title: An effective approach to prevent immune rejection of human ESC-derived allografts.
abstract: Human embryonic stem cells (hESCs) hold great promise for cell therapy as a source of diverse differentiated cell types. One key bottleneck to realizing such potential is allogenic immune rejection of hESC-derived cells by recipients. Here, we optimized humanized mice (Hu-mice) reconstituted with a functional human immune system that mounts a vigorous rejection of hESCs and their derivatives. We established knockin hESCs that constitutively express CTLA4-Ig and PD-L1 before and after differentiation, denoted CP hESCs. We then demonstrated that allogenic CP hESC-derived teratomas, fibroblasts, and cardiomyocytes are immune protected in Hu-mice, while cells derived from parental hESCs are effectively rejected. Expression of both CTLA4-Ig, which disrupts T cell costimulatory pathways, and PD-L1, which activates T cell inhibitory pathway, is required to confer immune protection, as neither was sufficient on their own. These findings are instrumental for developing a strategy to protect hESC-derived cells from allogenic immune responses without requiring systemic immune suppression.
authors.affiliation: Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA.
authors.forename: Zhili
authors.initials: Z
authors.lastname: Rong
authors.affiliation: Shenzhen Children's Hospital, Shenzhen, Guangdong 518026, China; Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA.
authors.forename: Meiyan
authors.initials: M
authors.lastname: Wang
authors.affiliation: First Hospital of Jilin University, Changchun, Jilin 130021, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Stradner
authors.affiliation: Shenzhen Children's Hospital, Shenzhen, Guangdong 518026, China; Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA.
authors.forename: Shengyun
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA.
authors.forename: Huijuan
authors.initials: H
authors.lastname: Kong
authors.affiliation: First Hospital of Jilin University, Changchun, Jilin 130021, China.
authors.forename: Huanfa
authors.initials: H
authors.lastname: Yi
authors.affiliation: Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA.
authors.forename: Ananda
authors.initials: A
authors.lastname: Goldrath
authors.affiliation: First Hospital of Jilin University, Changchun, Jilin 130021, China; Columbia Center for Translational Immunology, Columbia University Medical School, New York, NY 10032, USA.
authors.forename: Yong-Guang
authors.initials: YG
authors.lastname: Yang
authors.affiliation: Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA. Electronic address: yangxu@ucsd.edu.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Shenzhen Children's Hospital, Shenzhen, Guangdong 518026, China; Children's Hospital, Chongqing Medical University, Chongqing 400016, China. Electronic address: fxmzj2004@163.com.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Fu
mesh_terms: D000069594:Abatacept; D000818:Animals; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000032:analysis; D015153:Blotting, Western; D002454:Cell Differentiation; D049109:Cell Proliferation; D064987:Cell- and Tissue-Based Therapy; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D005333:Fetus / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D018796:Immunoconjugates / Q000235:genetics / Q000378:metabolism; D007165:Immunosuppression Therapy; D008099:Liver / Q000166:cytology / Q000378:metabolism; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013724:Teratoma / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D014184:Transplantation, Homologous
chemical_list: D060890:B7-H1 Antigen; D015415:Biomarkers; C498919:Cd274 protein, mouse; D018796:Immunoconjugates; D012333:RNA, Messenger; D000069594:Abatacept