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: Kei Ohnuma, Ryo Hatano, Thomas M Aune, Haruna Otsuka, Satoshi Iwata, Nam H Dang, Taketo Yamada, Chikao Morimoto
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 194 Issue 8 Pg. 3697-712 (Apr 15 2015) ISSN: 1550-6606 [Electronic] United States
• PMID: 25786689 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 by The American Association of Immunologists, Inc.

Chemical References

• CAV1 protein, human
• Caveolin 1
• IL26 protein, human
• Interleukins
• Receptors, Fc
• Recombinant Fusion Proteins
• Dipeptidyl Peptidase 4
• Dpp4 protein, mouse

Topics

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