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

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.

先天网络：血栓性微血管病，凝血和补体在敏化肾脏移植受体中的激活。

• 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

Targeting Calcium Release-activated Calcium Channel Is Not Sufficient to Prevent Rejection in Nonhuman Primate Kidney Transplantation.

靶向钙释放激活的钙通道不足以防止非人灵长类肾移植中的排斥反应。

• DOI: 10.1097/tp.0000000000003078
• 发表时间: 2020
• 期刊: Transplantation
• 影响因子: 6.2
• 作者: Kwun,Jean;Ezekian,Brian;Manook,Miriam;Park,Jaeberm;Yoon,Janghoon;Freischlag,Kyle;Song,Mingqing;Farris,AltonB;Sloan-Lancaster,Joanne;Fortier,Caroline;Rao,PatriciaE;Knechtle,StuartJ
• 通讯作者: Knechtle,StuartJ

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