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缺乏MHC II类分子的视网膜色素上皮条带的同种异体移植可避免非人灵长类动物眼睛发生排斥反应。

Allogenic Transplantation of RPE Strips Lacking MHC Class II Can Avoid Rejection in Nonhuman Primate Eyes.

作者信息

Ozaki Atsuta, Sugita Sunao, Ishida Masaaki, Nishida Mitsuhiro, Iseki Kyoko, Sakai Noriko, Hayashi Naoko, Shiina Takashi, Yokota Satoshi, Ito Shin-Ichiro, Fujihara Masashi, Kondo Mineo, Takahashi Masayo, Kurimoto Yasuo, Mandai Michiko

机构信息

Kobe City Eye Hospital, Hyogo, Japan.

Cell and Gene Therapy in Ophthalmology Laboratory, BZP, RIKEN, Saitama, Japan.

出版信息

Invest Ophthalmol Vis Sci. 2025 Jun 2;66(6):53. doi: 10.1167/iovs.66.6.53.

DOI:10.1167/iovs.66.6.53
PMID:40525923
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12178438/
Abstract

PURPOSE

We previously reported that suspensions of CIITA-/- monkey induced pluripotent stem cell-derived retinal pigment epithelium (moiPSC-RPE) that lacks expression of major histocompatibility complex (MHC) class Ⅱ avoided rejection without systemic immunosuppression. RPE strips represent a novel graft formulation for RPE impairment diseases that may enable mass engraftment but potentially increase rejection risk. This study evaluated host immune responses to allogeneic CIITA+/+ and CIITA-/- moiPSC-RPE strips in MHC-mismatched transplantation in monkey eyes with RPE damage, without systemic immunosuppression.

METHODS

RPE strips were generated from CIITA+/+ and CIITA-/- moiPSC-RPE. Following RPE ablation using a microsecond pulse laser, two RPE strips were transplanted into each eye at 1- to 3-week intervals. One monkey received CIITA+/+ moiPSC-RPE strips, while another received CIITA-/- moiPSC-RPE strips. Graft status was monitored through routine ophthalmic examinations, and immunohistologic evaluation was conducted after 5 months.

RESULTS

Fluorescein angiography revealed evident leakage in eyes with CIITA+/+ RPE strips beginning 1 to 2 months posttransplantation, with optical coherence tomography showing bulging at the graft site, indicating immune cell accumulation. Immunostaining confirmed the presence of immune cells (CD4, CD8, Iba1, IFN-γ, MHC class II, and CD20) at CIITA+/+ RPE strip grafts. In contrast, CIITA-/- RPE strip transplants showed no signs of rejection in either eye over 5 months and minimal immune cell presence at the graft site.

CONCLUSIONS

Allogeneic transplantation of CIITA-/- RPE strips may reduce rejection risk in RPE-ablated disease model eyes, suggesting potential clinical benefits of MHC class II-deficient RPE grafts, particularly for diseases with inflammatory pathology.

摘要

目的

我们之前报道过，缺乏主要组织相容性复合体（MHC）Ⅱ类表达的CIITA基因敲除猴诱导多能干细胞来源的视网膜色素上皮细胞（moiPSC-RPE）悬浮液在无全身免疫抑制的情况下可避免排斥反应。RPE条带是一种用于RPE损伤疾病的新型移植制剂，可能实现大规模移植，但也可能增加排斥风险。本研究评估了在没有全身免疫抑制的情况下，MHC不匹配的猴眼中，同种异体CIITA基因敲除阳性和CIITA基因敲除阴性的moiPSC-RPE条带移植后的宿主免疫反应。

方法

从CIITA基因敲除阳性和CIITA基因敲除阴性的moiPSC-RPE中制备RPE条带。使用微秒脉冲激光进行RPE消融后，每隔1至3周将两条RPE条带移植到每只眼中。一只猴子接受CIITA基因敲除阳性的moiPSC-RPE条带，另一只猴子接受CIITA基因敲除阴性的moiPSC-RPE条带。通过常规眼科检查监测移植物状态，并在5个月后进行免疫组织学评估。

结果

荧光素血管造影显示，移植后1至2个月开始，接受CIITA基因敲除阳性RPE条带的眼睛出现明显渗漏，光学相干断层扫描显示移植部位隆起，表明有免疫细胞聚集。免疫染色证实CIITA基因敲除阳性RPE条带移植物处存在免疫细胞（CD4、CD8、Iba1、IFN-γ、MHCⅡ类和CD20）。相比之下，CIITA基因敲除阴性RPE条带移植的两只眼睛在5个月内均未出现排斥迹象，移植部位的免疫细胞极少。

结论

CIITA基因敲除阴性RPE条带的同种异体移植可能会降低RPE消融疾病模型眼中的排斥风险，这表明MHCⅡ类缺陷RPE移植物具有潜在的临床益处，特别是对于有炎症病理的疾病。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bb64/12178438/9cf74d5fefe3/iovs-66-6-53-f006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bb64/12178438/a59a1f788290/iovs-66-6-53-f001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bb64/12178438/6622dbd215e5/iovs-66-6-53-f002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bb64/12178438/ad59bf8af7ed/iovs-66-6-53-f003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bb64/12178438/99d33621373d/iovs-66-6-53-f004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bb64/12178438/38f5ce209e83/iovs-66-6-53-f005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bb64/12178438/9cf74d5fefe3/iovs-66-6-53-f006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bb64/12178438/a59a1f788290/iovs-66-6-53-f001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bb64/12178438/6622dbd215e5/iovs-66-6-53-f002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bb64/12178438/ad59bf8af7ed/iovs-66-6-53-f003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bb64/12178438/99d33621373d/iovs-66-6-53-f004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bb64/12178438/38f5ce209e83/iovs-66-6-53-f005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bb64/12178438/9cf74d5fefe3/iovs-66-6-53-f006.jpg

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Graft survival of major histocompatibility complex deficient stem cell-derived retinal cells.主要组织相容性复合体缺陷的干细胞源性视网膜细胞的移植物存活情况。
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Hypoimmunogenic human iPSCs expressing HLA-G, PD-L1, and PD-L2 evade innate and adaptive immunity.
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Graft cell expansion from hiPSC-RPE strip after transplantation in primate eyes with or without RPE damage.在有或没有 RPE 损伤的灵长类动物眼中移植 hiPSC-RPE 条带后，进行移植物细胞的扩增。
Sci Rep. 2024 May 2;14(1):10044. doi: 10.1038/s41598-024-60895-w.
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