The Risks and Opportunities of Homeostatic Repopulation

摘要——总体 NHP 肾移植模型为提高理解和理解提供了独特而重要的途径。 为人体移植患者实施新疗法。作为近亲繁殖的大型动物模型 与人类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经过评估 在 NHP 模型中。大约三十年来，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。现在我们建议专注于新颖的策略 促进供体特异性耐受性，进一步加深我们对 CMV 之间相互关系的理解 感染和同种免疫，并推进我们解决 T 和 B 细胞反应的策略 同种异体抗原。我们开展了一项合作，使我们能够探究 T 细胞和 B 细胞受体 猕猴的全部功能及其对免疫干预反应的变化。这个新颖的工具将极大地 增强我们在细胞水平上测量恒河猴治疗效果的能力。此外，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滤泡辅助 T 细胞的变化，作为更好理解的手段 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方面的集体经验 移植和生物学来评估可转化为人肾移植的疗法，并将 还使用可以在人类身上进行的机械测定。除了转化效益之外 拟议的工作，例如供体特异性调节性 T 细胞增强，我们期望获得根本性的新成果 深入了解 B 细胞记忆持久性以及 T 和 B 细胞库与同种抗原的广度以及这些 随着治疗以及排斥或感染期间的变化。我们的提案涉及学术界和工业界多个领域 支持信证明了正在进行的合作。我们将继续培训有计划的人员 移植医学、外科和免疫学领域的职业生涯，以便他们准备好领导我们的未来 场。该提案具有广泛的影响，可能会使受末期影响的美国公民受益 肾功能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.