Pathways Regulating Lung Transplant Tolerance

 描述(申请人提供)：尽管在外科技术和围手术期护理方面取得了进步，但肺移植后的总体存活率仍然令人失望，远远落后于其他实体器官移植的长期成功率。这在很大程度上可能与与肺同种异体免疫反应相关的独特免疫因素有关，从而导致更高的移植物排斥率。该项目的压倒一切的假设是，如果开发出适当的治疗策略，可以实现更高的肺移植成功率，这些策略是专门针对肺的独特免疫学特征而量身定做的。项目1将研究移植物内淋巴样新生在诱导和维持肺移植耐受中的作用。该项目基于已发表的数据，表明耐受性肺移植拥有有组织的淋巴结构，这些结构富含调节细胞。这使肺有别于其他器官和组织移植，在这些器官和组织移植中，淋巴样新生与不良预后有关。这个项目将由Kreisel博士领导。项目2将建立在最近发表的数据的基础上，这些数据不同于其他器官的情况，记忆CD8+T细胞在肺移植后诱导耐受中发挥关键作用。项目2将由Krupnick博士指导。项目3将由盖尔曼博士领导。本项目将重点研究中性粒细胞在调节肺移植耐受中的独特和二分作用。该项目将建立在中性粒细胞如何调节控制肺移植耐受的适应性免疫反应的新观察基础上。所有这三个项目都将利用小鼠肺移植模型和肺移植的活体成像。这些手术将由一个显微外科核心协调，该核心将由经验丰富和开拓性的显微外科医生李博士指导。管理核心将由Gelman博士领导，它将为项目领导人和显微外科核心领导人之间的沟通提供框架，并提供财政监督和组织科学指导，以优化计划项目的科学生产力。综上所述，该计划项目将提供有关肺移植后诱导和维持耐受性要求的新的和基本的信息，为肺移植患者急需的新的治疗策略奠定基础。

 DESCRIPTION (provided by applicant): Despite advances in surgical techniques and peri-operative care overall survival rates after lung transplantation remain disappointing, lagging significantly behind long-term success rates achieved for other solid organ transplants. This may be in large part related to unique immunologic factors associated with the pulmonary alloimmune response leading to higher rates of graft rejection. The overriding hypothesis for this Program Project is that higher success rates after pulmonary transplantation can be achieved if proper treatment strategies are developed, which are tailored to specifically address the unique immunological characteristics of lungs. Project 1 will examine the role of intragraft lymphoid neogenesis in inducing and maintaining lung transplant tolerance. This project is based on published data demonstrating that tolerant lung allografts harbor organized lymphoid structures that are rich in regulatory cell populations. This sets the lung apart from other organ and tissue grafts where lymphoid neogenesis has been associated with poor outcomes. This project will be led by Dr. Kreisel. Project 2 will build upon recently published data that, unlike the case for othr organs, memory CD8+ T cells play a critical role in inducing tolerance after lung transplantation. Project 2 will be directed by Dr. Krupnick. Project 3 will be led by Dr. Gelman. This project will focus on the unique and dichotomous role of neutrophils in regulating lung transplant tolerance. This project will build upon novel observations on how neutrophils regulate adaptive immune responses that control lung transplant tolerance. All three projects will utilize mouse models of lung transplantation and intravital imaging of lung grafts. These procedures will be coordinated by a Microsurgery Core, which will be directed by Dr. Li, an experienced and pioneering microsurgeon. An Administrative Core, which will be directed by Dr. Gelman, will provide the framework for the communication between project leaders and the microsurgical core leader as well as provide fiscal oversight and organize scientific guidance to optimize program project scientific productivity. Taken together, this Program Project will provide novel and fundamental information with regard to requirements to induce and maintain tolerance after pulmonary transplantation, laying the foundation for new and much needed therapeutic strategies for lung transplant patients.