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We identified the domains of CD26 involved in the binding of Middle East respiratory syndrome coronavirus (MERS-CoV) using distinct clones of anti-CD26 monoclonal antibodies (MAbs). One clone, named 2F9, almost completely inhibited viral entry.The humanized anti-CD26 MAb YS110 also significantly inhibited infection. These findings indicate that both 2F9 and YS110 are potential therapeutic agents for MERS-CoV infection. YS110, in particular, is a good candidate for immediate testing as a therapeutic modality for MERS.A novel coronavirus, Middle East respiratory syndrome coronavirus (MERS-CoV), was identified in patients with severe lower respiratory tract infections with almost 50% of cases resulting in lethal lower respiratory tract infections (1-5). Initially, MERS-CoV infection occurred sporadically; however, horizontal infection among human patients has been demonstrated and has potential pandemic ramifications. While MERS-CoV was reported to be sensitive to alpha interferon or cyclosporine treatment (6, 7), there are no vaccines or effective therapies currently available for clinical cases of MERS-CoV infection.A recent report showed that the spike (S) protein of MERSCoV mediates infection (8) using dipeptidyl peptidase IV (DPPIV; EC 3.4.14.5) as a functional receptor (9). This receptor is conserved among different species, such as bats and humans, which partially explains the large host range of MERS-CoV. DPPIV is also known as CD26, which is a 110-kDa cell surface glycoprotein with dipeptidase activity in its extracellular domain (10). CD26/DPPIV is a multifunctional cell surface protein that is widely expressed in most cell types, including T lymphocytes, bronchial mucosa, and the brush border of proximal tubules. This distribution of CD26 may play a role in the systemic dissemination of MERS-CoV infection in humans (11-13). Therefore, an effective therapy for MERS-CoV infection is needed not only to block the entry of MERS-CoV into such CD26-expressing organs as the respiratory system, kidney, liver, or intestine but also to eliminate circulating MERS-CoV. More recently, crystal structure analysis revealed the CD26 -MERS-CoV binding regions (14,15), and manipulation of CD26/DPPIV levels or the development of inhibitors that target the interaction between the MERS-CoV S domain and its receptor may provide therapeutic opportunities to combat MERS-CoV infection. In the present study, we mapped MERS-CoV S protein binding regions in human CD26 molecules and demonstrated that anti-CD26 monoclonal antibodies (MAbs)

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Psoriasis is a chronic inflammatory skin disease characterized mainly by epidermal hyperplasia, scaling, and erythema; T helper 17 cells have a role in its pathogenesis. Although IL-26, known as a T helper 17 cytokine, is upregulated in psoriatic skin lesions, its precise role is unclear. We investigated the role of IL-26 in the imiquimod-induced psoriasis-like murine model using human IL-26 transgenic mice. Erythema symptoms induced by daily applications of imiquimod increased dramatically in human IL-26 transgenic mice compared with controls. Vascularization and immune cell infiltration were prominent in skin lesions of human IL-26 transgenic mice. Levels of fibroblast growth factor (FGF) 1, FGF2, and FGF7 were significantly upregulated in the skin lesions of imiquimod-treated human IL-26 transgenic mice and psoriasis patients. In vitro analysis demonstrated that FGF1, FGF2, and FGF7 levels were elevated in human keratinocytes and vascular endothelial cells following IL-26 stimulation. Furthermore, IL-26 acted directly on vascular endothelial cells, promoting proliferation and tube formation, possibly through protein kinase B, extracellular signaleregulated kinase, and NF-kB pathways. Moreover, similar effects of IL-26 were observed in the murine contact hypersensitivity model, indicating that these effects are not restricted to psoriasis. Altogether, our data indicate that IL-26 may be a promising therapeutic target in T cellemediated skin inflammation, including psoriasis.

Obliterative bronchiolitis is a potentially life-threatening noninfectious pulmonary complication after allogeneic hematopoietic stem cell transplantation and the only pathognomonic manifestation of pulmonary chronic graft-versus-host disease (cGVHD). In the current study, we identified a novel effect of IL-26 on transplant-related obliterative bronchiolitis. Sublethally irradiated NOD/Shi-scidIL2rγnull mice transplanted with human umbilical cord blood (HuCB mice) gradually developed clinical signs of graft-versus-host disease (GVHD) such as loss of weight, ruffled fur, and alopecia. Histologically, lung of HuCB mice exhibited obliterative bronchiolitis with increased collagen deposition and predominant infiltration with human IL-26+CD26+CD4 T cells. Concomitantly, skin manifested fat loss and sclerosis of the reticular dermis in the presence of apoptosis of the basilar keratinocytes, whereas the liver exhibited portal fibrosis and cholestasis. Moreover, although IL-26 is absent from rodents, we showed that IL-26 increased collagen synthesis in fibroblasts and promoted lung fibrosis in a murine GVHD model using IL-26 transgenic mice. In vitro analysis demonstrated a significant increase in IL-26 production by HuCB CD4 T cells following CD26 costimulation, whereas Ig Fc domain fused with the N-terminal of caveolin-1 (Cav-Ig), the ligand for CD26, effectively inhibited production of IL-26. Administration of Cav-Ig before or after onset of GVHD impeded the development of clinical and histologic features of GVHD without interrupting engraftment of donor-derived human cells, with preservation of the graft-versus-leukemia effect. These results therefore provide proof of principle that cGVHD of the lungs is caused in part by IL-26+CD26+CD4 T cells, and that treatment with Cav-Ig could be beneficial for cGVHD prevention and therapy.