title: Immunobiology of naïve and genetically modified HLA-class-I-knockdown human embryonic stem cells.
abstract: 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.
authors: Cardiothoracic Surgery Department, Stanford University, Stanford, CA 94305, USA.
authors: Tobias
authors: T
authors: Deuse
authors: Martina
authors: M
authors: Seifert
authors: Neil
authors: N
authors: Phillips
authors: Andrew
authors: A
authors: Fire
authors: Dolly
authors: D
authors: Tyan
authors: Mark
authors: M
authors: Kay
authors: Philip S
authors: PS
authors: Tsao
authors: Xiaoqin
authors: X
authors: Hua
authors: Joachim
authors: J
authors: Velden
authors: Thomas
authors: T
authors: Eiermann
authors: Hans-Dieter
authors: HD
authors: Volk
authors: Hermann
authors: H
authors: Reichenspurner
authors: Robert C
authors: RC
authors: Robbins
authors: Sonja
authors: S
authors: Schrepfer
mesh_terms: D000818:Animals; D053595:Embryonic Stem Cells / Q000166:cytology / Q000276:immunology* / Q000637:transplantation*; D055785:Gene Knockdown Techniques / Q000379:methods; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology*; D006680:HLA Antigens / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D014183:Transplantation, Heterologous
chemical_list: D006680:HLA Antigens