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Allogeneic bone marrow transplantation with co-stimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment

Nature Medicine volume 6, pages 464–469 (2000)Cite this article

Abstract

Allogeneic bone marrow transplantation (in immunocompetent adults) has always required cytoreductive treatment of recipients with irradiation or cytotoxic drugs to achieve lasting engraftment at levels detectable by non-PCR-based techniques (‘macrochimerism’ or ‘mixed chimerism’)1,2,3,4,5,6,7,8,9,10,11. Only syngeneic marrow engraftment at such levels has been achieved in unconditioned hosts12,13. This requirement for potentially toxic myelosuppressive host pre-conditioning has precluded the clinical use of allogeneic bone marrow transplantation for many indications other than malignancies, including tolerance induction. We demonstrate here that treatment of naive mice with a high dose of fully major histocompatibility complex-mismatched allogeneic bone marrow, followed by one injection each of monoclonal antibody against CD154 and cytotoxic T-lymphocyte antigen 4 immunoglobulin, resulted in multi-lineage hematopoietic macrochimerism (of about 15%) that persisted for up to 34 weeks. Long-term chimeras developed donor-specific tolerance (donor skin graft survival of more than 145 days) and demonstrated ongoing intrathymic deletion of donor-reactive T cells. A protocol of high-dose bone marrow transplantation and co-stimulatory blockade can thus achieve allogeneic bone marrow engraftment without cytoreduction or T-cell depletion of the host, and eliminates a principal barrier to the more widespread use of allogeneic bone marrow transplantation14,15,16,17,18. Although efforts have been made to minimize host pre-treatment for allogeneic bone marrow transplantation for tolerance induction, so far none have succeeded in eliminating pre-treatment completely. Our demonstration that this can be achieved provides the rationale for a safe approach for inducing robust transplantation tolerance in large animals and humans.

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Figure 1: Macrochimerism and tolerance after high-dose BMT with co-stimulatory blockade.

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Acknowledgements

We thank H. Auchincloss Jr., H. Winn and L.A. Turka for review of the manuscript; D.H. Sachs for support and advice; and D. Plemenos for secretarial assistance. This study was supported by National Institutes of Health Grant R01 HL49915 and in part by a sponsored research agreement between Massachusetts General Hospital and BioTransplant. M.H.S. is a recipient of the National Kidney Foundation Clinician Scientist Award. T.W. was supported by fellowships from the Max Kade Foundation and the Austrian Science Fund (Fonds zur Foerderung der wissenschaftlichen Forschung).

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  1. Thomas Wekerle

    Present address: Department of Surgery, Vienna General Hospital/University of Vienna, Währingergürtel 18, A-1090, Vienna, Austria

Authors and Affiliations

  1. BMT Section, Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, MGH East, Bldg. 149-5102, 13th Street, Boston, 02129, Massachusetts , USA

    Thomas Wekerle, Josef Kurtz, Hiroshi Ito, Joseph V. Ronquillo, Guiling Zhao, Juanita Shaffer & Megan Sykes

  2. The Laboratory of Immunogenetics and Transplantation Department of Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, 02115, Massachusetts, USA

    Victor Dong & Mohamed H. Sayegh

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Correspondence to Megan Sykes.

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Wekerle, T., Kurtz, J., Ito, H. et al. Allogeneic bone marrow transplantation with co-stimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment. Nat Med 6, 464–469 (2000). https://doi.org/10.1038/74731

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