Generation of hypoimmunogenic human pluripotent stem cells via expression of membrane-bound and secreted β2m-HLA-G fusion proteins

Shi, Lei; Li, Wenjing; Yang, Lianjuan; Chen, Zhenyu; Hui, Yi; Hao, Pengcheng; Xu, Xiangjie; Zhang, Shuwei; Feng, Hexi; Zhang, Bowen; Zhou, Shanshan; Li, Nan; Xiao, Lei; Liu, Ling; Ma, Lin; Zhang, Xiaoqing

doi:10.1002/stem.3269

Cited by 47 publications

(39 citation statements)

References 68 publications

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“…Different alternative approaches to overcome NK cell targeting have been investigated. Targeted disruption of classical HLA-A, -B and -C while retaining expression of non-classical HLA-E alone (37) or by the combinatorial expression of HLA-G, CD47 and PD-L1 (38,39) have been shown to protect hPSC from NK cell recognition and lysis. For these reasons, we explored the possibility of overexpressing the PD-L1 receptor and keeping expression of all HLA class I molecules to avoid NK cell lysis.…”

Section: Discussionmentioning

confidence: 99%

Protecting Stem Cell Derived Pancreatic Beta-Like Cells From Diabetogenic T Cell Recognition

Castro-Gutiérrez

Alkanani²,

Mathews³

et al. 2021

Front. Endocrinol.

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Type 1 diabetes results from an autoimmune attack directed at pancreatic beta cells predominantly mediated by T cells. Transplantation of stem cell derived beta-like cells (sBC) have been shown to rescue diabetes in preclinical animal models. However, how sBC will respond to an inflammatory environment with diabetogenic T cells in a strict human setting has not been determined. This is due to the lack of model systems that closely recapitulates human T1D. Here, we present a reliable in vitro assay to measure autologous CD8 T cell stimulation against sBC in a human setting. Our data shows that upon pro-inflammatory cytokine exposure, sBC upregulate Human Leukocyte Antigen (HLA) class I molecules which allows for their recognition by diabetogenic CD8 T cells. To protect sBC from this immune recognition, we utilized genome engineering to delete surface expression of HLA class I molecules and to integrate an inducible overexpression system for the immune checkpoint inhibitor Programmed Death Ligand 1 (PD-L1). Genetically engineered sBC that lack HLA surface expression or overexpress PD-L1 showed reduced stimulation of diabetogenic CD8 T cells when compared to unmodified cells. Here, we present evidence that manipulation of HLA class I and PD-L1 receptors on sBC can provide protection from diabetes-specific immune recognition in a human setting.

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Section: Discussionmentioning

confidence: 99%

Protecting Stem Cell Derived Pancreatic Beta-Like Cells From Diabetogenic T Cell Recognition

Castro-Gutiérrez

Alkanani²,

Mathews³

et al. 2021

Front. Endocrinol.

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“…ITL-2 is also anchored on dNK cells and thus can be potentially regulated by sHLA-G1. Studies reveal that the b2m-linked isoforms or disulfide-linked dimers of HLA-G execute the immuneassociated function whereas free b2m has no immune function (35,41). Gonen-Gross et al clarified that HLA-G free H chain complexes, which form without b2m, are present on the trophoblast cell surface but unimportant for ILT2 recognition (28).…”

Section: Bio-functional Character Of Hla-gmentioning

confidence: 99%

HLA-G: An Important Mediator of Maternal-Fetal Immune-Tolerance

2021

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Maternal-fetal immune-tolerance occurs throughout the whole gestational trimester, thus a mother can accept a genetically distinct fetus without immunological aggressive behavior. HLA-G, one of the non-classical HLA class I molecules, is restricted-expression at extravillous trophoblast. It can concordantly interact with various kinds of receptors mounted on maternally immune cells residing in the uterus (e.g. CD4+ T cells, CD8+ T cells, natural killer cells, macrophages, and dendritic cells) for maintaining immune homeostasis of the maternal-fetus interface. HLA-G is widely regarded as the pivotal protective factor for successful pregnancies. In the past 20 years, researches associated with HLA-G have been continually published. Indeed, HLA-G plays a mysterious role in the mechanism of maternal-fetal immune-tolerance. It can also be ectopically expressed on tumor cells, infected sites and other pathologic microenvironments to confer a significant local tolerance. Understanding the characteristics of HLA-G in immunologic tolerance is not only beneficial for pathological pregnancy, but also helpful to the therapy of other immune-related diseases, such as organ transplant rejection, tumor migration, and autoimmune disease. In this review, we describe the biological properties of HLA-G, then summarize our understanding of the mechanisms of fetomaternal immunologic tolerance and the difference from transplant tolerance. Furthermore, we will discuss how HLA-G contributes to the tolerogenic microenvironment during pregnancy. Finally, we hope to find some new aspects of HLA-G in fundamental research or clinical application for the future.

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“…Finally, the advent of safe and effective gene editing has propelled many efforts to apply these techniques into the field of IT. While many experiments using overexpression and underexpression of several molecules have shown promising results, specific efforts to prevent allo‐ 98–100 and autoimmune 101 destruction of islet could prove revolutionary. Viacyte Inc. has developed the cell product PEC‐QT, which consists of edited clonal hESC line (CyT49) that lacks the β2‐microglobulin gene and expresses a transgene encoding programmed death‐ligand 1 to protect cells from autoimmune attack 102 .…”

Section: Challenges and Potential Solutionsmentioning

confidence: 99%

Clinical islet transplantation: Current progress and new frontiers

Marfil‐Garza

Shapiro

Kin

2021

J Hepato Biliary Pancreat

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Islet transplantation (IT) is now a robust treatment for selected patients with type 1 diabetes suffering from recurrent hypoglycemia and impaired awareness of hypoglycemia. A global soar of clinical islet transplant programs attests to the commitment of many institutions and researchers to advance IT as a potential cure for this devastating disease. However, many challenges limiting the widespread applicability of clinical IT remain. In this review, we will touch on the milestones in the history of IT and its path to clinical success, discuss the current challenges around IT, propose some possible solutions, and elaborate on the frontiers envisioned in the future of clinical IT.

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Generation of hypoimmunogenic human pluripotent stem cells via expression of membrane-bound and secreted β2m-HLA-G fusion proteins

Cited by 47 publications

References 68 publications

Protecting Stem Cell Derived Pancreatic Beta-Like Cells From Diabetogenic T Cell Recognition

Protecting Stem Cell Derived Pancreatic Beta-Like Cells From Diabetogenic T Cell Recognition

HLA-G: An Important Mediator of Maternal-Fetal Immune-Tolerance

Clinical islet transplantation: Current progress and new frontiers

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