The management of graft-versus-host disease (GVHD) is a continuing problem in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Whereas considerable progress has been made in prevention and treatment of acute GVHD (aGVHD), chronic GVHD (cGVHD) remains virtually unsolved, diminishing the prognosis and quality of life of post-allo-HSCT patients. 1 There is no satisfactory animal model of cGVHD to study the immunological process of the disease. Accordingly, careful investigation of clinical samples obtained from cGVHD patients is of particular importance and it is the only reliable way to get insights into the pathogenesis of cGVHD. OX40 (CD134), a member of tumor necrosis factor (TNF) receptor family, is expressed on activated CD4þ as well as CD8þ T cells. The interaction of OX40 with its ligand (OX40L), a TNF family molecule, generates costimulatory signals, resulting in enhanced T-cell proliferation and cytokine production. The OX40 ligation is known to be crucial for appropriate antigen presentation by dendritic cells leading to clonal expansion and long-term survival of antigen-specific T cells. 2 In murine models, several reports have indicated that the OX40/OX40L system plays an important role in the pathogenesis of aGVHD. 3

We have previously shown that the percentage of OX40þ CD4þ T cells in peripheral blood correlated with the progression of cGVHD. 4 Then the obvious question appeared whether the interaction of OX40 and its ligand OX40L might be involved in the pathogenesis of cGVHD. To address the question, we examined the expression of OX40 and OX40L in the lesional skin specimens (Table 1). Immunohistochemical studies5 revealed that OX40þ cells were present in the almost all skin specimens (10/11 in aGVHD and 11/13 in cGVHD) and OX40Lþ cells were present in the skin specimens in 6/11 aGVHD patients and, more notably, in 14/15 cGVHD patients (Figure 1a) whereas such cells were absent or scarce in five normal controls (Figure 1j). These OX40Lþ cells were distributed in the dermis, especially around the blood vessels and the skin appendix (Figure 1a). OX40þ cells, presumably T cells, were localized mainly in the epidermal and