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Prepublished online as a Blood First Edition Paper on November 14, 2002; DOI 10.1182/blood-2002-10-3014. This Article Full Text (PDF) Erratum (v102,p1950) All Versions of this Article: 2002-10-3014v1 101/7/2886    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Blaha, P. Articles by Wekerle, T. Search for Related Content PubMed PubMed Citation Articles by Blaha, P. Articles by Wekerle, T. Social Bookmarking                   What's this? Submitted October 2, 2002 Accepted November 8, 2002 The influence of immunosuppressive drugs on tolerance induction through bone marrow transplantation with costimulation blockade Peter Blaha, Sinda Bigenzahn, Zvonimir Koporc, Maximilian Schmid, Felix Langer, Edgar Selzer, Helga Bergmeister, Friedrich Wrba, Josef Kurtz, Christopher Kiss, Erich Roth, Ferdinand Muehlbacher, Megan Sykes, and Thomas Wekerle* Division of Transplantation, Dept. of Surgery, Vienna General Hospital/University of Vienna, Vienna, Austria Department of Radiotherapy and Radiobiology, Vienna General Hospital/University of Vienna, Vienna, Austria Institute of Biomedical Research, Vienna General Hospital/University of Vienna, Vienna, Austria Institute of Clinical Pathology, Vienna General Hospital/University of Vienna, Vienna, Austria Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA Surgical Research Laboratories, Vienna General Hospital/University of Vienna, Vienna, Austria * Corresponding author; email: Thomas.Wekerle{at}akh-wien.ac.at. We have recently developed a murine protocol for the induction of allogeneic mixed chimerism and tolerance employing non-myeloablative total body irradiation (TBI), standard-dose bone marrow transplantation (BMT) and costimulation blockade (co.bl.) with an anti-CD154 monoclonal antibody (mAb) plus CTLA4Ig. We now evaluated whether a short course (1 month) of immunosuppressive drugs, which would be ethically required in the clinical setting of organ transplantation in order to prevent graft loss in case that tolerance is not achieved, interferes with tolerance induced with this regimen. Our results show that calcineurin inhibitors (cyclosporin A (CyA) or tacrolimus (FK)) inhibit development of long-term chimerism and abrogate tolerance induction in this model. Rapamycin (rapa), methylprednisolone (MP), FTY720 and mycophenolate mofetil (MMF), in contrast, have no negative effect on chimerism or tolerance development. Peripheral deletion of donor-reactive T cells, which usually occurs in the weeks following BMT in this model, is blocked by CyA and FK, but not by the other drugs tested. Furthermore, we found that the additional use of compatible immunosuppressive drugs (rapa plus MMF plus MP) allows the dose of TBI to be reduced, so that mixed chimerism and donor skin graft acceptance can be achieved with 1 Gy using clinically feasible cell numbers. Thus, our protocol of BMT with costimulation blockade can be safely combined with a clinically tested immunosuppressive regimen which even permits success with a lower dose of irradiation. These results should facilitate clinical application of this tolerance strategy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. Tchorsh-Yutsis, G. Hecht, A. Aronovich, E. Shezen, Y. Klionsky, C. Rosen, R. Bitcover, S. Eventov-Friedman, H. Katchman, S. Cohen, et al. 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