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.

项目概要/摘要 尽管存在免疫抑制，但移植受者体内仍会产生供体特异性抗体 (DSA)，这是一种重要的抗体。 多个器官急性和慢性移植物损失的原因。抗体介导的排斥（AMR）治疗 选项不具体，功效可变，并且不会改善长期结果。有效的治疗 抗微生物药物耐药性 (AMR) 的需求仍未得到满足，需要更好地了解调节体液免疫的机制 对于开发更有效的疗法至关重要。我们发现了一个新的 CD8+ T 细胞亚群（CD8+ TAb- supp）部分通过杀死同种引物 B 细胞来抑制同种抗体的产生。值得注意的是，采用 在同种异体细胞和实体器官移植后将 CD8+ Tab-supp 细胞转移到小鼠受体中会导致 减少同种抗体数量，改善 AMR 相关组织病理学，并提高移植物存活率。 此外，我们的实验室已确定人类 CD8+ T 细胞亚群与鼠 CD8+ 具有相同的表型 人肾移植受者外周循环中检测到的TAb-supp细胞及其数量 与 DSA 的发展成反比。该提案的目的是表征分子 CD8+ Tab-supp 细胞 1) 对同种异体 B 细胞发挥抗体抑制作用的机制 2) 进出淋巴库的交通。该项目的转化影响很大，作为博士后 和外科住院医师我期待获得免疫学研究方面的严格培训并为自己做好准备 移植外科医生科学家的职业生涯。我选择了俄亥俄州立大学 (OSU) 普通外科住院医师实习 该计划因其手术的广度和数量而闻名，其中包括美国十大移植中心之一 国家，以及该计划对研究培训的承诺（和受保护的时间）。 OSU 是最大的大学之一 公立机构，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科学研究生完成博士学位 以免疫学研究为重点的项目，包括高级免疫学、研究等课程 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 免疫肿瘤学研究所和糖尿病研究中心。我将从以下机构获得研究培训和职业建议 我的赞助商（Ginny L. Bumgardner MD 博士）和共同赞助商（Peter Stock MD 博士，加州大学 旧金山），两人都是移植外科医生兼科学家。我将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 博士（俄勒冈州立大学医师科学家培训主任 计划）和 Willa Hsueh 医学博士（糖尿病研究中心主任）。我将向我的同事介绍我的研究结果 职业咨询委员会每季度召开一次。我计划通过出版物传播我的研究成果 在同行评审期刊上发表论文、在俄勒冈州立大学研究论坛上发表演讲以及出席国家科学会议。