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  • Review Article
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Transplantation tolerance through mixed chimerism

Nature Reviews Nephrology volume 6, pages 594–605 (2010)Cite this article

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Abstract

The major factors that limit the success of organ transplantation are the host immune response to the foreign graft and the adverse effects of the chronic immunosuppressive therapy required to suppress this immune response. Deliberately establishing tolerance towards the donor tissue by reprogramming the immune system of the recipient thus holds great promise in improving organ transplant survival and eliminating the untoward effects of chronic drug therapy. The transplantation of donor bone marrow into recipients who are appropriately conditioned to allow development of either full or mixed chimerism has long been recognized to effectively induce donor-specific tolerance. Despite the demonstrated effectiveness of this technique, use of the mixed chimerism strategy in regular clinical practice has been hampered by the toxic side effects inherent to conventional bone marrow transplantation protocols. This Review addresses recent advances in preclinical and clinical studies inducing transplantation tolerance through mixed chimerism and discusses both the potential and the challenges of this approach.

Key Points

  • The life-long immunosuppressive drug therapy required by organ transplant recipients is associated with severe morbidity and does not effectively prevent chronic rejection; donor-specific tolerance could obviate these problems

  • The induction of mixed chimerism through the transplantation of donor hematopoietic stem cells into the recipient is an effective approach towards achieving tolerance

  • Although the mixed chimerism approach has shown success in humans, its widespread clinical application has been impeded by the toxic side effects associated with current bone marrow transplantation protocols

  • Work in mouse models has progressed by moving from non-myeloablative towards non-cytoreductive bone marrow transplantation protocols

  • Translation of the work in murine models to large animal (including non-human primate) models is slowed by a number of factors

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Figure 1: Timeline of selected milestones in the development of the mixed chimerism approach.
Figure 2: The concept of tolerance through mixed chimerism.
Figure 3: The strategy of combining TREG cell therapy with the mixed chimerism approach: the TREG-chimerism protocol.

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Acknowledgements

Some of the work described in this Review was supported by research grants from the Austrian Science Fund (FWF, SFB-F2310) and the European Society for Organ Transplantation (ESOT).

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  1. Division of Transplantation, Department of Surgery, Vienna General Hospital, Medical University of Vienna, Waehringer Guertel 18–20, Vienna, 1090, Austria

    Nina Pilat & Thomas Wekerle

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Both authors contributed to researching data for the article, discussing the content, writing the article, and reviewing and editing the manuscript before submission.

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Correspondence to Thomas Wekerle.

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T. Wekerle declares associations with the following companies: Bristol-Myers Squibb (grant/research support), Wyeth (speakers' bureau). N. Pilat declares no competing interests.

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Pilat, N., Wekerle, T. Transplantation tolerance through mixed chimerism. Nat Rev Nephrol 6, 594–605 (2010). https://doi.org/10.1038/nrneph.2010.110

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