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The Role of Complement Inhibition in Expanded Criteria Kidney Transplantation

补体抑制在扩展标准肾移植中的作用

基本信息

批准号：
9033073
负责人：
LUIS Alberto FERNANDEZ
金额：
$ 73.68万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-12 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9033073
关键词：
Acute Acute Kidney Failure Address Affect Allografting Anaphylatoxins Antibodies Antigens Attention Attenuated Automobile Driving Brain Death Brain Injuries CD4 Positive T Lymphocytes Cell Differentiation process Cell physiology Cells Clinical Trials Coagulation Process Complement Complement 1q Complement 3a Complement 5a Complement Activation Complement Factor D Complement Inactivators Complement component C1r Complement component C1s Complication Dendritic Cells Dialysis procedure Disabled Persons Effector Cell Endothelial Cells Eragrostis Event Exposure to Fibrosis Future G-Protein-Coupled Receptors Generations Genomics Goals Graft Survival Health Helper-Inducer T-Lymphocyte Human Immune Immune response Immune system Infiltration Inflammation Inflammatory Inflammatory Infiltrate Inflammatory Response Inherited Injury Ischemia Kallikrein-Kinin System Kidney Kidney Transplantation Lectin Lytic MASP2 gene Macrophage Activation Maintenance Mediating Modeling Molecular Natural Immunity Oliguria Operative Surgical Procedures Organ Organ Transplantation Pathogenesis Pathway interactions Patients Pattern Peptides Perinatal Exposure Phase Play Prevention Protease Inhibitor Reactive Oxygen Species Recording of previous events Recovery Recruitment Activity Regulation Regulatory T-Lymphocyte Reperfusion Injury Reperfusion Therapy Risk Role Serpins Shapes Signal Transduction Syndrome System T cell response T-Lymphocyte Testing Therapeutic Therapeutic Effect Therapeutic Uses Transplant Recipients Transplantation Vascular Permeabilities activation product adaptive immunity complement C3 precursor complement pathway complement system computerized delayed graft function digital imaging efficacy testing hereditary angioneurotic edema immunogenicity improved inhibitor/antagonist injured insight kidney allograft macrophage monocyte neutrophil nonhuman primate novel pre-clinical prevent renal ischemia response treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The complement system is an important effector of innate immunity and there is new strong evidence suggesting complement has a role in shaping the adaptive immune response. In the context of transplantation, the integral role of complement activation in kidney transplant recipients has been extensively studied in models of renal ischemia-reperfusion injury and antibody-mediated rejection. However, its potential therapeutic use as a donor pre-treatment to improve the quality of organs for transplantation from expanded criteria donors has not been studied. C1 inhibitor (C1INH) is a serpin protease inhibitor that regulates both complement and contact (kallikrein-kinin) system activation and its deficiency of C1INH results hereditary angioedema. We propose here a translational pre-clinical non-human primate (NHP) model in kidney transplantation to evaluate the effect of donor pre-treatment in brain death (BD) donors by inhibiting complement inhibition via the classical and alternative pathways and to understand whether complement inhibition a) prevents delayed graft function (DGF); b) ameliorates activation of innate and adaptive immune systems; c) prevents fibrosis progression in kidney transplantation; and d) regulates T cell responses, from directing the initiation phase to driving lineage commitment and differentiation. Finally, we will also study the additive therapeutic effect of blocking complement in both donors and recipients in an expanded criteria model of kidney transplantation.

描述（由申请人提供）：补体系统是先天免疫的重要效应器，并且有新的有力证据表明补体在形成适应性免疫反应中发挥作用。在移植方面，补体激活在肾移植受者中的不可或缺的作用已在肾缺血再灌注损伤和抗体介导的排斥反应模型中得到了广泛研究。然而，其作为供体预处理以提高扩展标准供体移植器官质量的潜在治疗用途尚未得到研究。 C1 抑制剂 (C1INH) 是一种丝氨酸蛋白酶抑制剂，可调节补体和接触（激肽释放酶-激肽）系统的激活，C1INH 缺乏会导致遗传性血管性水肿。我们在此提出一种肾移植的临床前转化非人灵长类动物 (NHP) 模型，通过经典途径和替代途径抑制补体抑制来评估供体预处理对脑死亡 (BD) 供体的效果，并了解补体抑制是否 a) 防止移植物功能延迟 (DGF)； b) 改善先天性和适应性免疫系统的激活； c) 预防肾移植中的纤维化进展； d) 调节 T 细胞反应，从指导起始阶段到驱动谱系定型和分化。最后，我们还将研究在肾移植的扩展标准模型中，阻断补体对供体和受体的附加治疗效果。