Immunobiology of naïve and genetically modified HLA-class-I-knockdown human embryonic stem cells

DOI PDF 被引用文献2件
  • Tobias Deuse
    Cardiothoracic Surgery, Stanford University, Stanford, CA 94305, USA
  • Martina Seifert
    Institute of Medical Immunology and Berlin-Brandenburg Center for Regenerative Therapies (BCRT) Charité Campus Virchow-Klinikum, Berlin 13353, Germany
  • Neil Phillips
    Pediatrics, Human Gene Therapy, Stanford University, Stanford, CA 94305, USA
  • Andrew Fire
    Pathology, Stanford University, Stanford, CA 94305, USA
  • Dolly Tyan
    Pathology, Stanford University, Stanford, CA 94305, USA
  • Mark Kay
    Pediatrics, Human Gene Therapy, Stanford University, Stanford, CA 94305, USA
  • Philip S. Tsao
    Cardiovascular Medicine, Stanford University, Stanford, CA 94305, USA
  • Xiaoqin Hua
    Cardiovascular Surgery, TSI-laboratory, University Hospital Hamburg, Hamburg 20246, Germany
  • Joachim Velden
    Pathology, University Hospital Hamburg, Hamburg 20246, Germany
  • Thomas Eiermann
    Transfusion Medicine, University Hospital Hamburg, Hamburg 20246, Germany
  • Hans-Dieter Volk
    Institute of Medical Immunology and Berlin-Brandenburg Center for Regenerative Therapies (BCRT) Charité Campus Virchow-Klinikum, Berlin 13353, Germany
  • Hermann Reichenspurner
    Cardiovascular Surgery, TSI-laboratory, University Hospital Hamburg, Hamburg 20246, Germany
  • Robert C. Robbins
    Cardiothoracic Surgery, Stanford University, Stanford, CA 94305, USA
  • Sonja Schrepfer
    Cardiothoracic Surgery, Stanford University, Stanford, CA 94305, USA

抄録

<jats:p>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 (hESCKD). 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 hESCKD was 88%–99% reduced. T cell activation after hESCKD 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 hESCKD was prolonged. Because of their very low expression of stimulatory NK ligands, NK-susceptibility of naïve hESCs and hESCKD 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.</jats:p>

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