Regulation of pulmonary graft-versus-host disease by IL-26+CD26+CD4 T lymphocytes.

Ohnuma K, Hatano R, Aune TM, Otsuka H, Iwata S, Dang NH, Yamada T, Morimoto C
J Immunol. 2015 194 (8): 3697-712

PMID: 25786689 · PMCID: PMC4568737 · DOI:10.4049/jimmunol.1402785

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.

Copyright © 2015 by The American Association of Immunologists, Inc.

MeSH Terms (18)

Animals Caveolin 1 CD4-Positive T-Lymphocytes Cord Blood Stem Cell Transplantation Dermis Dipeptidyl Peptidase 4 Graft vs Host Disease Graft vs Leukemia Effect Humans Interleukins Lung Lung Diseases Mice Mice, Inbred NOD Mice, Knockout NIH 3T3 Cells Receptors, Fc Recombinant Fusion Proteins

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