Immunobiology of naïve and genetically modified HLA-class-I-knockdown human embryonic stem cells.
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Immunobiology of naïve and genetically modified HLA-class-I-knockdown human embryonic stem cells. / Deuse, Tobias; Seifert, Martina; Phillips, Neil; Fire, Andrew; Tyan, Dolly; Kay, Mark; Tsao, Philip S; Hua, Xiaoqin; Velden, Joachim; Eiermann, Thomas; Volk, Hans-Dieter; Reichenspurner, Hermann; Robbins, Robert C; Schrepfer, Sonja.
in: J CELL SCI, Jahrgang 124, Nr. Pt 17, Pt 17, 2011, S. 3029-3037.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Immunobiology of naïve and genetically modified HLA-class-I-knockdown human embryonic stem cells.
AU - Deuse, Tobias
AU - Seifert, Martina
AU - Phillips, Neil
AU - Fire, Andrew
AU - Tyan, Dolly
AU - Kay, Mark
AU - Tsao, Philip S
AU - Hua, Xiaoqin
AU - Velden, Joachim
AU - Eiermann, Thomas
AU - Volk, Hans-Dieter
AU - Reichenspurner, Hermann
AU - Robbins, Robert C
AU - Schrepfer, Sonja
PY - 2011
Y1 - 2011
N2 - Human embryonic stem cells (hESCs) can serve as a universal cell source for emerging cell or tissue replacement strategies, but immune rejection of hESC derivatives remains an unsolved problem. Here, we sought to describe the mechanisms of rejection for naïve hESCs and upon HLA class I (HLA I) knockdown (hESC(KD)). hESCs were HLA I-positive but negative for HLA II and co-stimulatory molecules. Transplantation of naïve hESC into immunocompetent Balb/c mice induced substantial T helper cell 1 and 2 (Th1 and Th2) responses with rapid cell death, but hESCs survived in immunodeficient SCID-beige recipients. Histology revealed mainly macrophages and T cells, but only scattered natural killer (NK) cells. A surge of hESC-specific antibodies against hESC class I, but not class II antigens, was observed. Using HLA I RNA interference and intrabody technology, HLA I surface expression of hESC(KD) was 88%-99% reduced. T cell activation after hESC(KD) transplantation into Balb/c was significantly diminished, antibody production was substantially alleviated, the levels of graft-infiltrating immune cells were reduced and the survival of hESC(KD) was prolonged. Because of their very low expression of stimulatory NK ligands, NK-susceptibility of naïve hESCs and hESC(KD) was negligible. Thus, HLA I recognition by T cells seems to be the primary mechanism of hESC recognition, and T cells, macrophages and hESC-specific antibodies participate in hESC killing.
AB - Human embryonic stem cells (hESCs) can serve as a universal cell source for emerging cell or tissue replacement strategies, but immune rejection of hESC derivatives remains an unsolved problem. Here, we sought to describe the mechanisms of rejection for naïve hESCs and upon HLA class I (HLA I) knockdown (hESC(KD)). hESCs were HLA I-positive but negative for HLA II and co-stimulatory molecules. Transplantation of naïve hESC into immunocompetent Balb/c mice induced substantial T helper cell 1 and 2 (Th1 and Th2) responses with rapid cell death, but hESCs survived in immunodeficient SCID-beige recipients. Histology revealed mainly macrophages and T cells, but only scattered natural killer (NK) cells. A surge of hESC-specific antibodies against hESC class I, but not class II antigens, was observed. Using HLA I RNA interference and intrabody technology, HLA I surface expression of hESC(KD) was 88%-99% reduced. T cell activation after hESC(KD) transplantation into Balb/c was significantly diminished, antibody production was substantially alleviated, the levels of graft-infiltrating immune cells were reduced and the survival of hESC(KD) was prolonged. Because of their very low expression of stimulatory NK ligands, NK-susceptibility of naïve hESCs and hESC(KD) was negligible. Thus, HLA I recognition by T cells seems to be the primary mechanism of hESC recognition, and T cells, macrophages and hESC-specific antibodies participate in hESC killing.
KW - Animals
KW - Humans
KW - Male
KW - Mice
KW - Mice, Inbred BALB C
KW - Transplantation, Heterologous
KW - Mice, SCID
KW - Embryonic Stem Cells/cytology/immunology/transplantation
KW - Gene Knockdown Techniques/methods
KW - Graft Rejection/genetics/immunology
KW - HLA Antigens/genetics/immunology
KW - Animals
KW - Humans
KW - Male
KW - Mice
KW - Mice, Inbred BALB C
KW - Transplantation, Heterologous
KW - Mice, SCID
KW - Embryonic Stem Cells/cytology/immunology/transplantation
KW - Gene Knockdown Techniques/methods
KW - Graft Rejection/genetics/immunology
KW - HLA Antigens/genetics/immunology
M3 - SCORING: Journal article
VL - 124
SP - 3029
EP - 3037
JO - J CELL SCI
JF - J CELL SCI
SN - 0021-9533
IS - Pt 17
M1 - Pt 17
ER -
