Mechanisms of Selective CD28 Blockade on T Follicular Helper Cell-mediated Donor-specific Antibody Responses in Transplantation

项目总结/摘要 肾移植是终末期肾病患者的首选治疗方法。虽然短期 结果很好，但长期同种异体移植物存活率仍然不足。人们日益 认识到抗HLA供体特异性抗体（DSA）在慢性淋巴细胞白血病的发展中起着重要作用， 排斥和纤维化导致晚期肾移植物丢失。DSA产生的机制 对DSA的了解很少;因此，更好地了解DSA的细胞机制 移植后的形成有可能指导目前免疫抑制剂的优化， 策略和开发新的治疗方法来控制DSA。K 08职业的申请人 发展奖是一个早期的职业生涯腹部器官移植外科医生与强大的背景， 临床前非人灵长类动物模型和临床移植，寻求提高他的基本知识， 免疫学和获得先进的技能，在实验小鼠模型，以回答基本的 实现新的方法来控制DSA的床旁转换所需的机械问题， 肾移植患者在这个应用中，他建议检查共刺激和共抑制 在CD 28背景下驱动T滤泡辅助细胞（Tfh）介导的DSA反应的机制 在小鼠皮肤移植模型中的共刺激阻断。通过一系列相互关联的实验，他将 测试移植后Tfh细胞和DSA反应的抑制改善的假设， 选择性CD 28阻断依赖于共抑制剂CTLA-4，CTLA-4介导其 以Tfh-内在方式对DSA的共抑制作用。这项工作还将检查，如果减少表达的 Tfh细胞上的共刺激分子ICOS是抗CD 28诱导的DSA抑制的机制。这个项目的总体目标是 项目是阐明共刺激阻断介导的Tfh细胞抑制的机制基础， DSA预防。拟议的工作与NIAID确定治疗靶点的战略优先事项保持一致 通过临床前研究来提高移植肾存活率。一 一流的导师团队，由主要导师Mandy福特博士和共同导师Christian Larsen博士领导 和拉里博伊西，博士，将支持申请人的直接目标，启动他的独立研究 事业在这个过程中，通过正式的课程和结构化的专业发展计划，这个K 08 将帮助申请人建立一个平台，从追求他的长期职业目标，创造一个翻译 该研究计划将Tfh细胞介导的DSA形成的基本机制的发现与临床 在移植受者中提高控制肾脏中抗HLA抗体的能力的观察 移植 !

Project Summary/Abstract Kidney transplantation is the treatment of choice for patients with end-stage renal disease. Although short-term outcomes are excellent, long-term allograft survival rates remain inadequate. It has been increasingly recognized that anti-HLA donor-specific antibodies (DSA) play a significant role in the development of chronic rejection and fibrosis that lead to late renal allograft loss. The mechanisms that underlie the generation of DSA are poorly understood; therefore, a better understanding of the cellular mechanisms responsible for DSA formation following transplantation has potential to guide the optimization of current immunosuppressive strategies and the development of novel therapies to control DSA. The applicant for this K08 career development award is an early career abdominal organ transplant surgeon with a strong background in preclinical nonhuman primate models and clinical transplantation seeking to enhance his knowledge of basic immunology and acquire advanced skills in experimental mouse models to answer the fundamental mechanistic questions necessary to realize bench-to-bedside translation of novel approaches to control DSA in kidney transplant recipients. In this application, he proposes to examine the costimulatory and coinhibitory mechanisms that drive T follicular helper (Tfh) cell-mediated DSA responses in the setting of CD28 costimulation blockade in a murine skin transplant model. Through a series of interrelated experiments, he will test the hypothesis that improved inhibition of Tfh cell and DSA responses following transplantation with selective CD28 blockade is dependent upon the coinhibitor CTLA-4, and that CTLA-4 is mediating its coinhibitory effect on DSA in a Tfh-intrinsic manner. The work will also examine if reduced expression of the costimulator ICOS on Tfh cells is a mechanism of anti-CD28-induced DSA inhibition. The overall goal of this project is to elucidate the mechanistic underpinnings of costimulation blockade-mediated Tfh cell inhibition and DSA prevention. The proposed work is aligned with the NIAID strategic priority of identifying therapeutic targets for the enhancement of translational efforts to extend renal allograft survival through preclinical research. A first-class mentor team, led by primary mentor Mandy Ford, PhD, and co-mentors Christian Larsen, MD, DPhil and Larry Boise, PhD, will support the applicant's immediate goal of launching his independent research career. In the process, through formal coursework and a structured professional development plan, this K08 will help the applicant build a platform from which to pursue his long-term career goal of creating a translational research program that links findings on the basic mechanisms of Tfh cell-mediated DSA formation to clinical observations in transplant recipients to advance the ability to control anti-HLA antibodies in kidney transplantation. !