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Sunao Sugita, Yuko Iwasaki, Kenichi Makabe, Hiroyuki Kamao, Michiko Mandai, Masayo Takahashi; Failure of T-cell immune attack on iPS cells-derived retinal pigment epithelial cells from HLA homozygous donors. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1845.
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© ARVO (1962-2015); The Authors (2016-present)
To determine whether human retinal pigment epithelial (RPE) cells derived from induced pluripotent stem (iPS) cells are recognized by T cells in MHC restriction.
After obtaining informed consent, fresh skin tissues or dental pulp cells were collected from healthy donors (HLA-A, B, DRB1 locus homozygote) and used to establish the iPS-derived RPE (iPS-RPE) target cells. We also prepared allogeneic T cells (CD4 or CD8) as responder cells from healthy volunteers. T-cell recognition was evaluated by the proliferation (CFSE flow cytometry) and cytokine assays (IFN-g or granzyme B ELISA). Monkey iPS-RPE cells from MHC homozygote iPS cells were used for the in vivo animal model. In addition, we transplanted iPS-RPE cells into monkey eyes in MHC matched or mismatched heterozygote donors (cynomolgus monkeys w/o immunosuppression). The graft was monitored by color fundus pictures, fluorescein angiography (FA) and optical coherence tomography (OCT) at 1, 2, 4, 8, and 12 weeks, and at 6 months after surgery.
The in vitro human assay showed T lymphocytes directly recognized HLA molecules on allogeneic iPS-RPE cells that express HLA antigens. However, these T cells from HLA-matched donors failed to induce an immune response to iPS-derived RPE cells from HLA homozygous donors in vitro. Moreover, we observed no rejection signs in the allografts of the MHC matched monkeys, e.g., fundus photographs revealed no rejection, FA showed no vascular leakage of fluorescein, and OCT indicated there was no retinal edema around the transplanted RPE cells. In contrast, FA revealed hyperfluorescence, while OCT indicated there was retinal edema, serous retinal detachment, and disappearance of the outer retinal layers around the graft in MHC mismatched monkeys.
As T cells cannot recognize HLA homozygote RPE cells in MHC restriction, their derivatives from HLA homozygous donors may be useful in treating retinal diseases in histocompatible recipients.
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