Cellular Strategies for Tolerance Induction

摘要： 肾移植是终末期肾病患者的一线治疗方法， 最近的数据显示，一年的成功率很高。然而，患者继续面临严重的发病率。 以及移植后的死亡率，包括慢性同种异体移植排斥反应和与 标准的免疫抑制方案。鉴于这些双重风险，这一领域的最终目标是诱导 移植后的免疫耐受，承诺终身接受同种异体移植物，而不需要 用于持续的免疫抑制，更重要的是，保护免疫。虽然很新奇 药物和基于抗体的治疗在延长同种异体移植物存活方面是真正有希望的。 和减少脱靶毒性，小鼠研究强烈表明，最有力的策略是诱导 免疫耐受结合了细胞疗法，包括基于调节性T细胞的方法和混合T细胞疗法。 嵌合体诱导(特别是联合T细胞共刺激阻断)。这两种疗法 承诺从根本上重新设置受体免疫，支持同种异体移植的接受，因此 为肾移植受者提供了一条获得免疫耐受的直接途径。在这项提案中，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 通过以下目标：目标1：设计一种最佳抑制调节性T细胞产品，能够 提供肾移植后同种异体移植物特异性免疫耐受。目标2：诱导免疫耐受 通过诱导稳定的多系混合造血嵌合体进行保存的同种异体肾移植 在T细胞共刺激阻断的背景下的保护性免疫。该项目的可交付成果包括 两种非常有希望的临床翻译耐受诱导策略的开发，如果 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.