Cellular Strategies for Tolerance Induction

摘要： 肾移植是终末期肾病患者的一线治疗， 最近的数据显示，一年的成功率很高。然而，患者仍然面临着严重的发病率， 和移植后的死亡率，无论是慢性同种异体移植排斥反应， 标准免疫抑制方案。考虑到这些双重风险，这一领域的最终目标是引入 移植后的免疫耐受，这保证了移植物的终身接受，而不需要 持续的免疫抑制，重要的是，保护性免疫力的保存。虽然小说 药理学和抗体治疗在延长同种异体移植物存活方面代表了真实的希望 和减少脱靶毒性，小鼠研究强烈表明，最稳健的诱导策略， 免疫耐受结合细胞疗法，包括基于调节性T细胞的方法和混合- 嵌合诱导（特别是与T细胞共刺激阻断组合）。这两种疗法 有希望从根本上重置受体免疫力，有利于同种异体移植物的接受，因此 为肾移植受者提供通向免疫耐受的直接途径。在本提案中，我们将 研究基于Treg和混合嵌合体的细胞疗法的耐受诱导潜力 目的1：设计最佳抑制性调节性T细胞产物，其能够 在肾移植后提供同种异体移植物特异性免疫耐受。目的2：诱导免疫耐受 通过诱导稳定的多系混合造血嵌合体并保存的肾移植 在T细胞共刺激阻断的情况下保护性免疫。本项目的可交付成果包括 两个非常有前途的临床翻译耐受诱导策略的发展，如果 成功，可能会改变肾移植的临床实践。

ABSTRACT: Renal transplantation represents first-line therapy for patients with end-stage renal disease, with the most recent data documenting high one-year success rates. However, patients continue to face significant morbidity and mortality after transplant, both from chronic allograft rejection and from the toxicities associated with standard immunosuppressive regimens. Given these dual risks, the ultimate goal in this field is the induction of immune tolerance after transplantation, which promises life-long acceptance of an allograft, without the need for ongoing immunosuppression and importantly, with preservation of protective immunity. While novel pharmacologic and antibody-based therapies represent real promise in terms of prolonging allograft survival and reducing off-target toxicities, murine studies strongly suggest that the most robust strategies for inducing immune tolerance incorporate cellular therapies, including both regulatory T cell-based approaches and mixed- chimerism induction (especially in combination with T cell costimulation blockade). Both of these therapies hold the promise of fundamentally resetting recipient immunity in favor of allograft acceptance, and thus providing a direct pathway towards immune tolerance for renal transplant recipients. In this proposal, we will investigate the tolerance-induction potential of both Treg- and Mixed-Chimerism-based cellular therapies through the following Aims: Aim 1: To engineer an optimally suppressive regulatory T cell product, able to provide allograft-specific immune tolerance after renal transplantation. Aim 2: To induce immune tolerance to a renal allograft through the induction of stable, multilineage mixed-hematopoietic chimerism with preservation of protective immunity in the setting of T cell costimulation blockade. The deliverables for this Project include the development of two highly promising tolerance-induction strategies for clinical translation, which, if successful, could change clinical practice in renal transplantation.