC亚群在外周淋巴器官中的分布和分化的假说; 2）验证HO-1通过调节移植肾中DC的活化和归巢来调节CAN中炎症、纤维化和血管疾病的发展的假说; 3）通过验证HO-1过表达DC可延长移植物存活、改善肾功能和减轻CAN的组织学特征的假设，确定调控DC中HO-1表达对同种异体肾移植的治疗潜力。 目前关于实体器官同种异体移植物的免疫应答的控制的研究和范例集中在T细胞活化和克隆扩增的控制上。这种方法在减少急性同种异体移植物排斥反应方面是成功的，但对于由于慢性排斥反应而导致的长期移植物损失，还没有取得令人满意的进展。拟议的研究旨在通过检查一个独特的分子靶点血红素加氧酶-1（HO-1）的作用来解决这一需求，血红素加氧酶-1（HO-1）是一组应激蛋白的一部分，可提供细胞保护。HO-1在这些蛋白质中是独特的，因为它与免疫调节，以及对纤维化和血管疾病的保护有关。通过操纵HO-1活性或其底物和产物的相对丰度来实现该分子的安全、有效的治疗应用，需要更好地理解其在免疫和长期移植物存活中的作用。

DESCRIPTION (provided by applicant): The heme oxygenase-1 (HO-1) system consists of the enzyme heme oxygenase-1 and the products of the degradation of heme, carbon monoxide, biliverdin, and iron. Overexpression of HO-1 protects cells and tissues from immune-mediated injury as well as oxidative damage, indicating that HO-1 and its products are an important immunoregulatory mechanism. The mechanisms of this regulation are unknown. We have shown that the absence of HO-1 strongly affects differentiation of resident dendritic cell (DC) subsets in vivo and abrogates regulatory T cell mediated suppression of T cell activation by DC in vitro. These findings support the concept that modulation of the immune response, and therefore allograft rejection, is through the effect of HO- 1 on the differentiation and function of DCs. In support of our overall goal of identification of unique molecular targets for modulation of immune responses, we propose to determine how host HO-1 expression affects the differentiation of resident DC subpopulations and how expression of HO-1 by DCs modulates inflammatory responses in vivo in a renal allograft model of chronic rejection. This objective will be pursued using unique tools developed by the PIs, including i) a transgenic floxed HO-1 mouse strain permitting selective expression of HO-1 by cross-breeding with the appropriate cre recombinants; a CD11c-DC specific HO-1 overexpressing strain; ii) a GFP+ HO-1-/- mouse strain; and iii) an orthotopic murine renal transplantation model of chronic allograft nephropathy (CAN) with features that resemble human CAN. We will address the following specific aims: 1) to test the hypothesis that HO-1 regulates the distribution and differentiation of DC subpopulations in the peripheral lymphoid organs; 2) to test the hypothesis that HO-1 regulates the development of inflammation, fibrosis and vascular disease in CAN by modulation of DC activation and homing in renal allografts; 3) to determine the therapeutic potential of manipulation of HO-1 expression in DCs for kidney allografts by testing the hypothesis that HO-1 overexpressing DC will prolong graft survival, improve renal function and alleviate histological features of CAN. Current research and paradigms with respect to the control of the immune response to solid organ allografts are centered on control of T cell activation and clonal expansion. This approach has been successful in reducing acute allograft rejection, but has not made satisfactory inroads into long-term graft losses due to chronic rejection. The proposed studies are designed to address this need by examining the role of a unique molecular target, heme oxygenase-1 (HO-1), which is part of a group of stress proteins shown to provide cytoprotection. HO-1 is unique among these proteins because of its association with immunomodulation, and protection against fibrosis and vascular disease. Safe, effective therapeutic application of this molecule, effected by manipulation of HO-1 activity or the relative abundance of its substrates and products, requires a much better understanding of its role in immunity and long-term graft survival.