Morelli Adrian E, Larregina Adriana T
T.E. Starzl Transplantation Institute, Department of Surgery.
Departments of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213, USA.
Stem Cells. 2016 May;34(5):1142-50. doi: 10.1002/stem.2326. Epub 2016 Feb 29.
The main limitations to the success of transplantation are the antigraft response developed by the recipient immune system, and the adverse side effects of chronic immunosuppression. Graft-versus-host disease (GVHD) triggered by donor-derived T lymphocytes against the recipient tissues is another serious obstacle in the field of hematopoietic stem cell transplantation. Several laboratories have tested the possibility of promoting antigen (Ag)-specific tolerance for therapy of graft rejection, GVHD, and autoimmune disorders, by developing methodologies that mimic the mechanisms by which the immune system maintains peripheral tolerance in the steady state. It has been long recognized that the silent clearance of cells undergoing apoptosis exerts potent immune-regulatory effects and provides apoptotic cell-derived Ags to those Ag-presenting cells (APCs) that internalize them, in particular macrophages and dendritic cells. Therefore, in situ-targeting of recipient APCs by systemic administration of leukocytes in early apoptosis and bearing donor Ags represents a relatively simple approach to control the antidonor response against allografts. Here, we review the mechanisms by which apoptotic cells are silently cleared by phagocytes, and how such phenomenon leads to down-regulation of the innate and adaptive immunity. We discuss the evolution of apoptotic cell-based therapies from murine models of organ/tissue transplantation and GVHD, to clinical trials. We make emphasis on potential limitations and areas of concern of apoptotic cell-based therapies, and on how other immune-suppressive therapies used in the clinics or tested experimentally likely also function through the silent clearance of apoptotic cells by the immune system. Stem Cells 2016;34:1142-1150.
移植成功的主要限制因素是受者免疫系统产生的抗移植反应以及慢性免疫抑制的不良副作用。供体来源的T淋巴细胞引发的移植物抗宿主病（GVHD）是造血干细胞移植领域的另一个严重障碍。几个实验室通过开发模拟免疫系统在稳态下维持外周耐受机制的方法，测试了促进抗原（Ag）特异性耐受以治疗移植排斥、GVHD和自身免疫性疾病的可能性。长期以来人们已经认识到，对正在经历凋亡的细胞进行沉默清除具有强大的免疫调节作用，并将凋亡细胞衍生的抗原提供给那些内化它们的抗原呈递细胞（APC），特别是巨噬细胞和树突状细胞。因此，通过全身给予处于早期凋亡状态且携带供体抗原的白细胞，原位靶向受者的APC，是一种控制针对同种异体移植物的抗供体反应的相对简单的方法。在这里，我们回顾了吞噬细胞对凋亡细胞进行沉默清除的机制，以及这种现象如何导致固有免疫和适应性免疫的下调。我们讨论了基于凋亡细胞的疗法从器官/组织移植和GVHD的小鼠模型到临床试验的发展过程。我们强调了基于凋亡细胞的疗法的潜在局限性和关注点，以及临床上使用或实验测试的其他免疫抑制疗法可能如何也通过免疫系统对凋亡细胞的沉默清除发挥作用。《干细胞》2016年；34卷：1142 - 1150页
