Generation of hypoimmunogenic human pluripotent stem cells

被引：234

作者：

Han, Xiao ^{[1
,2
]}

Wang, Mengning ^{[1
,2
]}

Duan, Songwei ^{[1
,2
]}

Franco, Paul J. ^{[1
,2
]}

Kenty, Jennifer Hyoje-Ryu ^{[1
,2
]}

Hedrick, Preston ^{[1
,2
]}

Xia, Yulei ^{[1
,2
]}

Allen, Alana ^{[1
,2
]}

Ferreira, Leonardo M. R. ^{[1
,2
,3
]}

Strominger, Jack L. ^{[1
,2
]}

Melton, Douglas A. ^{[1
,2
]}

Meissner, Torsten B. ^{[1
,2
,4
,5
]}

Cowan, Chad A. ^{[1
,2
,4
,5
,6
]}

机构：

[1] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA

[2] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA

[3] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA

[4] Beth Israel Deaconess Med Ctr, Div Cardiovasc Med, Boston, MA 02115 USA

[5] Harvard Med Sch, Dept Med, Boston, MA 02115 USA

[6] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2019年 / 116卷 / 21期

关键词：

HLA allobarrier; NK cells; macrophages; cell therapy; stem cell engineering; HLA-E; HEMATOPOIETIC STEM; IMMUNE-SYSTEM; REJECTION; EXPRESSION; IMMUNOGENICITY; DISRUPTION; RESPONSES; BINDING; LYSIS;

D O I：

10.1073/pnas.1902566116

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Polymorphic HLAs form the primary immune barrier to cell therapy. In addition, innate immune surveillance impacts cell engraftment, yet a strategy to control both, adaptive and innate immunity, is lacking. Here we employed multiplex genome editing to specifically ablate the expression of the highly polymorphic HLA-A/-B/-C and HLA class II in human pluripotent stem cells. Furthermore, to prevent innate immune rejection and further suppress adaptive immune responses, we expressed the immunomodulatory factors PD-L1, HLA-G, and the macrophage "don't-eat me" signal CD47 from the AAVS1 safe harbor locus. Utilizing in vitro and in vivo immunoassays, we found that T cell responses were blunted. Moreover, NK cell killing and macrophage engulfment of our engineered cells were minimal. Our results describe an approach that effectively targets adaptive as well as innate immune responses and may therefore enable cell therapy on a broader scale.

引用

页码：10441 / 10446

页数：6

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