The Journal of Experimental Medicine
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Published 5 August 2002. doi:10.1084/jem.20020399
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*Bone Marrow Transplantation
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© Rockefeller University Press, 0022-1007/2002/8/389/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 3, August 5, 2002 389-399

Donor-type CD4+CD25+ Regulatory T Cells Suppress Lethal Acute Graft-Versus-Host Disease after Allogeneic Bone Marrow Transplantation

Petra Hoffmann1, Joerg Ermann1, Matthias Edinger2, C. Garrison Fathman1 and Samuel Strober1

1 Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305
2 Division of Bone Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305

Address correspondence to Samuel Strober, Division of Immunology and Rheumatology, Department of Medicine, CCSR Building, 2215-C, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305. Phone: 650-725-6500; Fax: 650-725-6104; E-mail: sstrober{at}stanford.edu

Acute graft-versus-host disease (aGVHD) is still a major obstacle in clinical allogeneic bone marrow (BM) transplantation. CD4+CD25+ regulatory T (Treg) cells have recently been shown to suppress proliferative responses of CD4+CD25- T cells to alloantigenic stimulation in vitro and are required for ex vivo tolerization of donor T cells, which results in their reduced potential to induce aGVHD. Here we show that CD4+CD25+ T cells isolated from the spleen or BM of donor C57BL/6 (H-2b) mice that have not been tolerized are still potent inhibitors of the alloresponse in vitro and of lethal aGVHD induced by C57BL/6 CD4+CD25- T cells in irradiated BALB/c (H-2d) hosts in vivo. The addition of the CD4+CD25+ Treg cells at a 1:1 ratio with responder/inducer CD4+CD25- T cells resulted in a >90% inhibition of the mixed leukocyte reaction and marked protection from lethal GVHD. This protective effect depended in part on the ability of the transferred CD4+CD25+ T cells to secrete interleukin 10 and occurred if the Treg cells were of donor, but not host, origin. Our results demonstrate that the balance of donor-type CD4+CD25+ Treg and conventional CD4+CD25- T cells can determine the outcome of aGVHD.

Key Words: immune regulation • T lymphocytes • IL-10 • mixed leukocyte reaction • alloimmunity


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