Generation of Retinal Pigment Epithelial Cells Derived from Human Embryonic Stem Cells Lacking Human Leukocyte Antigen Class I and II

Petrus‐Reurer, Sandra; Winblad, Nerges; Kumar, Pankaj; Gorchs, Laia; Chrobok, Michael; Wagner, Arnika K.; Bartuma, Hammurabi; Lardner, Emma; Aronsson, Monica; Reyes, Álvaro Plaza; André, Helder; Alici, Evren; Kaipe, Helen; Kvanta, Anders; Lanner, Fredrik

doi:10.1016/j.stemcr.2020.02.006

Cited by 43 publications

(57 citation statements)

References 52 publications

(58 reference statements)

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“…Human RPE cell xenografts have also been shown to cause inflammation in the subretinal space of experimental animals, e.g., a human fetal RPE cell sheet transplantation into the subretinal space caused severe choroidal inflammation [11] or immunological rejection in rabbits [12]. When human embryonic stem cell-derived RPE cells (ESC-RPE cells; xenografts) were transplanted into the subretinal space of rabbits, these cells were also rejected [13][14][15]. In the present study, we used human iPSC-RPE cells as RPE xenografts that were transplanted into cynomolgus monkeys.…”

Section: Introductionmentioning

confidence: 99%

A Strategy for Personalized Treatment of iPS-Retinal Immune Rejections Assessed in Cynomolgus Monkey Models

Fujii

Sugita

Futatsugi

et al. 2020

IJMS

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Recently, we successfully transplanted an autograft, or major histocompatibility complex (MHC)-matched allografts, from induced-pluripotent-stem-cell-derived retinal pigment epithelial (iPSC-RPE) cells in patients with age-related macular degeneration. However, there was an issue regarding immune rejection after transplantation. In this study, we established a preoperational in vitro “drug–lymphocytes–grafts immune reaction (Drug-LGIR)” test to determine the medication for immune rejection using host immunocompetent cells (lymphocytes) and transplant cells (target iPSC-RPE cells) together with different medications. The adequacy of the test was assessed by in vivo transplantation in monkey models together with medication based on in vitro data. In the results of Drug-LGIR tests, some drugs exhibited significant suppression of RPE cell-related allogeneic reactions, while other drugs did not, and the efficacy of each drug differed among the recipient monkeys. Based on the results of Drug-LGIR, we applied cyclosporine A or local steroid (triamcinolone) therapy to two monkeys, and successfully suppressed RPE-related immune rejections with RPE grafts, which survived without any signs of rejection under drug administration. We propose that our new preoperational in vitro Drug-LGIR test, which specifies the most efficacious medication for each recipient, is useful for controlling immune attacks with personalized treatment for each patient after retinal transplantation.

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Section: Introductionmentioning

confidence: 99%

A Strategy for Personalized Treatment of iPS-Retinal Immune Rejections Assessed in Cynomolgus Monkey Models

Fujii

Sugita

Futatsugi

et al. 2020

IJMS

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“…All of their gene‐edited cells suppressed both CD4 + and CD8 + T‐cell activation, but these edited cells enhanced NK cell activation, although they did not show a stronger cytotoxic activity than wild‐type (WT) hESCs. Furthermore, the edited cells were transplanted into a rabbit xenograft model without an immunosuppressive regimen, and the cells suppressed the early rejection response and delayed the production of anti‐human antibodies in the late rejection response 20 …”

Section: Preparation Methods Of Universal (Hypoimmunogenic) Hpscsmentioning

confidence: 99%

“…Several investigators have designed hPSCs in which B2M is knocked out ( Table 2). 5,[19][20][21][22][23][24][25][26][27] This is because the B2M protein forms a heterodimer with HLA class I proteins and is required for HLA class I expression on the cell surface ( Figure 2A). 11 Knocking out the B2M gene can restrict an immune response from cytotoxic CD8 + T cells by depleting all HLA class I molecules (HLA-A, -B, -C, -E, -F and -G), although B2M-knockout hPSCs become sensitive to natural killer (NK) cell-mediated killing because they lack the missing-self response ( Figure 2B(a)).…”

Section: Generation Of Universal Hpscs By Knocking Out B2mmentioning

confidence: 99%

Generation of universal and hypoimmunogenic human pluripotent stem cells

Sung

Yang

et al. 2020

Cell Proliferation

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“…Studies have demonstrated that MHC expression are of prime importance in allograft rejection and may be the precedent step to xenograft rejection 29,30 . Human breast cancer cells (MDA-MB-231), which express high-level HLA-ABC, were quickly rejected after transplanted into the striatum (Fig.S5A).…”

Section: Hla-abc Expression Was Not the Trigger For The Late-onset Rementioning

confidence: 99%

Hypoproliferative human NPC xenografts survived extendedly in the brain of immunocompetent rats

Liu

Wang

Huang

et al. 2020

Preprint

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Background: There is a huge controversy about whether xenograft or allograft in the “immune-privileged” brain needs immunosuppression. In animal studies, prevailing sophiscated immunosuppression or immunodeficiency is detrimental for the recipients, which results in short lifespan of animals, and confounds functional behavioral readout of the graft benefit, discouraging long-term follow-up. Methods: Neuron-restricted human neural progenitor cells (NPCs) were derived from human embryonic stem cells (ESCs, including H1, its gene-modified cell lines for better visualization, and HN4), propagated for different passages and then transplanted into the brain of immunocompetent rats without use of immunosuppressant. The graft survivals, their cell fates and HLA expression levels were examined over time (up to months after transplantation). We compared the survival capability of NPCs from different passages, and in different transplantation sites (brain parenchyma vs. para-and intra-ventricular sites). The host responses to the grafts were also investigated.Results: Our results show that human ESC-derived neuron-restricted NPCs survive extendedly in adult rat cerebro-parenchyma with no need of immunosuppression whereas a late-onset graft rejection seems inevitable. Both donor HLA expression level and host MHC-II expression level remain relatively low and little change over the long-term survival, and therefore can’t predict the late-onset rejection. Human grafts in or close to cerebroventricle are more vulnerable to the immune attack than the intra-striatum grafts. Prevention of graft hyperplasia by using hypoproliferative late-passaged human NPCs further significantly extends the graft survival time. Our new data also shows that a subpopulation of host microglia upregulate MHC-II expression in response to the human graft, but fail to present the human antigen to the host immune system, suggestive of the immune-isolation role of the blood–brain barrier (BBB). Conclusions: The present study confirms the “immune privilege” of the brain parenchyma, and more importantly, unveils that choosing hypoproliferative NPCs for transplantation can benefit graft outcome in terms of both lower tumor-genic risk and the prolonged survival time without immunosuppression.

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Generation of Retinal Pigment Epithelial Cells Derived from Human Embryonic Stem Cells Lacking Human Leukocyte Antigen Class I and II

Cited by 43 publications

References 52 publications

A Strategy for Personalized Treatment of iPS-Retinal Immune Rejections Assessed in Cynomolgus Monkey Models

A Strategy for Personalized Treatment of iPS-Retinal Immune Rejections Assessed in Cynomolgus Monkey Models

Generation of universal and hypoimmunogenic human pluripotent stem cells

Hypoproliferative human NPC xenografts survived extendedly in the brain of immunocompetent rats

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