诱导人干细胞移植及其分化后代的耐受。

Tolerance induction to human stem cell transplants with extension to their differentiated progeny.

机构信息

1] Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK [2] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA [3] Department of Chemical Pathology; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China.

Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.

出版信息

Nat Commun. 2014 Dec 1;5:5629. doi: 10.1038/ncomms6629.

DOI:10.1038/ncomms6629

PMID:25434740

Abstract

There is increasing interest in transplantation of human stem cells for therapeutic purposes. It would benefit future application if one could achieve their long-term acceptance and functional differentiation in allogeneic hosts using minimal immunosuppression. Allogeneic stem cell transplants differ from conventional tissue transplants insofar as not all alloantigens are revealed during tolerance induction. This risks that the immune system tolerized to antigens expressed by progenitors may still remain responsive to antigens expressed later during differentiation. Here we show that brief induction with monoclonal antibody-mediated coreceptor and costimulation blockade enables long-term engraftment and tolerance towards murine ESCs, hESCs, human induced pluripotent stem cells (iPSCs) and hESC-derived progenitors in outbred murine recipients. Tolerance induced to PSC-derived progenitors extends to their differentiated progenies, and sometimes even to different tissues derived from the same donor. Global gene expression profiling identifies clear features in T cells from tolerized grafts that are distinct from those involved in rejection.

摘要

人们对人类干细胞移植用于治疗目的越来越感兴趣。如果能够在使用最小免疫抑制的情况下，使异体宿主长期接受和功能性分化人类干细胞，将有益于未来的应用。与传统的组织移植不同，同种异体干细胞移植并非所有同种异体抗原在诱导耐受时都能被揭示。这意味着免疫系统对祖细胞表达的抗原产生耐受，仍可能对分化过程中后期表达的抗原产生反应。在这里，我们表明，通过单克隆抗体介导的共受体和共刺激阻断的短暂诱导，能够在外来小鼠受体中实现对鼠胚胎干细胞、人胚胎干细胞、人诱导多能干细胞和人胚胎干细胞衍生祖细胞的长期植入和耐受。对 PSC 衍生祖细胞的诱导可扩展到其分化后代，有时甚至可扩展到来自同一供体的不同组织。全基因表达谱分析确定了来自耐受移植物的 T 细胞的明显特征，这些特征与参与排斥反应的特征不同。