HLA-Matched Allogeneic iPS Cells-Derived RPE Transplantation for Macular Degeneration.

Sunao Sugita,Kyoko Iseki,Satoshi Sugiyama,Naoshi Koide,Noriko Sakai,Masaki Nomura,Mitsuhiro Matsuzaki,Hirokazu Sakaguchi,Naoki Amano,Misato Tozaki,Michiko Mandai,Masataka Igeta,Kohji Nishida,Mitsuhiro Nishida,Masashi Fujihara,Yasuhiko Hirami,Hiromi Dohi,Tadao Maeda,Midori Yamamoto,Ayumi Hono,Utako Shirono,Naoko Hayashi,Seiji Takagi,Chikako Hara,Masayo Takahashi,Yasuo Kurimoto,Shoko Fujino,Takashi Daimon,Kota Totani,Kouichi Maruyama ,Makoto Terada ,Yu Shibata ,Toshikane Oda

doi:10.3390/jcm9072217

Abstract

Immune attacks are key issues for cell transplantation. To assess the safety and the immune reactions after iPS cells-derived retinal pigment epithelium (iPS-RPE) transplantation, we transplanted HLA homozygote iPS-RPE cells established at an iPS bank in HLA-matched patients with exudative age-related macular degeneration. In addition, local steroids without immunosuppressive medications were administered. We monitored immune rejections by routine ocular examinations as well as by lymphocytes-graft cells immune reaction (LGIR) tests using graft RPE and the patient’s blood cells. In all five of the cases that underwent iPS-RPE transplantation, the presence of graft cells was indicated by clumps or an area of increased pigmentation at 6 months, which became stable with no further abnormal growth in the graft during the 1-year observation period. Adverse events observed included corneal erosion, epiretinal membrane, retinal edema due to epiretinal membrane, elevated intraocular pressure, endophthalmitis, and mild immune rejection in the eye. In the one case exhibiting positive LGIR tests along with a slight fluid recurrence, we administrated local steroid therapy that subsequently resolved the suspected immune attacks. Although the cell delivery strategy must be further optimized, the present results suggest that it is possible to achieve stable survival and safety of iPS-RPE cell transplantation for a year.

Highlights

Immune cells are capable of discriminating between self and non-self cells by recognizing major histocompatibility complex (MHC) antigens that are expressed on the cell surface
We experimentally demonstrated that immune responses could be avoided when retinal pigment epithelial (RPE) cells generated from iPS cells derived from an MHC homozygous donor were transplanted to a recipient with matched MHC [1,2,3]
Using RPE cells derived from MHC homozygote monkey iPS cells, we developed an in vivo experimental method that could be used to test the immune-response in primates [1,3]

Summary

Introduction

Immune cells are capable of discriminating between self and non-self cells by recognizing major histocompatibility complex (MHC) antigens that are expressed on the cell surface. When immune cells encounter MHC molecules they do not recognize, an immune response is triggered in order to get to rid the body of the foreign entity This mechanism is important for protecting against antigens from pathogens, it can be a hindrance when performing cell transplantations from one individual to another. We established an in vitro evaluation protocol to test the graft immunogenicity by co-culturing human iPS-RPE graft cells with human immune cells including T cells from the recipients [2]. Results from these preclinical studies showed that MHC (HLA)-class II molecules, as well as class I, were critical for the mechanisms of RPE cells-related immune rejections after transplantation. RPE cells constitutively express MHC class I, and inducibly express MHC class II during the stress of inflammation (e.g., rejection) [1,2], making these cells potential targets for T lymphocytes

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