The Risks and Opportunities of Homeostatic Repopulation

稳态增殖的风险和机遇

• 批准号: 10622054
• 负责人: Stuart Johnston Knechtle
• 金额: $ 327.57万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622054
• 关键词: Acceleration; Address; Affect; Alloantigen; Animal Model; Antibodies; Antithymoglobulin; Award; B cell repertoire; B-Cell Antigen Receptor; B-Lymphocytes; Biological Assay; Biology; Cardiovascular Diseases; Cause of Death; Cessation of life; Chronic; Clinical Trials; Collaborations; Cytomegalovirus Infections; Data; Drug Combinations; End stage renal failure; Evaluation; Funding; Future; Genetic; Genetic Identity; Goals; Grant; Health; Helper-Inducer T-Lymphocyte; Human; IL2 gene; Immune; Immune Tolerance; Immune response; Immunology; Immunosuppression; Immunosuppressive Agents; Individual; Indolent; Industry Collaboration; Infection; Infusion procedures; Kidney Failure; Kidney Transplantation; Learning; Letters; Longevity; Macaca; Macaca mulatta; Malignant Neoplasms; Measures; Mediating; Memory B-Lymphocyte; Methodology; Modeling; National Institute of Allergy and Infectious Disease; Operative Surgical Procedures; Organ Transplantation; Pathway interactions; Patients; Pharmaceutical Preparations; Population; Publishing; Quality of life; Regulation; Regulatory T-Lymphocyte; Research; Risk; Safety; Sirolimus; Structure of germinal center of lymph node; T-Lymphocyte; Therapeutic immunosuppression; Training; Translating; Transplant Recipients; Transplantation; United States; United States National Institutes of Health; Work; allotransplant; antibody-mediated rejection; career; experience; immunological intervention; improved; insight; isoimmunity; lymph nodes; nonhuman primate; novel; novel strategies; novel therapeutics; pharmacologic; prevent; response; tool; transplant model; transplantation medicine; virtual

ABSTRACT – Overall The NHP kidney transplant model offers unique and important pathways to the improved understanding and implementation of novel therapies for human transplant patients. Being an outbred, large animal model with close genetic similarities to humans allows more accurate modeling of mechanisms and drugs/drug combinations, and virtually all recently approvedimmunosuppressive agents and strategies have beenevaluated in a NHP model. Our group has contributed to these advances substantially for approximately three decades, resulting in over five clinical trials arising from our NHP research. Now we propose to focus on novel strategies to promote donor-specific tolerance, to further develop our understanding of the interrelationship between CMV infection and alloimmunity, and to advance our strategies for addressing the T and B cell response to alloantigens. We have developed a collaboration that allows us to interrogate the T cell and B cell receptor repertoire of macaques and their changes in response to immune interventions. This novel tool will greatly enhance our ability to measure the impact of therapies at the cellular level in rhesus monkeys. In addition, we have pioneered methodologies to assess the immune response within lymph nodes of rhesus monkeys and measure germinal center changes and changes of T follicular helper cells as a means of better understanding the B cell response to allotransplantation. We plan to use our collective experience in rhesus monkey kidney transplantation and biology to evaluate therapies that are translatable to human kidney transplantation and will also use mechanistic assays that can be performed in humans. In addition to the translational benefits of the proposed work such as donor-specific regulatory T cell augmentation, we expect to gain fundamental new insights into B cell memory durability and the breadth of T and B cell repertoires to alloantigens and how these change with therapy and during rejection or infection. Our proposal involves many academic and industry collaborations that are ongoing as attested by letters of support. We will continue to train individuals who plan careers in transplant medicine, surgery, and immunology such that they will be prepared to lead the future of our field. The impact of this proposal has broad implications that may benefit U.S. citizens affected by end stage renal failure or by immune-mediated illnesses or infections.

摘要 - 总体 NHP肾脏移植模型为改善理解和 针对人类移植患者的新疗法实施。是一个示意，大型动物模型 与人类的紧密遗传相似性可以更准确地建模机制和药物/药物 对组合以及几乎所有最近批准的免疫抑制剂和策略已经进行了评估 在NHP模型中。我们的小组在大约三十年中为这些进步做出了贡献， 由我们的NHP研究引起了五次临床试验。现在我们建议专注于新颖的策略 促进捐助者特定的宽容，进一步发展我们对CMV之间相互关系的理解 感染和同种免疫，并促进我们解决T和B细胞反应的策略 同种植物。我们已经开发了一种协作，使我们能够询问T细胞和B单元接收器 猕猴的曲目及其对免疫干预措施的变化。这个新颖的工具将极大地 增强了我们测量恒河猴细胞水平上疗法影响的能力。另外，我们 采用开创性的方法来评估恒河猴淋巴结中的免疫反应和 测量卵泡辅助细胞的生发中心变化和变化，以便更好地理解 B细胞对同种异体移植的反应。我们计划利用我们在恒河猴肾脏中的集体经验 移植和生物学评估可翻译为人类肾脏移植的疗法，并将 还使用可以在人类中执行的机械测定法。除了转化的好处 拟议的工作，例如捐助者特定的调节T细胞增强，我们希望获得基本的新 洞悉B细胞记忆耐用性以及T和B细胞库的宽度与同种抗原的范围以及如何 随着治疗和拒绝或感染而改变。我们的建议涉及许多学术和行业 由支持信证明的持续的合作。我们将继续培训计划的个人 移植医学，手术和免疫学的职业，因此他们将准备领导我们的未来 场地。该提案的影响具有广泛的含义，可能使在末期影响的美国公民受益 肾衰竭或免疫介导的疾病或感染。

项目成果

Preoperative carfilzomib and lulizumab based desensitization prolongs graft survival in a sensitized non-human primate model.

• DOI: 10.1016/j.kint.2020.08.020
• 发表时间: 2021-01
• 期刊: Kidney international
• 影响因子: 19.6
• 作者: Schroder PM;Schmitz R;Fitch ZW;Ezekian B;Yoon J;Choi AY;Manook M;Barbas A;Leopardi F;Song M;Farris AB;Collins B;Kwun J;Knechtle SJ
• 通讯作者: Knechtle SJ

Innate networking: Thrombotic microangiopathy, the activation of coagulation and complement in the sensitized kidney transplant recipient.

• DOI: 10.1016/j.trre.2018.01.001
• 发表时间: 2018-07
• 期刊: Transplantation reviews (Orlando, Fla.)
• 作者: Manook M;Kwun J;Sacks S;Dorling A;Mamode N;Knechtle S
• 通讯作者: Knechtle S

Letter to the editor in response to: Measuring success in pig to non-human-primate renal xenotransplantation: Systematic review and comparative outcomes analysis of 1051 life sustaining NHP renal allo- and xeno-transplants by Firl and Markmann.

• DOI: 10.1111/ajt.17007
• 发表时间: 2022-07
• 期刊: AMERICAN JOURNAL OF TRANSPLANTATION
• 影响因子: 8.8
• 作者: Anwar, Imran J.;DeLaura, Isabel;Gao, Qimeng;Knechtle, Stuart;Kwun, Jean
• 通讯作者: Kwun, Jean

Experimental modeling of desensitization: What have we learned about preventing AMR?

• DOI: 10.1111/ajt.15873
• 发表时间: 2020-06
• 期刊: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
• 作者: Kwun J;Knechtle S
• 通讯作者: Knechtle S

The past, present, and future of costimulation blockade in organ transplantation.

器官移植中共刺激阻断的过去、现在和未来。

• DOI: 10.1097/mot.0000000000000656
• 发表时间: 2019
• 期刊: Current opinion in organ transplantation
• 影响因子: 2.2
• 作者: Schroder,PaulM;Fitch,ZacharyW;Schmitz,Robin;Choi,AshleyY;Kwun,Jean;Knechtle,StuartJ
• 通讯作者: Knechtle,StuartJ