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。过表达HO-1可以保护细胞和组织免受免疫介导的损伤和氧化损伤，表明HO-1及其产物是一种重要的免疫调节机制。这种调节的机制尚不清楚。我们已经证明，HO-1的缺失会强烈影响体内常驻树突状细胞（DC）亚群的分化，并在体外消除DC介导的调节性T细胞对T细胞活化的抑制。这些发现支持了这样一个概念，即免疫反应的调节，因此同种异体移植排斥反应，是通过HO- 1对dc分化和功能的影响。为了支持我们确定调节免疫反应的独特分子靶点的总体目标，我们建议确定宿主HO-1表达如何影响居住DC亚群的分化，以及DC表达HO-1如何调节体内慢性排斥肾移植模型中的炎症反应。这一目标将使用pi开发的独特工具来实现，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flxed HO-1小鼠菌株；CD11c-DC特异性HO-1过表达菌株；ii) GFP+ HO-1-/-小鼠品系；iii)具有类似人类慢性同种异体肾病（CAN）特征的原位小鼠肾移植模型。我们将解决以下具体目的：1)验证HO-1调节DC亚群在外周血淋巴器官的分布和分化的假设；2)验证HO-1通过调节DC激活和肾移植归巢调节CAN炎症、纤维化和血管疾病的发生的假说；3)通过验证过表达HO-1的DC会延长移植物存活、改善肾功能和缓解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。目前关于实体器官移植物免疫反应控制的研究和范式主要集中在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排斥反应方面取得了成功，但在慢性排斥反应引起的长期移植损失方面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标血红素加氧酶-1 （HO-1）的作用来解决这一需求，血红素加氧酶-1是一组显示提供细胞保护的应激蛋白的一部分。HO-1在这些蛋白中是独一无二的，因为它与免疫调节、防止纤维化和血管疾病有关。通过调控HO-1活性或其底物和产物的相对丰度来安全、有效地应用该分子进行治疗，需要更好地了解其在免疫和移植物长期存活中的作用。

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. PUBLIC HEALTH RELEVANCE: Inflammation, especially chronic inflammation, remains one of the most problematic clinical phenomena. This grant explores the mechanisms of a recently discovered mode of regulation of inflammation that is part of the body's system of handling toxic heme molecules, the generation of carbon monoxide, biliverdin, and iron by the heme oxygenase---1 enzyme. The new information generated here could lead to new therapeutic targets by which we could control inflammation, one of the most highly sought goals in public health.