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 Blood, 15 July 2007, Vol. 110, No. 2, pp. 776-782.
Prepublished online as a Blood First Edition Paper on March 15, 2007; DOI 10.1182/blood-2006-08-043612.

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TRANSPLANTATION

Costimulatory molecule-targeted immunotherapy of cutaneous graft-versus-host disease

Juyang Kim1, Hye J. Kim1, Keunhee Park1, Jiyoung Kim1, Hye-Jeong Choi2, Hideo Yagita3, Seok H. Nam4, Hong R. Cho5, and Byungsuk Kwon1

1 Department of Biological Science and Immunomodulation Reseach Center, University of Ulsan, Republic of Korea; 2 Department of Pathology, Ulsan University Hospital, Republic of Korea; 3 Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan; 4 Department of Biological Science, Ajou University, Suwon, Republic of Korea; and 5 Department of Surgery and Biomedical Research Center, Ulsan University Hospital, Republic of Korea

Chronic graft-versus-host disease (cGVHD) is an increasingly frequent complication of allogeneic stem cell transplantation. Current therapies for cGVHD reduce symptoms but are not cures. The B10.D2->Balb/c (H-2d) minor histocompatibility antigen-mismatched model, which reflects clinical and pathological symptoms of human cGVHD, was used in this study. We demonstrated that a single injection of an agonistic monoclonal antibody (mAb) against CD137, a member of the tumor necrosis factor receptor superfamily, reverses skin fibrosis, ulceration, and alopecia, a dominant feature of cGVHD (cutaneous GVHD), ultimately improving general health conditions. The reversal is associated with markedly reduced CD4+ T-cell cytokines and increased apoptosis of donor CD4+ T cells. The Fas pathway is required for ameliorating cutaneous GVHD by anti-CD137 mAb. Taken together, these data indicate that the anti-CD137 mAb has a therapeutic effect on cutaneous GVHD by removing donor CD4+ T cells that cause cutaneous GVHD. Thus, our study demonstrates an agonistic mAb, specific for a costimulatory molecule, as a possible target for therapeutic intervention in cutaneous GVHD.


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