Serpin-6 Expression Protects Embryonic Stem Cells from Lysis by Antigen-Specific CTL

Abdullah, Zeinab; Šarić, Tomo; Kashkar, Hamid; Baschuk, Nikola; Yazdanpanah, Benjamin; Fleischmann, Bernd K.; Hescheler, Jürgen; Krönke, Martin; Utermöhlen, Olaf

doi:10.4049/jimmunol.178.6.3390

Cited by 51 publications

(96 citation statements)

References 42 publications

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“…Together, the expression of MHC-I and -II antigens on stem cell-derived grafts theoretically will determine the immunological reaction after transplantation (6,29,30,32,33). Previous reports showed that MHC-I molecules were not detected in mouse ESCs (1,17) but were detectable in undifferentiated hESCs at low levels (16,18,19,21,26). However, the expression of MHC-I molecules is increased after differentiation of mouse ESCs (15,38) and hESCs (4,(19)(20)(21)38).…”

Section: Discussionmentioning

confidence: 99%

Characteristic Expression of Major Histocompatibility Complex and Immune Privilege Genes in Human Pluripotent Stem Cells and Their Derivatives

Chen

et al. 2015

Cell Transplant

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Pluripotent stem cells, including human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs), have been regarded as useful sources for cell-based transplantation therapy. However, immunogenicity of the cells remains the major determinant for successful clinical application. We report the examination of several hESC lines (NTU1 and H9), hiPSC lines, and their derivatives (including stem cell-derived hepatocytes) for the expression of major histocompatibility complex (MHC), natural killer (NK) cell receptor (NKp30, NKp44, NKp46) ligand, immune-related genes, human leukocyte antigen (HLA) haplotyping, and the effects in functional mixed lymphocyte reaction (MLR). Flow cytometry showed lower levels (percentages and fluorescence intensities) of MHC class I (MHC-I) molecules, b2-microglobulin, and HLA-E in undifferentiated stem cells. The levels were increased after cotreatment with interferon-g and/or in vitro differentiation. Antigen-presenting cell markers (CD11c, CD80, and CD86) and MHC-II (HLA-DP, -DQ, and -DR) remained low throughout the treatments. Recognition of stem cells/derivatives by NK lysis receptors were lower or absent. Activation of responder lymphocytes was significantly lower by undifferentiated stem cells than by allogeneic lymphocytes in MLR, but differentiated NTU1 hESCs induced a cell number-dependent lymphocyte proliferation comparable with that by allogeneic lymphocytes. Interestingly, activation of lymphocytes by differentiated hiPSCs or H9 cells became blunted at higher cell numbers. Real-time reverse transcriptase PCR (RT-PCR) showed significant differential expression of immune privilege genes Arginase 2, Indole 1, GATA3, POMC, VIP, CALCA, CALCB, CD95L, CR1L, Serpine 1, HMOX1, IL6, LGALS3, HEBP1, THBS1, CD59, and LGALS1) in pluripotent stem cells/derivatives when compared to somatic cells. It was concluded that pluripotent stem cells/derivatives are predicted to be immunogenic, though evidence suggests some level of potential immune privilege. In addition, differential immunogenicity may exist between different pluripotent stem cell lines and their derivatives.

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Section: Discussionmentioning

confidence: 99%

Characteristic Expression of Major Histocompatibility Complex and Immune Privilege Genes in Human Pluripotent Stem Cells and Their Derivatives

Chen

et al. 2015

Cell Transplant

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“…Serine protease inhibitor 6 (Spi6) is the mouse homolog of PI-9 in humans and is required to protect CTLs from GrBmediated death (21,22). PI-9 is expressed in the cytoplasm and nuclei of CTLs, immunoprivileged cells (23), and embryonic stem cells (24); PI-9 overexpression allows for the evasion of GrBmediated cytotoxicity (25,26). Endogenous GrB inhibitors have been characterized in both mice and humans.…”

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confidence: 99%

The Novel Role of SERPINB9 in Cytotoxic Protection of Human Mesenchymal Stem Cells

Haddad

Moore

Heathcote

et al. 2011

The Journal of Immunology

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Clinical trials using allogeneic mesenchymal stem cells (MSCs) are ongoing for the purpose of providing therapeutic benefit for a variety of human disorders. Pertinent to their clinical use are the accessibility to sufficient quantities of these cells allowing for repetitive administration, as well as a better understanding of the specific mechanisms by which allogeneic MSCs evade host immune responses that in turn influence their life span following administration. In this report, we sought to characterize and compare human peripheral blood MSCs (hPB-MSCs) with bone marrow-derived MSCs. hPB-MSCs met the established criteria to characterize this cellular lineage, including capacity for self-renewal, differentiation into tissues of mesodermal origin, and expression of phenotypic surface markers. In addition, hPB-MSCs suppressed alloreactive proliferation as well as the production of proinflammatory cytokines. Examination of the mechanisms by which allogeneic MSCs evade the host immune response, which is crucial for their therapeutic use, demonstrated that constitutive expression of serine protease inhibitor 9 (PI-9) on hPB-MSCs and bone marrow-derived MSCs is a major defense mechanism against granzyme B-mediated destruction by NK cells. Similarly, MSCs treated with small interfering RNA for PI-9 increased MSC cellular death, whereas expression of transgenic PI-9 following retroviral transduction protected MSCs. These data significantly advance our understanding of the immunomodulatory role for hPB-MSCs as well as the mechanisms by which they evade host immune responses. These findings contribute to the development of MSC-based therapies for diseases.

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“…In addition, because of their early stage of development, ESCs are considered "immune privileged," i.e, unrecognizable by the recipient immune defenses (Magliocca et al, 2006;Ichiryu and Fairchild, 2013). Moreover, it has been reported that mESCs are resistant to antigen-specific cytotoxic T lymphocyte (CTL) due to the expression of serpin-6, an endogenous inhibitor of granzyme B (Abdullah et al, 2007). Dressel et al (2008) stated that the MPI-II cells they used were susceptible to granule exocytosis-mediated killing by rat NK cells and also by peptide-specific mouse CTL.…”

Section: Discussionmentioning

confidence: 99%

Teratoma Formation in Immunocompetent Mice After Syngeneic and Allogeneic Implantation of Germline Capable Mouse Embryonic Stem Cells

Aldahmash

Atteya²,

Elsafadi³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Background: Embryonic stem cells (ESCs) have the potential to form teratomas when implanted into immunodeficient mice, but data in immunocompetent mice are limited. We therefore investigated teratoma formation after implantation of three different mouse ESC (mESC) lines into immunocompetent mice. Materials and Methods: BALB/c mice were injected with three highly germline competent mESCs (129Sv, BALB/c and C57BL/6) subcutaneously or under the kidney capsule. After 4 weeks, mice were euthanized and examined histologically for teratoma development. The incidence, size and composition of teratomas were compared using Pearson Chi-square, t-test for dependent variables, one-way analysis of variance and the nonparametric KruskalWallis analysis of variance and median test. Results: Teratomas developed from all three cell lines. The incidence of formation was significantly higher under the kidney capsule compared to subcutaneous site and occurred in both allogeneic and syngeneic mice. Overall, the size of teratoma was largest with the 129Sv cell line and under the kidney capsule. Diverse embryonic stem cell-derived tissues, belonging to the three embryonic germ layers, were encountered, reflecting the pluripotency of embryonic stem cells. Most commonly represented tissues were nervous tissue, keratinizing stratified squamous epithelium (ectoderm), smooth muscle, striated muscle, cartilage, bone (mesoderm), and glandular tissue in the form of gut-and respiratory-like epithelia (endoderm). Conclusions: ESCs can form teratomas in immunocompetent mice and, therefore, removal of undifferentiated ESC is a pre-requisite for a safe use of ESC in cell-based therapies. In addition the genetic relationship of the origin of the cell lines to the ability to transplant plays a major role.

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Serpin-6 Expression Protects Embryonic Stem Cells from Lysis by Antigen-Specific CTL

Cited by 51 publications

References 42 publications

Characteristic Expression of Major Histocompatibility Complex and Immune Privilege Genes in Human Pluripotent Stem Cells and Their Derivatives

Characteristic Expression of Major Histocompatibility Complex and Immune Privilege Genes in Human Pluripotent Stem Cells and Their Derivatives

The Novel Role of SERPINB9 in Cytotoxic Protection of Human Mesenchymal Stem Cells

Teratoma Formation in Immunocompetent Mice After Syngeneic and Allogeneic Implantation of Germline Capable Mouse Embryonic Stem Cells

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