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Preimplantation-stage stem cells induce long-term allogeneic graft acceptance without supplementary host conditioning

Nature Medicine volume 8, pages 171–178 (2002)Cite this article

Abstract

Hematopoietic stem cells have been successfully employed for tolerance induction in a variety of rodent and large animal studies. However, clinical transplantation of fully allogeneic bone marrow or blood-borne stem cells is still associated with major obstacles, such as graft-versus-host disease or cytoreductive conditioning-related toxicity. Here we show that when rat embryonic stem cell-like cells of WKY origin are injected intraportally into fully MHC-mismatched DA rats, they engraft permanently (>150 days) without supplementary host conditioning. This deviation of a potentially alloreactive immune response sets the basis for long-term graft acceptance of second-set transplanted WKY cardiac allografts. Graft survival was strictly correlated with a state of mixed chimerism, which required functional thymic host competence. Our results provide a rationale for using preimplantation-stage stem cells as vehicles in gene therapy and for the induction of long-term graft acceptance.

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Figure 1: Morphology and markers of RESC.
Figure 2: In vivo trafficking of intraportally injected RESC.
Figure 3: Thymic competence is required for RESC-induced donor-specific graft acceptance.
Figure 4: RESC suppress donor-specific immune responses in vivo.

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Acknowledgements

This work was supported in part by a grant of the Interdisziplinäre Forschergruppe Transplantationsmedizin (IFTM) of the University of Kiel and partly by a grant from the Deutsche Forschungsgemeinschaft (Za 131/7-3). We thank P. Boll, K. Broetzmann, P. Krüger, K.-A. Y. Ott, I. Schellhorn and M. Hauberg for excellent technical support.

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Author notes

  1. Fred Fändrich and Xiongbin Lin: F.F. and X.L contributed equally to this study.

Authors and Affiliations

  1. Department of General Surgery and Thoracic Surgery, University of Kiel, Kiel, 24105, Germany

    Fred Fändrich, Xiongbin Lin, Maren Schulze, Julia Holle & Dong-Sheng Huang

  2. Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, 13092, Germany

    Gui X. Chai, Detlev Ganten, Michael Bader & Bert Binas

  3. Pathology Department, BML 116, Yale University School of Medicine, New Haven, 06520-8023, Connecticut, USA

    Gui X. Chai

  4. Institute of Hematopathology, University of Kiel, Kiel, 24105, Germany

    Reza Parwaresch

  5. University Iowa Hospitals and Clinics &VA Medical Center, Iowa City, Iowa, USA

    Nicholaus Zavazava

  6. Department of Veterinary Pathobiology, College of Veterinary Medicine, Texas A&M University, Texas, USA

    Bert Binas

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  1. Fred Fändrich
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Correspondence to Fred Fändrich.

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Fändrich, F., Lin, X., Chai, G. et al. Preimplantation-stage stem cells induce long-term allogeneic graft acceptance without supplementary host conditioning. Nat Med 8, 171–178 (2002). https://doi.org/10.1038/nm0202-171

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