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，以提高对 为人类移植患者实施新疗法。作为一个远缘繁殖的大型动物模型， 与人类的遗传相似性使机制和药物的建模更加准确 联合用药，以及几乎所有最近批准的免疫抑制剂和策略都已得到评估 在NHP模型中。我们的团队在大约30年的时间里为这些进步做出了巨大贡献， 导致我们的NHP研究产生了五项以上的临床试验。现在我们建议把重点放在新的策略上 促进供者特异性耐受性，进一步加深我们对CMV之间相互关系的理解 感染和同种异体免疫，并推进我们的战略，以解决T和B细胞反应 同种异体抗原。我们已经开发了一种协作，允许我们询问T细胞和B细胞受体 猕猴曲目及其对免疫干预的反应变化。这一新工具将极大地 提高我们在细胞水平上衡量治疗对恒河猴影响的能力。此外，我们 开创了评估恒河猴淋巴结内免疫反应的方法，并 测量生发中心变化和T滤泡辅助细胞的变化以更好地了解 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方面的集体经验 移植和生物学，以评估可移植到人类肾移植和将 也可以使用可以在人体上进行的机械性化验。除了翻译方面的好处外， 拟议的工作，如供体特异性调节性T细胞增强，我们预计将获得根本性的新进展 对B细胞记忆持久性和T和B细胞对同种异体抗原的广度的洞察，以及这些 随着治疗和排斥或感染的发生而改变。我们的建议涉及许多学术界和工业界 通过支持函证明正在进行的合作。我们将继续培训有计划的个人 在移植医学、外科和免疫学方面的职业生涯，以便他们准备好领导我们的未来 菲尔德。这项提案的影响具有广泛的影响，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性疾病或感染。

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.