NOVEL IN VIVO MODEL OF CHRONIC ALLOGRAFT REJECTION

慢性同种异体移植排斥的新颖体内模型

• 批准号: 8116409
• 负责人: David M. Briscoe
• 金额: $ 26.03万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8116409
• 关键词: 70-kDa Ribosomal Protein S6 Kinases; Acute; Address; Adoptive Transfer; Allografting; Antigens; Attenuated; Binding; CD4 Positive T Lymphocytes; CTLA4-Ig; Cardiac; Cell Adhesion Molecules; Cell Proliferation; Cell Survival; Cell surface; Cells; Chemotactic Factors; Chronic; Clinical; Cytokine Activation; Delayed Hypersensitivity; Development; Endothelial Cells; Endothelium; Event; Excision; Exploratory/Developmental Grant; Fibrosis; Future; Genes; Goals; Graft Rejection; Graft Survival; Growth Factor; Heart; Heart Transplantation; Human; Immune; Immune Tolerance; Immune response; Immunosuppressive Agents; Inbred BALB C Mice; Individual; Infiltration; Inflammation; Inflammatory; Isoantibodies; Leukocytes; Life; MHC Class II Genes; Maintenance; Mediating; Modeling; Monitor; Mononuclear; Mus; NF-kappa B; Nature; Organ Donor; Organ Transplantation; Outcome; Partner in relationship; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Physiological; Play; Process; Proto-Oncogene Proteins c-akt; Reaction; Regimen; Regulation; Research Proposals; Role; SCID Mice; Shapes; Signal Pathway; Signal Transduction; Sirolimus; Solid; Study models; Survival Rate; T-Lymphocyte; TNFSF5 gene; Tetracyclines; Therapeutic; Time; Trans-Activators; Transgenes; Transgenic Mice; Transgenic Model; Transgenic Organisms; Transplant Recipients; Transplantation; Vascular Diseases; Vascular Endothelial Cell; allograft rejection; cadherin 5; cell motility; chemokine; cytokine; drinking water; end-stage organ failure; graft failure; human FRAP1 protein; immunoregulation; improved; in vivo; in vivo Model; mTOR Inhibitor; mTOR Signaling Pathway; mouse model; novel; novel therapeutics; overexpression; public health relevance; receptor; response; tool

DESCRIPTION (provided by applicant): Current state-of-the-art immunosuppressive strategies have been most successful at inhibiting acute rejection and have significantly improved short-term graft survival rates. However, these same strategies have failed to interrupt the development of, and more importantly, the progression of chronic allograft rejection. Since chronic allograft rejection is currently the leading cause of graft failure following solid organ transplantation, it has become most apparent that there is a great need to develop new paradigms and models in order that novel therapeutics can be developed to target this process. The prevailing view is that the nature or magnitude of the immune response to donor antigen determines the rejection process. In addition, it is thought that the phenotype of the immune response (and the local inflammatory cytokine milieu) determines the activation state of the allograft. However, it is evident from recent studies that the graft itself, and not the immune response, can be dominant to shape the rejection process (even in the face of immune tolerance). Consistently, several studies have identified the activation state of the graft endothelial cell (EC) as a determinant of acute and chronic rejection. Furthermore, recent studies indicating that mTOR inhibitors target graft EC indicate that the effect of these agents to attenuate the progression of chronic rejection (and chronic vascular disease(s)), may be associated with their ability to target the EC activation response. Nevertheless, to date, the select role of the graft EC in the development of rejection has been difficult to study. In EC, mTOR signals enhance the activity of the kinase Akt, which in turn regulate many EC activation responses. In this exploratory research proposal, we plan to utilize the unique VE-Cadherin:tTA+/TET-Akt+ double transgenic mouse, in which it is possible to regulate Akt selectively within the endothelium. We will use hearts from this mouse as donors of cardiac transplants such that we can: Aim 1, develop a transplantation model to study the select role of Akt-inducible and EC activation responses in the chronic rejection process; Aim 2, evaluate the dominance of the graft EC in the development of chronic rejection, and Aim 3, study the effect of Akt-induced activation of donor EC in immune regulation and tolerance. The development of this unique model of chronic rejection will provide us with an exciting opportunity for the first time to directly assess the role and functional effect of the graft EC in the development of chronic allograft rejection and/or in the maintenance of alloimmune tolerance. PUBLIC HEALTH RELEVANCE: Organ transplantation is a life saving therapy for individuals with end stage organ failure. However, despite the development of novel immunosuppressive strategies, all transplants eventually fail due to a reaction called chronic allograft rejection. While currently dogma dictates that the immune response is the major determinant of acute rejection, additional events within the graft also dictate the development and progression of chronic rejection. In this research proposal we will develop a novel and unique transgenic mouse model in which we will establish whether the graft itself, and specifically the vasculature within the graft is a major functional determinant of this process. Our goal is to develop new paradigms to understand and treat chronic rejection.

描述（由申请人提供）：当前的最新免疫抑制策略最成功地抑制急性排斥，并显着提高了短期移植物存活率。但是，这些相同的策略未能中断慢性同种异体移植排斥的发展，更重要的是，也没有中断。由于慢性同种异体移植抑制目前是固体器官移植后移植失败的主要原因，因此最明显的是，需要开发新的范式和模型，以便可以开发出新的治疗剂来针对这一过程。主要的观点是，免疫反应对供体抗原的性质或大小决定了排斥过程。此外，人们认为免疫反应（和局部炎症性细胞因子环境）的表型决定了同种异体移植的激活状态。但是，从最近的研究中可以明显看出，移植物本身而非免疫反应可以主导塑造排斥过程（即使面对免疫耐受性）。一致地，一些研究确定了移植内皮细胞（EC）的激活状态是急性和慢性排斥的决定因素。此外，最近的研究表明，MTOR抑制剂靶向移植EC表明，这些药物减弱慢性排斥反应（和慢性血管疾病）的影响可能与靶向EC激活反应的能力有关。然而，迄今为止，很难研究移植EC在拒绝发展中的精选作用。在EC中，MTOR信号增强了激酶AKT的活性，进而调节许多EC激活反应。在这项探索性研究建议中，我们计划利用独特的VE-钙粘蛋白：TTA+/TET-AKT+双转基因小鼠，在该小鼠中可以选择性地调节Akt在内皮中。我们将使用该小鼠的心脏作为心脏移植的供体，以便我们可以：AIM 1，开发一种移植模型来研究Akt诱导和EC激活反应在慢性拒绝过程中的选择作用； AIM 2，评估移植EC在慢性排斥发展中的主导地位，并研究AKT诱导的供体EC激活在免疫调节和耐受性中的影响。这种独特的慢性拒绝模型的发展将为我们提供令人兴奋的机会，以直接评估移植EC在慢性同种异体拒绝和/或维持同种异体免疫耐受性方面的作用和功能效果。 公共卫生相关性：器官移植是终端器官衰竭患者的挽救生命疗法。然而，尽管有新型免疫抑制策略的发展，但由于一种称为慢性同种异体移植排斥反应的反应，所有移植最终都失败了。虽然目前的教条规定免疫反应是急性排斥反应的主要决定因素，但移植物中的其他事件也决定了慢性排斥的发展和进展。在这项研究建议中，我们将开发一种新颖而独特的转基因小鼠模型，在该模型中，我们将确定移植物本身，特别是移植物中的脉管系统是否是该过程的主要功能决定因素。我们的目标是开发新的范式来理解和治疗慢性拒绝。