Genetic ablation of adhesion ligands averts rejection of allogeneic immune cells

Hammer, Quirin; Perica, Karlo; van Ooijen, Hanna; Mbofung, Rina; Momayyezi, Pouria; Varady, Erika; Martin, Karen E.; Pan, Yijia; Jelcic, Mark; Groff, Brian; Abujarour, Ramzey; Krokeide, Silje; Lee, Tom; Williams, Alan; Goodridge, Jode P.; Valamehr, Bahram; Önfelt, Björn; Sadelain, Michel; Malmberg, Karl-Johan

doi:10.1101/2023.10.09.557143

Cited by 3 publications

(1 citation statement)

References 53 publications

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“…CD47 has been reported to inhibit not only phagocytosis by macrophages but also NK cell-mediated lysis [ 8 , 14 ]. In addition to the add-on strategy, deleting ligands of active NK receptors works to prevent NK cell-mediated lysis [ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Hypoimmunogenic human iPSCs expressing HLA-G, PD-L1, and PD-L2 evade innate and adaptive immunity

Tsuneyoshi,

Hosoya,

Takeno

et al. 2024

Stem Cell Res Ther

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Background The human induced pluripotent stem cells (hiPSCs) can generate all the cells composing the human body, theoretically. Therefore, hiPSCs are thought to be a candidate source of stem cells for regenerative medicine. The major challenge of allogeneic hiPSC-derived cell products is their immunogenicity. The hypoimmunogenic cell strategy is allogenic cell therapy without using immune suppressants. Advances in gene engineering technology now permit the generation of hypoimmunogenic cells to avoid allogeneic immune rejection. In this study, we generated a hypoimmunogenic hiPSC (HyPSC) clone that had diminished expression of human leukocyte antigen (HLA) class Ia and class II and expressed immune checkpoint molecules and a safety switch. Methods First, we generated HLA class Ia and class II double knockout (HLA class Ia/II DKO) hiPSCs. Then, a HyPSC clone was generated by introducing exogenous β-2-microglobulin (B2M), HLA-G, PD-L1, and PD-L2 genes, and the Rapamycin-activated Caspase 9 (RapaCasp9)-based suicide gene as a safety switch into the HLA class Ia/II DKO hiPSCs. The characteristics and immunogenicity of the HyPSCs and their derivatives were analyzed. Results We found that the expression of HLA-G on the cell surface can be enhanced by introducing the exogenous HLA-G gene along with B2M gene into HLA class Ia/II DKO hiPSCs. The HyPSCs retained a normal karyotype and had the characteristics of pluripotent stem cells. Moreover, the HyPSCs could differentiate into cells of all three germ layer lineages including CD45+ hematopoietic progenitor cells (HPCs), functional endothelial cells, and hepatocytes. The HyPSCs-derived HPCs exhibited the ability to evade innate and adaptive immunity. Further, we demonstrated that RapaCasp9 could be used as a safety switch in vitro and in vivo. Conclusion The HLA class Ia/II DKO hiPSCs armed with HLA-G, PD-L1, PD-L2, and RapaCasp9 molecules are a potential source of stem cells for allogeneic transplantation.

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