title: Regulation of pulmonary graft-versus-host disease by IL-26+CD26+CD4 T lymphocytes.
abstract: 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-scidIL2rγ(null) 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.
authors: Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan;
authors: Kei
authors: K
authors: Ohnuma
authors: Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan;
authors: Ryo
authors: R
authors: Hatano
authors: Department of Medicine, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232;
authors: Thomas M
authors: TM
authors: Aune
authors: Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan;
authors: Haruna
authors: H
authors: Otsuka
authors: Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan;
authors: Satoshi
authors: S
authors: Iwata
authors: Division of Hematology and Oncology, University of Florida, Gainesville, FL 32610; and.
authors: Nam H
authors: NH
authors: Dang
authors: Department of Pathology, Keio University School of Medicine, Tokyo, 160-8582, Japan.
authors: Taketo
authors: T
authors: Yamada
authors: Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan; morimoto@ims.u-tokyo.ac.jp.
authors: Chikao
authors: C
authors: Morimoto
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D051242:Caveolin 1 / Q000235:genetics / Q000494:pharmacology; D036101:Cord Blood Stem Cell Transplantation; D020405:Dermis / Q000276:immunology / Q000473:pathology; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000276:immunology*; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D020544:Graft vs Leukemia Effect / Q000235:genetics; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008171:Lung Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D011961:Receptors, Fc / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology
chemical_list: C495540:CAV1 protein, human; D051242:Caveolin 1; C406767:IL26 protein, human; D007378:Interleukins; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse