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。基于我们实验室几十年来对非人灵长类动物(NHP)的研究开发的预适应方案，我们现在已经通过混合嵌合体方法成功地实现了人类白细胞抗原不相合的人肾移植受者的移植耐受。然而，这种方法的局限性在于它不适用于已故供者移植，并且不能诱导非肾器官/细胞的耐受。为了将这一方法扩展到已故供者移植，我们最近开发了一种新的“延迟耐受”诱导策略，即首先在常规免疫抑制的情况下进行肾移植，然后在晚些时候进行调理和供体骨髓移植。在我们的初步NHP研究中，已经确定了使用这种新方法诱导一致耐受的几个障碍，包括较高的同种异体记忆T细胞(TMEM)和炎症反应。为了开发一种稳定可靠的预适应方案用于临床应用于已故的供体肾移植受者，有必要确定其他方法来有效地减轻炎症和TMEM反应，而不增加受者的发病率。因此，该项目的目标1和2旨在评估新的抗炎药(抗IL6R单抗和α1抗胰蛋白酶)和克服TMEM反应(共刺激阻断和B细胞耗尽)的策略。该项目的目标还包括扩大我们的方法在肾脏以外的器官/细胞移植方面的适用性。这似乎是通过将肾脏与耐受性较差的器官/细胞进行联合移植的新策略来实现的。我们的研究表明，同种异体肾移植在诱导和维持联合移植器官/细胞的耐受中起着关键作用。因此，本研究的目的3旨在通过胰岛和肾脏的联合移植来诱导同种异体胰岛移植耐受。而项目2将在活体供者移植中追求同种异体胰岛移植的耐受性。项目1将开发在已故供者移植中诱导同种异体胰岛移植耐受的策略。由于胰岛对炎症和TMEM反应特别敏感，我们将把AIMS 1和2中确定的新模式纳入诱导胰岛同种异体移植耐受的预适应方案。最后，(短暂的)混合嵌合体和肾移植诱导同种异体胰岛移植耐受的机制，将与项目3合作进行充分的研究。

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.