Human Embryonic Stem Cells Possess Immune‐Privileged Properties

Li, Li; Baroja, Miren L.; Majumdar, Anish Sen; Chadwick, Kristin; Rouleau, Anne; Gallacher, Lisa; Ferber, Iris; Lebkowski, Jane; Martin, Tanya; Madrenas, Joaquı́n; Bhatia, Mickie

doi:10.1634/stemcells.22-4-448

Cited by 333 publications

(278 citation statements)

References 19 publications

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“…Low expression of HLA by hESCs and hESC-derived cells underlies the hypoimmunogenicity observed in most published studies, effectively hiding cells from T cell recognition and alloreactive antibodies, while differentiation can upregulate HLA and increase vulnerability to immunity [17][18][19][20][21]. In our study, immunogenicity to alloreactive and peptide (CMV)-specific responses was related to HLA expression.…”

Section: Discussionmentioning

confidence: 50%

“…Preproinsulin (PPI)-specific T cell clone 1E6 generation was described previously [23]. Briefly, PBMCs from an individual with type 1 diabetes were stimulated with PPI [15][16][17][18][19][20][21][22][23][24] peptide. PPI-specific cytotoxic T lymphocytes (CTLs) were sorted by FACS and expanded.…”

Section: Methodsmentioning

confidence: 99%

“…However, differentiation of hESCs to other cell types can result in the loss of this immunological privilege [17][18][19][20][21]. Insights into the immunogenicity of the alternative sources of beta cells can help to guide the choice of immune-protective strategies and the relevant immune monitoring to be employed in clinical introduction.…”

Section: Introductionmentioning

confidence: 99%

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Immunogenicity of human embryonic stem cell-derived beta cells

et al. 2016

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Aims/hypothesis To overcome the donor shortage in the treatment of advanced type 1 diabetes by islet transplantation, human embryonic stem cells (hESCs) show great potential as an unlimited alternative source of beta cells. hESCs may have immune privileged properties and it is important to determine whether these properties are preserved in hESC-derived cells. Methods We comprehensively investigated interactions of both innate and adaptive auto-and allo-immunity with hESC-derived pancreatic progenitor cells and hESC-derived endocrine cells, retrieved after in-vivo differentiation in capsules in the subcutis of mice. Results We found that hESC-derived pancreatic endodermal cells expressed relatively low levels of HLA endorsing protection from specific immune responses. HLA was upregulated when exposed to IFNγ, making these endocrine progenitor cells vulnerable to cytotoxic T cells and alloreactive antibodies. In vivo-differentiated endocrine cells were protected from complement, but expressed more HLA and were targets for alloreactive antibody-dependent cellular cytotoxicity and alloreactive cytotoxic T cells. After HLA compatibility was provided by transduction with HLA-A2, preproinsulin-specific T cells killed insulin-producing cells. Conclusions/interpretation hESC-derived pancreatic progenitors are hypoimmunogenic, while in vivo-differentiated endocrine cells represent mature targets for adaptive immune responses. Our data support the need for immune intervention in transplantation of hESC-derived pancreatic progenitors. Cell-impermeable macro-encapsulation may suffice.

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Section: Discussionmentioning

confidence: 50%

Section: Methodsmentioning

confidence: 99%

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Immunogenicity of human embryonic stem cell-derived beta cells

et al. 2016

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“…Although pluripotent cells are naive in terms of immune reactivity and only express some human leukocyte antigen types [65], transplantation into retina results in immune reaction to differentiated progeny. The immune privilege of retina and reduced immunogenicity of undifferentiated ESCs may favor immune compatibility, but these conditions are not sufficient to prevent rejection, and immune suppression after transplantation of allogenic ESC-derived cells into the retina is needed to prevent rejection of transplanted tissue [36].…”

Section: Pluripotent Stem Cellsmentioning

confidence: 99%

Stem Cells for Retinal Replacement Therapy

Stern

Temple

2011

Neurotherapeutics

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Retinal degenerative disease has limited therapeutic options and the possibility of stem cell-mediated regenerative treatments is being actively explored for these blinding retinal conditions. The relative accessibility of this central nervous system tissue and the ability to visually monitor changes after transplantation make the retina and adjacent retinal pigment epithelium prime targets for pioneering stem cell therapeutics. Prior work conducted for several decades indicated the promise of cell transplantation for retinal disease, and new strategies that combine these established surgical approaches with stem cell-derived donor cells is ongoing. A variety of tissue-specific and pluripotent-derived donor cells are being advanced to replace lost or damaged retinal cells and/or to slow the disease processes by providing neuroprotective factors, with the ultimate aim of long-term improvement in visual function. Clinical trials are in the early stages, and data on safety and efficacy are widely anticipated. Positive outcomes from these stem cell-based clinical studies would radically change the way that blinding disorders are approached in the clinic.

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“…There are several reports of a robust immune-privileged ('tolerogenic') state of ESC of mice, humans and rats after engraftment [1][2][3], while others described an increase of immunogenicity following transplantation with proceeding differentiation [4,5]. Expression of structures recognized by the host immune system varies between the species, e.g.…”

Section: Introductionmentioning

confidence: 99%

Low immunogenicity of endothelial derivatives from rat embryonic stem cell-like cells

et al. 2009

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Embryonic stem cells (ESC) are suggested to be immune-privileged, but they carry the risk of uncontrolled expansion and malignancy. Upon differentiation they lose their tumor-forming capacity, but they become immunogenic by the expression of a normal set of MHC molecules. This immunogenicity might trigger rejection after application in regenerative therapies. In this study MHC expression of and immune responses to endothelial derivatives of rat embryonic stem cell-like cells (RESC) under inflammatory conditions were determined in comparison to primary rat aortic endothelial cells (ECs). Cellular as well as humoral allo-recognition was analyzed in vitro. In addition, immune reactions in vivo were assessed by allo-antibody production and determination of interferon-γ (IFNγ)-secreting allo-reactive T cells. RESC derivatives expressed low but significant levels of MHC class I, and no MHC class II. In response to IFNγ MHC class I expression was enhanced, while class II transactivator induction failed completely in these cells; MHC class II expression remained consistently absent. Functionally, the RESC derivatives showed a reduced allo-stimulatory capacity, protection against humoral allo-recognition in vitro and a slightly diminished susceptibility to cytotoxic T cell lysis. Furthermore, in vivo experiments demonstrated that these cells do not trigger host immune reactions, characterized by no allo-antibody production and no induction of allo-reactive memory T cells. Our results show that endothelial derivatives of RESC have a distinctive reduced immunogenic potency even under inflammatory conditions.

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Human Embryonic Stem Cells Possess Immune‐Privileged Properties

Cited by 333 publications

References 19 publications

Immunogenicity of human embryonic stem cell-derived beta cells

Immunogenicity of human embryonic stem cell-derived beta cells

Stem Cells for Retinal Replacement Therapy

Low immunogenicity of endothelial derivatives from rat embryonic stem cell-like cells

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