Alloantigen gene transfer to hepatocytes promotes tolerance to pancreatic islet graft by inducing CD8+ regulatory T cells
Alloantigen gene transfer to hepatocytes promotes tolerance to pancreatic islet graft by inducing CD8+ regulatory T cells
复制标题
DOI：
10.1016/j.jhep.2016.11.019
复制
发表时间：
2017-04-01
影响因子：
25.7
通讯作者：
Conchon, Sophie
中科院分区：
文献类型：
--
作者：
Le Guen, Valentin;Judor, Jean-Paul;Conchon, Sophie
背景与目的：诱导供体特异性免疫耐受是移植患者替代慢性终身免疫抑制的良好选择。供体主要组织相容性复合体（MHC）分子是移植受者异体免疫反应的主要靶点。肝靶向基因转移与病毒载体诱导对编码抗原耐受。这项工作的目的是确定同种异体抗原基因转移到肝细胞是否诱导耐受性和促进移植物接受。方法：在BALB/c小鼠（H-2d）的完全异体胰岛移植前，用靶向MHC I类分子H-2K(d)的腺相关病毒（AAV）载体治疗C57BL/6 （H-2b）小鼠。结果：AAV H-2K(d)处理的小鼠对同种异体抗原具有耐受性，即使在腺病毒载体的高度免疫原性攻击后，其在肝细胞中的长期表达也证明了这一点。化学诱导糖尿病后，AAV处理的小鼠对完全异体胰岛移植的排斥反应明显延迟，超过40%的受体耐受（100天）。aav介导的H-2Kd在肝脏中的表达诱导CD8(+) T淋巴细胞的局部扩张，具有同种异体特异性抑制特性。将这些肝脏生成的CD8(+) Tregs过继移植到幼年糖尿病小鼠体内，可促进同种异体胰岛移植物的长期存活。结论：aav介导的肝脏中单个MHC I类分子的长期表达可诱导异体特异性CD8(+) Treg细胞亚群的产生，促进对完全异体移植物的耐受。肝脏基因转移是体内诱导供体特异性耐受的一种很有前途的策略。总结：肝脏有一个特殊的免疫系统，偏向于耐受性。在这项研究中，我们研究了利用肝脏的这一特性诱导对同种异体移植的耐受的可能性。我们首次证明了异体抗原与腺相关病毒载体的体内基因转移到小鼠肝细胞诱导CD8（+）调节性T淋巴细胞群的扩增。这些treg在防止移植到这些动物体内的异体胰岛的排斥反应中起着重要作用。同种异体移植是许多器官终末期疾病的主要治疗方法。终身免疫抑制治疗仍然需要限制移植排斥，这些治疗表现出严重的副作用。我们目前的研究结果为通过体内诱导CD8(+) Treg扩增促进异体特异性耐受性开辟了新的途径。(C) 2016欧洲肝脏研究协会。Elsevier b.v.版权所有。
Background & Aims: Induction of donor-specific immune tolerance is a good alternative to chronic life-long immunosuppression for transplant patients. Donor major histocompatibility complex (MHC) molecules represent the main targets of the allogeneic immune response of transplant recipients. Liver targeted gene transfer with viral vectors induces tolerance toward the encoded antigen. The aim of this work was to determine whether alloantigen gene transfer to hepatocytes induces tolerance and promotes graft acceptance.Methods: C57BL/6 (H-2b) mice were treated with adeno-associated viral (AAV) vector targeting the expression of the MHC class I molecule H-2K(d) to hepatocytes, before transplantation with fully allogeneic pancreatic islet from BALB/c mice (H-2d).Results: AAV H-2K(d) treated mice were tolerant to the alloantigen, as demonstrated by its long-term expression by the hepatocytes, even after a highly immunogenic challenge with an adenoviral vector. After chemical induction of diabetes, the AAV treated mice had significantly delayed rejection of fully allogeneic pancreatic islet grafts, with more than 40% of recipients tolerant (>100 days). AAV-mediated expression of H-2Kd in the liver induced the local expansion of CD8(+) T lymphocytes with allospecific suppressive properties. The adoptive transfer of these liver-generated CD8(+) Tregs into naive diabetic mice promoted the long-term survival of allogeneic pancreatic islet grafts.Conclusion: AAV-mediated long-term expression of a single MHC class I molecule in the liver induces the generation of a subset of allo-specific CD8(+) Treg cells, which promote tolerance toward fully allogeneic graft. Liver gene transfer represents a promising strategy for in vivo induction of donor-specific tolerance.Lay summary: The liver has a special immune system, biased toward tolerance. In this study, we investigated the possibility of harnessing this property of the liver to induce tolerance to an allogeneic transplantation.We demonstrate for the first time that the in vivo gene transfer of an allogeneic antigen with an adeno-associated viral vector to mouse hepatocytes induces the expansion of a population of CD8(+) regulatory T lymphocytes. These Tregs are then instrumental in preventing the rejection of allogeneic pancreatic islets transplanted in these animals.Allogeneic transplantation is the main treatment for the end-stage diseases of a number of organs. Life-long immunosuppressive treatments are still required to limit graft rejection, and these treatments exhibit serious side effects. Our present findings open a new avenue for promoting allo-specific tolerance via in vivo induction of CD8(+) Treg expansion. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B. V. All rights reserved.