The molecular and spatial interactions between antibody suppressor CD8+ T cells and B cells that regulate alloantibody production after transplant

抗体抑制 CD8 T 细胞和 B 细胞之间的分子和空间相互作用调节移植后同种抗体的产生

• 批准号: 10431812
• 负责人: Jing Light Han
• 金额: $ 2.27万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10431812
• 关键词: Acute; Adoptive Transfer; Advisory Committees; Allogenic; Allografting; Animal Model; Antibodies; Antibody Suppression; Antigens; Apoptosis; B-Lymphocytes; BLR1 gene; Biometry; Blood Circulation; CCR5 gene; CD19 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; California; Cell Therapy; Cell Transplantation; Cells; Chronic; Clinical; Country; Data; Degree program; Development; Diabetes Mellitus; Doctor of Philosophy; Doctor' s Degree; Educational workshop; Effector Cell; Experimental Models; Family; Fibrinogen; Future; Gene Proteins; Graft Survival; Grant; Histopathology; Homologous Gene; Human; Humoral Immunities; Immune; Immune response; Immunity; Immunology; Immunooncology; Immunosuppression; Immunosuppressive Agents; Impairment; In Vitro; Infection; Inflammation; Institutes; Institution; Interferon Type II; Isoantibodies; Journals; Kidney Transplantation; Knockout Mice; Laboratories; Ligands; Link; Literature; Lymphocyte; Lymphoid; Lymphoid Tissue; Mediating; Mentors; Modeling; Molecular; Mouse Strains; Mus; Ohio; Operative Surgical Procedures; Organ; Organ Transplantation; Outcome; Pathology; Pattern; Peer Review; Peripheral; Phenotype; Physicians; Play; Postdoctoral Fellow; Production; Publications; Publishing; Reporting; Research; Research Ethics; Research Training; Residencies; Risk; Role; San Francisco; Schools; Science; Scientist; Signal Transduction; Site; Solid; Specificity; Sphingosine-1-Phosphate Receptor; Structure of germinal center of lymph node; Surgeon; T-Cell Depletion; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Tissues; Training; Training Programs; Translational Research; Transplant Recipients; Transplant Surgeon; Transplantation; Universities; Up-Regulation; Work; Writing; antagonist; antibody-mediated rejection; career; cell killing; chemokine receptor; clinical center; college; cytotoxic; cytotoxicity; donor-specific antibody; effective therapy; improved; in vivo; interest; isoimmunity; lymphoid organ; meetings; microbial; migration; novel; perforin; peripheral blood; post-transplant; prevent; programs; symposium; targeted agent; targeted treatment; tool; trafficking; transcriptome sequencing; translational impact; transplant centers; transplant model; treatment strategy

Project Summary/Abstract Donor specific antibodies (DSA) develop in transplant recipients despite immunosuppression and is a significant cause of acute and chronic graft loss across multiple organs. Antibody mediated rejection (AMR) treatment options are non-specific, have variable efficacy, and do not improve long-term outcomes. An effective treatment for AMR remains an unmet need, and a better understanding of mechanisms that regulate humoral immunity are critical to develop more effective therapies. We have discovered a novel subset of CD8+ T cells (CD8+ TAb- supp) that suppresses alloantibody production in part through the killing of alloprimed B cells. Notably, adoptive transfer of CD8+ TAb-supp cells into murine recipients after allogeneic cellular and solid organ transplant results in decreased alloantibody quantity, improved AMR-associated histopathology, and enhanced graft survival. Moreover, our lab has determined that a human CD8+ T cell subset with the same phenotype as murine CD8+ TAb-supp cells is detected in the peripheral circulation of human kidney transplant recipients and their quantity inversely correlates with the development of DSA. The objective of this proposal is to characterise the molecular mechanisms by which CD8+ TAb-supp cells 1) exert their antibody-suppressive effect upon alloprimed B cells and 2) traffic to and from lymphoid depots. The translational impact of this project is high and as a postdoctoral fellow and surgery resident I look forward to gaining rigorous training in immunology research and to preparing myself for a transplant surgeon-scientist career. I chose the Ohio State University (OSU) General Surgery Residency Program because of its breadth and volume of surgery, including one of the top ten transplant centers in the country, and the program’s commitment (and protected time) for research training. OSU is one of the largest public institutions, comprising fifteen colleges and a Graduate School that offers nearly 100 doctoral degree programs. My training plan includes completion of a doctoral degree through the Biomedical Sciences Graduate Program with a research emphasis in immunology that includes coursework in advanced immunology, research ethics, biostatistics, and grant writing. I will pursue research related seminars, workshops, and conferences offered by the OSU Center for Clinical Translational Science, Comprehensive Transplant Center, Pelotonia ImmunoOncology Institute, and Diabetes Research Center. I will gain research training and career advice from my Sponsor (Ginny L. Bumgardner MD PhD) and Co-Sponsor (Peter Stock MD PhD, University of California San Francisco), both of whom are transplant surgeon-scientists. I will broaden my understanding of immunology research through interactions with a diverse Career Advisory Committee consisting of Eugene Oltz PhD (Chair, Microbial Infection and Immunity), Robert Baiocchi MD PhD (Director, OSU Physician Scientist Training Program), and Willa Hsueh MD (Director, Diabetes Research Center). I will present results of my research to my Career Advisory Committee on a quarterly basis. I plan to disseminate my research findings through publications in peer-reviewed journals, presentations at OSU research forums, and attendance at national scientific meetings.

项目总结/摘要 供体特异性抗体（DSA）在移植受者中发展，尽管免疫抑制， 导致多个器官的急性和慢性移植物丢失。抗体介导的排斥反应（AMR）治疗 选择是非特异性的，具有不同的功效，并且不会改善长期结果。一种有效的治疗方法 AMR仍然是一个未满足的需求，更好地了解调节体液免疫的机制 对开发更有效的疗法至关重要。我们已经发现了一种新的CD 8 + T细胞亚群（CD 8 + TAb-1）。 supp），其部分通过杀死同种抗原致敏的B细胞来抑制同种抗体的产生。特别是，收养 在同种异体细胞和实体器官移植后，将CD 8 + TAb-supp细胞转移到小鼠受体中， 减少同种抗体数量，改善AMR相关的组织病理学，提高移植物存活率。 此外，我们的实验室已经确定，具有与鼠CD 8 + T细胞相同表型的人CD 8 + T细胞亚群， 人肾移植受者外周血中TAb-supp细胞的检测及其数量 与DSA的发展呈负相关。该提案的目的是使分子 CD 8 + TAb-supp细胞1）对同种异体致敏的B细胞发挥其抗体抑制作用的机制， 2)进出淋巴库的流量。这个项目的翻译影响很高，作为一名博士后研究员， 作为外科住院医师，我期待着在免疫学研究方面获得严格的培训， 成为一名移植外科医生兼科学家我选择了俄亥俄州州立大学（OSU）普外科住院医师 计划，因为它的广度和手术量，包括在世界十大移植中心之一， 国家，以及该计划对研究培训的承诺（和保护时间）。俄勒冈州立大学是美国最大的 公共机构，包括15个学院和一个研究生院，提供近100个博士学位 程序.我的培训计划包括通过生物医学研究生课程完成博士学位 以免疫学为研究重点的项目，包括高级免疫学课程、研究 伦理学、生物统计学和资助写作。我将参加与研究相关的研讨会、讲习班和会议 由俄勒冈州立大学临床转化科学中心，综合移植中心，Pelotonia提供 免疫肿瘤研究所和糖尿病研究中心。我将获得研究培训和职业建议， 我的担保人（金妮L. Bumgaret MD PhD）和共同申办者（Peter Stock MD PhD，加州大学 弗朗西斯科），两人都是移植外科医生科学家。我会拓宽我对免疫学的理解 通过与由尤金奥尔茨博士（主席， 微生物感染和免疫），Robert Baiocchi MD PhD（OSU医师科学家培训主任 Willa Hsueh MD（糖尿病研究中心主任）。我将把我的研究成果提交给我的 职业咨询委员会，每季度一次。我计划通过出版物传播我的研究成果 在同行评审的期刊，在俄勒冈州立大学研究论坛上的演讲，并出席国家科学会议。