2014
DOI: 10.1016/j.stem.2013.11.014
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An Effective Approach to Prevent Immune Rejection of Human ESC-Derived Allografts

Abstract: Summary 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 knock-in hESCs that constitutively express CTLA4-Ig and PD-L1 before and after differentiation, … Show more

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Cited by 223 publications
(208 citation statements)
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References 44 publications
(60 reference statements)
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“…hiPSC-derived β cells from T1D patients can serve as an autologous source for cell replacement therapy that would obviate the need for systemic immune suppression (16); however, these cells are not protected from autoimmune destruction in T1D patients, and likely would still need to be implanted within an encapsulation device. Recent studies suggest that gene editing strategies can be used to generate hPSCs that are invisible to the immune system and could escape at least allogenic rejection (177). Similar strategies could perhaps also allow the cells to evade autoimmune destruction.…”
Section: Challenges For Therapeutic Implementationmentioning
confidence: 99%
“…hiPSC-derived β cells from T1D patients can serve as an autologous source for cell replacement therapy that would obviate the need for systemic immune suppression (16); however, these cells are not protected from autoimmune destruction in T1D patients, and likely would still need to be implanted within an encapsulation device. Recent studies suggest that gene editing strategies can be used to generate hPSCs that are invisible to the immune system and could escape at least allogenic rejection (177). Similar strategies could perhaps also allow the cells to evade autoimmune destruction.…”
Section: Challenges For Therapeutic Implementationmentioning
confidence: 99%
“…In another strategy, Rong et al produced knock-in hESCs that constitutively expressed immunosuppressive molecules such as cytotoxic T lymphocyte antigen 4-immunoglobulin fusion protein (CTLA4-Ig) and programmed death ligand-1. They reported immune-protection of these allogeneic cells in humanized mice (29).…”
Section: Human Embryonic Stem Cell-derived B Cellsmentioning
confidence: 99%
“…Drawbacks, however, include activation of the complement and coagulation system (IBMIR), surgical side effects such as intraabdominal hemorrhage and portal vein thrombosis, and lack of a safe way to detect early graft rejection. BM (29) and the striated muscle, brachioradialis, (30) are alternative sites that have been tested successfully in human trials.…”
Section: Sites Of Transplantationmentioning
confidence: 99%
“…They have genetically modified hESCs by "knocking-in" genes for ligands for two potent inhibitory receptors expressed by T lymphocytes (CTLA4 and PD-1). A humanized mouse, with a functional human immune system that could mount allogeneic immune rejection of hESC-derived cells, was used to demonstrate the tolerance of the CTLA4 Ig/PD-L1 engineered cells, in contrast to unmodified cells that were rapidly rejected [20]. One potential risk of this approach is that it would allow an hESC-derived graft that developed tumorigenic potential to escape immune surveillance.…”
Section: Novel Stem Cell-based Approaches To Induce Tolerance To Stemmentioning
confidence: 99%