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调理方案，我们现在已经通过混合嵌合方法成功地在HLA不匹配的人类肾移植受者中实现了肾脏同种异体移植耐受。然而，这种方法的局限性在于它不适用于已故供体移植，并且不能诱导非肾器官/细胞的耐受性。为了将这种方法扩展到已故供体移植，我们最近开发了一种“延迟耐受”诱导的新策略，其中肾移植首先采用传统的免疫抑制，然后进行调节和稍后的供体骨髓移植。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，包括更高的同种反应记忆T细胞（Tmem）和炎症反应。为了开发一种持续可靠的调理方案，用于临床应用于已故供体肾受者，有必要确定其他方式，以有效减轻炎症和Tmem反应，而不增加受者的发病率。因此，该项目的目的1和2旨在评估新型抗炎药物（抗il6r单抗和α 1抗胰蛋白酶）和克服Tmem反应（共刺激阻断和B细胞耗竭）的策略。该项目的目标还包括将我们的方法扩展到肾脏以外的器官/细胞移植的适用性。这似乎可以通过肾脏与较少耐受性器官/细胞共同移植的新策略实现。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/细胞的耐受性方面起着关键作用。因此，本研究的目的3旨在通过胰岛和肾脏共移植诱导同种异体胰岛移植耐受。而项目2将研究活体供体移植中胰岛异体移植物的耐受性。项目1将开发在死亡供体移植中诱导胰岛异体移植物耐受的策略。由于胰岛对炎症和Tmem反应特别敏感，我们将在Aims 1和2中确定新的模式纳入诱导胰岛异体移植物耐受的调节方案。最后，（短暂）混合嵌合和肾异体移植物诱导胰岛异体移植物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.