Pathak Shiva, Meyer Everett H
Division of Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA, United States.
Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, United States.
Front Immunol. 2021 Jan 29;11:612737. doi: 10.3389/fimmu.2020.612737. eCollection 2020.
Pancreatic islet transplantation is a promising method for the treatment of type 1 and type 3 diabetes whereby replacement of islets may be curative. However, long-term treatment with immunosuppressive drugs (ISDs) remains essential for islet graft survival. Current ISD regimens carry significant side-effects for transplant recipients, and are also toxic to the transplanted islets. Pre-clinical efforts to induce immune tolerance to islet allografts identify ways in which the recipient immune system may be reeducated to induce a sustained transplant tolerance and even overcome autoimmune islet destruction. The goal of these efforts is to induce tolerance to transplanted islets with minimal to no long-term immunosuppression. Two most promising cell-based therapeutic strategies for inducing immune tolerance include T regulatory cells (T) and donor and recipient hematopoietic mixed chimerism. Here, we review preclinical studies which utilize T for tolerance induction in islet transplantation. We also review myeloablative and non-myeloablative hematopoietic stem cell transplantation (HSCT) strategies in preclinical and clinical studies to induce sustained mixed chimerism and allograft tolerance, in particular in islet transplantation. Since T play a critical role in the establishment of mixed chimerism, it follows that the combination of T and HSCT may be synergistic. Since the success of the Edmonton protocol, the feasibility of clinical islet transplantation has been established and nascent clinical trials testing immune tolerance strategies using T and/or hematopoietic mixed chimerism are underway or being formulated.
胰岛移植是治疗1型和3型糖尿病的一种有前景的方法，通过移植胰岛可能实现治愈。然而，长期使用免疫抑制药物（ISDs）对于胰岛移植的存活仍然至关重要。目前的ISD方案对移植受者有显著的副作用，并且对移植的胰岛也有毒性。临床前诱导对胰岛同种异体移植免疫耐受的努力旨在寻找重新教育受者免疫系统以诱导持续移植耐受甚至克服自身免疫性胰岛破坏的方法。这些努力的目标是以最小化或无长期免疫抑制来诱导对移植胰岛的耐受。两种最有前景的基于细胞的诱导免疫耐受的治疗策略包括调节性T细胞（Treg）和供体与受体造血混合嵌合体。在此，我们综述利用Treg在胰岛移植中诱导耐受的临床前研究。我们还综述在临床前和临床研究中用于诱导持续混合嵌合体和同种异体移植耐受的清髓性和非清髓性造血干细胞移植（HSCT）策略，特别是在胰岛移植中。由于Treg在混合嵌合体的建立中起关键作用，因此Treg与HSCT的联合可能具有协同作用。自埃德蒙顿方案成功以来，临床胰岛移植的可行性已得到确立，并且正在进行或正在制定使用Treg和/或造血混合嵌合体测试免疫耐受策略的初期临床试验。
