Tolerance of Kidney and Islet Transplants via the Mixed Chimerism Approach

诱导特异性免疫耐受是器官移植的最终目标。基于我们实验室在非人灵长类动物（NHP）中长达数十年的研究开发的预处理方案，我们现在已经成功地通过混合嵌合体方法在HLA不匹配的人肾移植受者中实现了肾移植耐受。然而，这种方法的局限性在于其不适用于死亡供体移植，并且不能诱导非肾器官/细胞的耐受。为了将这种方法扩展到死亡供体移植，我们最近开发了一种新的策略“延迟耐受”诱导，首先进行肾移植，然后进行预处理和供体骨髓移植。在我们初步的NHP研究中，已经确定了使用这种新方法诱导一致耐受性的几个障碍，包括更高的同种异体反应性记忆T细胞（T细胞）和炎症反应。为了开发一致可靠的预处理方案用于已故供体肾接受者的临床应用，必须确定其他方式来有效减轻炎症和炎症反应，而不增加接受者的发病率。因此，本项目的目的1和2旨在评价新型抗炎药（抗IL 6 R mAb和α 1抗胰蛋白酶）和克服Tcl 3应答的策略（共刺激阻断和B细胞耗竭）。该项目的目标还包括将我们的方法的适用性扩展到肾脏以外的器官/细胞移植。这似乎可以通过肾脏与致耐受性较低的器官/细胞共移植的新策略来实现。我们的研究表明，同种异体肾移植在诱导和维持共移植器官/细胞耐受中起着关键作用。因此，本研究的目的3是通过胰岛和肾脏的共移植来诱导胰岛移植耐受。而项目2将在活体供体移植中追求胰岛同种异体移植耐受性。项目1将开发在死亡供体移植中诱导胰岛移植耐受的策略。由于胰岛对炎症和Tissue反应特别敏感，我们将在目的1和2中确定的新方法纳入诱导胰岛同种异体移植耐受的预处理方案。最后，（短暂）混合嵌合体和肾移植诱导胰岛移植耐受的机制将与项目3合作进行全面研究。

Induction of specific immunologic tolerance is an ultimate goal of organ transplantation. Based on the conditioning regimen developed in our laboratory by decades-long research in nonhuman primates (NHP), we have now successfully achieved renal allograft tolerance in HLA mismatched human kidney transplant recipients via the mixed chimerism approach. However, limitations of this approach have been its inapplicability for deceased donor transplantation and the inability to induce tolerance of non-renal organs/cells. To extend this approach to deceased donor transplantation, we recently developed a novel strategy of "delayed tolerance" induction, where kidney transplantation is performed first with conventional immunosuppression, followed by conditioning and donor bone marrow transplantation at a later date. In our preliminary NHP investigations, several barriers to consistent tolerance induction with this novel approach have been identified including higher alloreactive memory T cells (Tmem) and inflammatory responses. In order to develop a consistently reliable conditioning regimen for clinical application to deceased donor kidney recipients, it is essential to identify additional modalities to effectively mitigate inflammatory and Tmem responses without increasing morbidity in the recipients. Aims 1 and 2 of this project are, therefore, designed to evaluate novel anti-inflammatory agents (anti-IL6R mAb and alpha1 antitrypsin) and strategies to overcome Tmem responses (costimulatory blockade and B cell depletion). This Project's goals also include extension of the applicability of our approach to organ/cell transplantation other than the kidney. This appears to be possible via the novel strategy of co-transplantation of the kidney with less tolerogenic organs/cells. Our studies have shown that the kidney allograft plays a critical role for induction and maintenance of tolerance of the co-transplanted organ/cells. Aim 3 of the current study is thus designed to induce islet allograft tolerance by co-transplantation of islets and the kidney. While Project 2 will pursue islets allograft tolerance in living donor transplantation. Project 1 will develop the strategy to induce islet allograft tolerance in deceased donor transplantation. Since islets are especially susceptible to inflammatory and Tmem responses, we will incorporate novel modalities to be identified in Aims 1 and 2 into the conditioning regimen for induction of islet allograft tolerance. Finally, mechanisms by which (transient) mixed chimerism and the renal allograft induce islet allograft tolerance, will be fully investigated in collaboration with Project 3.