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Immunogenicity of autologous and allogeneic human primary cholangiocyte organoids

ABSTRACT: Primary human cells cultured in 3D organoid format have great promise as potential regenerative cellular therapies, but their immunogenicity has not yet been fully characterized. In this study, we use in vitro co-cultures and in vivo humanized mouse experimental models to examine the human immune response to autologous and allogeneic primary cholangiocyte organoids (PCOs). Our data demonstrate that PCOs upregulate the expression of HLA-I and HLA-II in inflammatory conditions. The immune response to allogeneic PCOs is driven by both HLA-I and HLA-II and is substantially ameliorated by donor-recipient HLA matching. Autologous PCOs induce a low-level immune infiltration into the graft site, while allogeneic cells display evolving stages of immune rejection in vivo. Our findings have important implications for the design and clinical translation of autologous and allogeneic organoid cellular therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE253679 | GEO | 2024/01/20

REPOSITORIES: GEO

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Project description:Dozens of transplants generated from pluripotent stem cells are currently in clinical trials. The creation of patient-specific iPSCs makes personalized therapy possible due to their main advantage of immunotolerance. However, some reports have claimed recently that aberrant gene expression followed by proteome alterations and neoantigen formation can result in iPSCs recognition by autologous T-cells. Meanwhile, the possibility of NK-cell activation has not been previously considered. This study focused on the comparison of autologous and allogeneic immune response to iPSC-derived cells and isogeneic parental somatic cells used for reprogramming. Here we report that cells differentiated from iPSCs can be recognized by NK-cells rather than by autologous T-cells. We observed that iPS-fibro elicited a high level of NK-cell degranulation and cytotoxicity, while isogeneic parental skin fibroblasts used to obtain iPSCs barely triggered an NK-cell response. iPSC-derivatives with B2M knockout did not cause an additional increase in NK-cell activation, although they were devoid of HLA-I, the major inhibitory molecules for NK-cells. Transcriptome analysis revealed a significant imbalance of ligands for activating and inhibitory NK-cell receptors in iPS-fibro. Compared to parental fibroblasts, iPSC-derivatives had a reduced expression of HLA-I simultaneously with an increased gene expression of major activating ligands, such as MICA, NECTIN2, and PVR. The lack of inhibitory signals might be due to insufficient maturity of cells differentiated from iPSCs. In addition, we showed that pretreatment of iPS-fibro with proinflammatory cytokine IFNγ restored the ligand imbalance, thereby reducing the degranulation and cytotoxicity of NK-cells. In summary, we showed that iPSC-derived cells can be sensitive to the cytotoxic potential of autologous NK-cells regardless of HLA-I status. Thus, the balance of ligands for NK-cell receptors should be considered prior to iPSC-based cell therapies.

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Immunogenicity of autologous and allogeneic human primary cholangiocyte organoids

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