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Title
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CD26 costimulatory blockade improves lung allograft rejection and is associated with enhanced interleukin-10 expression
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Author
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Abstract
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| BACKGROUND: The ectoenzyme CD26/dipeptidyl peptidase 4 (DPP4) has costimulatory activity that contributes to T cell activation and proliferation. Here, we aimed to target this costimulatory activity for the attenuation of the alloreactive Th17 cell response during acute rejection after mouse lung transplantation. METHODS: To test the CD26-costimulatory blockade in vitro, mixed lymphocyte reaction was performed between major histocompatibility complex class I and II fully mismatched cells (CD4(+) splenocytes, C57BL/6, responders, and antigen-presenting cells, BALB/c, stimulators) by adding the CD26 inhibitor vildagliptin (0-15 mu g). Lung transplantation between BALB/c (donor) and C57BL/6 (recipient) mice was performed, including controls, CD26-inhibited (CD26-I, daily administration of vildagliptin [GLSynthesis, Worcester, MA], 10 mg/kg subcutaneous), and CD26 knockout (CD26KO) mice was performed. Analysis on Day 1 and 5 after transplant included immunohistochemistry, fluorescence-activated cell sorting, and enzyme-linked immunosorbent assay (ELISA) for immune cell detection and their key cytokines. RESULTS: In vitro, there was a significant reduction of the Th17 cytokines interleukin (IL)-17 and IL-21. In vivo, CD26-I treated and. CD26KO mice showed significantly preserved macroscopic and histologic characteristics on Day 5 (p < 0.01), a higher partial pressure of arterial oxygen/fraction of inspired oxygen ratio (p <= 0.05), fewer infiltrating CD3(+) T cells (p < 0.01), but more interstitial macrophages on Day 1 (p < 0.01) compared with control. Fewer IL-17(+) cells were found in CD26-I allografts on Day 1(p = 0.05). Higher levels of IL-10 in CD26-I and CD26KO allografts on day 5 were seen (p < 0.05). IL-10/CD206 double-staining (alternative macrophages) revealed more positive cells in CD26-I and CD26KO on Day 1 and 5 (p < 0.01). CONCLUSIONS: CD26 costimulatory blockade promotes lung allograft acceptance via reduced T cell infiltration, less expression of IL-17, and increased expression of IL-10, likely to be derived from alternatively activated macrophages. (C) 2016 International Society for Heart and Lung Transplantation. All rights reserved. |
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Language
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English
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Source (journal)
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Journal of heart and lung transplantation. - St-Louis, Mo.
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Publication
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St-Louis, Mo.
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2016
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ISSN
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1053-2498
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DOI
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10.1016/J.HEALUN.2015.11.002
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Volume/pages
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35
:4
(2016)
, p. 508-517
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ISI
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000374278700015
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Pubmed ID
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26755203
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Full text (Publisher's DOI)
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Full text (publisher's version - intranet only)
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