Secreted cytokines provide local immune tolerance for human stem cell-derived islets

Gerace, Dario; Zhou, Quan; Kenty, Jennifer Hyoje-Ryu; Sintov, Elad; Wang, Xi; Boulanger, Kyle; Li, Hongfei; Melton, Douglas A.

doi:10.1101/2022.05.09.487072

Cited by 3 publications

(1 citation statement)

References 62 publications

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“…Another strategy to control Cas9-induced off-targets is to use its high-fidelity variants. However, in the case of iPSCs, only a small number of studies utilize Cas9 variants with increased specificity (Table 3), such as Hi-Fi Cas9 [128,176,184,185], also in one of the papers the authors used Cas9n nickase [111], a known high-fidelity Cas9 modification [186]. Lamothe at al., in their work, demonstrated the successful use of novel CRISPR-editing systems based on modified type II and type V nucleases for the genetic engineering of primary immune cells and iPSCs [187].…”

Section: Challenges In Crispr/cas9-based Generation Of Immunoprivileg...mentioning

confidence: 99%

Challenges of CRISPR/Cas-Based Cell Therapy for Type 1 Diabetes: How Not to Engineer a “Trojan Horse”

Karpov,

Sosnovtseva,

Pylina

et al. 2023

IJMS

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Type 1 diabetes mellitus (T1D) is an autoimmune disease caused by the destruction of insulin-producing β-cells in the pancreas by cytotoxic T-cells. To date, there are no drugs that can prevent the development of T1D. Insulin replacement therapy is the standard care for patients with T1D. This treatment is life-saving, but is expensive, can lead to acute and long-term complications, and results in reduced overall life expectancy. This has stimulated the research and development of alternative treatments for T1D. In this review, we consider potential therapies for T1D using cellular regenerative medicine approaches with a focus on CRISPR/Cas-engineered cellular products. However, CRISPR/Cas as a genome editing tool has several drawbacks that should be considered for safe and efficient cell engineering. In addition, cellular engineering approaches themselves pose a hidden threat. The purpose of this review is to critically discuss novel strategies for the treatment of T1D using genome editing technology. A well-designed approach to β-cell derivation using CRISPR/Cas-based genome editing technology will significantly reduce the risk of incorrectly engineered cell products that could behave as a “Trojan horse”.

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Section: Challenges In Crispr/cas9-based Generation Of Immunoprivileg...mentioning

confidence: 99%

Challenges of CRISPR/Cas-Based Cell Therapy for Type 1 Diabetes: How Not to Engineer a “Trojan Horse”

Karpov,

Sosnovtseva,

Pylina

et al. 2023

IJMS

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Immune Editing: Overcoming Immune Barriers in Stem Cell Transplantation

2022

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Purpose of Review Human pluripotent stem cells have the potential to revolutionize the treatment of inborn and degenerative diseases, including aging and autoimmunity. A major barrier to their wider adoption in cell therapies is immune rejection. Genome editing allows for tinkering of the human genome in stem and progenitor cells and raises the prospect for overcoming the immune barriers to transplantation. Recent Findings Initial attempts have focused primarily on the major histocompatibility barrier that is formed by the human leukocyte antigens (HLA). More recently, immune checkpoint inhibitors, such as PD-L1, CD47, or HLA-G, are being explored both, in the presence or absence of HLA, to mitigate immune rejection by the various cellular components of the immune system. Summary In this review, we discuss progress in surmounting immune barriers to cell transplantation, with a particular focus on genetic engineering of human pluripotent stem and progenitor cells and the therapeutic cell types derived from them.

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Toward Improving Immunotolerance for Stem Cell-Derived Islets

Zhou

Gerace

et al. 2022

Preprint

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Transplanting human stem cell-derived islets (SC-islets) is a promising therapy for insulin-dependent diabetes. While functional SC-islets have been produced for clinical application, immune rejection by the host remains a challenge. Present attempts, including chronic immunosuppression and/or physical encapsulation, have some disadvantages. Here we explore a strategy to induce an immune-tolerant environment based on the immune privilege observed in the male gonad. Sperm appears after the maturation of the immune system and development of systemic self-tolerance and the testis protects these autoreactive germ cells by the physical structure of blood-testis-barrier (BTB) and active local immunosuppression. Human SC-islets transplanted into the mouse testis can be physically protected by the BTB and we find that the testis secretes cytokines that induce a population of regulatory T cells (Tregs) that express both CD4 and CD8. We identified cytokines secreted by testis and used a cocktail of IL-2, IL-10, and TGF-β for in vitro co-culture and in vivo transplantation demonstrating improved survival of SC-islets and the induction of Tregs.

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Secreted cytokines provide local immune tolerance for human stem cell-derived islets

Cited by 3 publications

References 62 publications

Challenges of CRISPR/Cas-Based Cell Therapy for Type 1 Diabetes: How Not to Engineer a “Trojan Horse”

Challenges of CRISPR/Cas-Based Cell Therapy for Type 1 Diabetes: How Not to Engineer a “Trojan Horse”

Immune Editing: Overcoming Immune Barriers in Stem Cell Transplantation

Toward Improving Immunotolerance for Stem Cell-Derived Islets

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