THORACIC ALLOGRAFT TOLERANCE IN NON-HUMAN PRIMATES

非人类灵长类动物胸廓同种异体移植耐受性

• 批准号: 7684757
• 负责人: Joren C Madsen
• 金额: $ 129.22万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7684757
• 关键词: THORACIC; ALLOGRAFT; TOLERANCE; NON; HUMAN

DESCRIPTION (provided by applicant): Significant improvements in early post transplant survival rates have been achieved with induction of newer pharmacologic immunosuppressive agents over the last decade. Nevertheless, the need for further refinement of available therapeutic protocols is emphasized by the morbidity and the annual attrition rate of 3-4% observed in clinically treated allograft recipients, primarily as a result of chronic rejection. The objective of this Program Project is to improve the outcome following heart and lung transplantation by defining the essential conditions for and clarifying the mechanisms involved in donor-specific tolerance induction. The rational linking the objectives of the 3 inter-related Projects and 2 Core units is that since long-term donor-specific nonreactivity can be induced in many experimental models, including non-human primates, it should be possible to identify and reproducibly provide the immunologic perturbations which lead to this state in man. As "proof of principle" one approach employing mixed chimerism has achieved tolerance in several patients who received simultaneous kidney and bone marrow transplants from living donor MHG-matched siblings. In Project 1, Dr. Madsen and co-investigators will test three exciting new tolerance induction regimens alone and in combination to achieve synergy. In Project 2, Dr. Benichou and colleagues will investigate how memory T cells affect the ability of different protocols to achieve a state of tolerance in heart and lung recipients. In Project 3, Dr. Allan will apply the concept of mixed chimerism to lung transplantation for the first time. In the Immunopathology Core B, Dr. Colvin will provide the infrastructure and technology to perform morphologic, immunopathologic and molecular analysis of tissue and peripheral blood mononuclear cells provided by Projects 1 and 2. Dr. Madsen along with Dr. Schoenfeld will lead the Administrative and Biostatistics Core which will coordinate all administrative, statistical and data management issues of the Program Project. Our studies should yield clinically relevant information that will result in the development of new tolerance strategies applicable to heart and lung allografts recipients and lead to the development of better assays to monitor and predict patients that achieve tolerance and those at risk for the development of chronic graft loss.

描述（由申请人提供）： 在过去的十年中，随着新型药理免疫抑制剂的出现，移植后早期存活率得到了显着提高。然而，在临床治疗的同种异体移植受者中观察到的发病率和每年 3-4% 的损耗率（主要是由于慢性排斥反应）强调了进一步完善现有治疗方案的必要性。该计划项目的目标是通过定义供体特异性耐受诱导的基本条件并阐明其机制来改善心肺移植后的结果。将 3 个相互关联的项目和 2 个核心单元的目标合理地联系起来是，由于可以在许多实验模型（包括非人类灵长类动物）中诱导长期供体特异性无反应性，因此应该有可能识别并可重复地提供导致人类这种状态的免疫紊乱。作为“原理证明”，一种采用混合嵌合的方法已经在几名同时接受来自活体捐赠者 MHG 匹配兄弟姐妹的肾脏和骨髓移植的患者中实现了耐受。在项目 1 中，Madsen 博士和合作研究人员将单独测试三种令人兴奋的新耐受诱导方案，并组合测试以实现协同作用。在项目 2 中，Benichou 博士及其同事将研究记忆 T 细胞如何影响不同方案在心肺接受者中实现耐受状态的能力。在项目3中，Allan博士将首次将混合嵌合的概念应用于肺移植。在免疫病理学核心 B 中，Colvin 博士将提供基础设施和技术，对项目 1 和 2 提供的组织和外周血单核细胞进行形态学、免疫病理学和分子分析。Madsen 博士和 Schoenfeld 博士将领导管理和生物统计核心将协调该计划项目的所有行政、统计和数据管理问题。我们的研究应该产生临床相关信息，这些信息将导致开发适用于心脏和肺同种异体移植受者的新耐受策略，并导致开发更好的检测方法来监测和预测达到耐受性的患者以及有慢性移植物发展风险的患者损失。

项目成果

Effects of an agonist interleukin-2/Fc fusion protein, a mutant antagonist interleukin-15/Fc fusion protein, and sirolimus on cardiac allograft survival in non-human primates.

激动剂白细胞介素 2/Fc 融合蛋白、突变拮抗剂白细胞介素 15/Fc 融合蛋白和西罗莫司对非人灵长类同种异体心脏移植物存活的影响。

• DOI: 10.1016/j.healun.2012.01.864
• 发表时间: 2012
• 期刊: The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
• 作者: Millington,Timothy;Koulmanda,Maria;Ng,Choo;Boskovic,Svjetlan;Nadazdin,OgnjenkaM;Benichou,Gilles;Zheng,XinXiao;Strom,TerryB;Madsen,JorenC
• 通讯作者: Madsen,JorenC