The Risks and Opportunities of Homeostatic Repopulation

摘要-总体 NHP肾移植模型提供了独特和重要的途径，以改善对肾脏移植的理解， 为人类移植患者实施新疗法。作为一个远系繁殖的大型动物模型， 与人类密切的遗传相似性允许更准确地建模机制和药物/药物 组合，几乎所有最近批准的免疫抑制剂和策略都已被评估 在NHP模型中。近三十年来，我们的团队为这些进步做出了巨大贡献， 我们的NHP研究产生了超过五项临床试验。现在我们建议关注新颖的策略 促进供者特异性耐受，进一步加深我们对CMV与 感染和同种异体免疫，并推进我们的战略，解决T和B细胞反应， 同种抗原我们已经开发了一种合作，使我们能够询问T细胞和B细胞受体 猕猴的剧目和它们对免疫干预的反应变化。这一新工具将大大 增强我们在恒河猴细胞水平上测量治疗效果的能力。另外我们 开创了评估恒河猴淋巴结内免疫反应的方法， 测量生发中心的变化和T滤泡辅助细胞的变化，作为更好地了解 同种异体移植后B细胞反应。我们计划利用我们在恒河猴肾脏方面的集体经验 移植和生物学来评估可转化为人类肾移植的疗法， 也使用可以在人体中进行的机械分析。除了翻译的好处， 建议的工作，如供体特异性调节性T细胞扩增，我们希望获得基本的新的 深入了解B细胞记忆的持久性和T细胞和B细胞对同种异体抗原的库的宽度，以及这些细胞是如何产生记忆的。 随着治疗和排斥或感染而变化。我们的建议涉及许多学术界和工业界 正在进行的合作，如支持信所证明的。我们将继续培训那些计划 在移植医学，外科手术和免疫学的职业生涯，使他们将准备领导我们的未来， 领域这项提案的影响具有广泛的意义，可能使受终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。

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.