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CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation

Nature Medicine volume 9, pages 11441150 (2003) | Download Citation

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Abstract

Mature donor T cells cause graft-versus-host disease (GVHD), but they are also the main mediators of the beneficial graft-versus-tumor (GVT) activity of allogeneic bone marrow transplantation. Suppression of GVHD with maintenance of GVT activity is a desirable outcome for clinical transplantation. We have previously shown that donor-derived CD4+CD25+ regulatory T cells inhibit lethal GVHD after allogeneic bone marrow transplantation across major histocompatibility complex (MHC) class I and II barriers in mice. Here we demonstrate that in host mice with leukemia and lymphoma, CD4+CD25+ regulatory T cells suppress the early expansion of alloreactive donor T cells, their interleukin-2-receptor (IL-2R) α-chain expression and their capacity to induce GVHD without abrogating their GVT effector function, mediated primarily by the perforin lysis pathway. Thus, CD4+CD25+ T cells are potent regulatory cells that can separate GVHD from GVT activity mediated by conventional donor T cells.

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Acknowledgements

We thank C. Arber for assistance with stem cell isolation, L. Ailles for the lentiviral vector constructs and C.H. Contag for access to the imaging equipment. This work was supported in part by NIH grants P01-CA49605, HL57443 and RO1s CA8006, HL58520, CA92225, CA65237, DK61925 and AI49903, and by fellowship grants from the Clinique LaPrairie Research Foundation (P.H.) and the Dr. Mildred Scheel Stifung (M.E.).

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Affiliations

  1. Divisions of Bone Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, USA.

    • Matthias Edinger
    • , Kathryn Drago
    •  & Robert S Negrin
  2. Divisions of Rheumatology and Immunology, Department of Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, USA.

    • Petra Hoffmann
    • , Joerg Ermann
    • , C Garrison Fathman
    •  & Samuel Strober
  3. Department of Hematology and Oncology, University Hospital Regensburg, Franz-Josef-Strauss Allee 11, 93053 Regensburg, Germany.

    • Matthias Edinger
    •  & Petra Hoffmann

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The authors declare no competing financial interests.

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Correspondence to Robert S Negrin.

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https://doi.org/10.1038/nm915