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CD26 costimulatory blockade improves lung allograft rejection and is associated with enhanced interleukin-10 expression - Zurich Open Repository and Archive


Yamada, Yoshito; Jang, Jae-Hwi; De Meester, Ingrid; Baerts, Lesley; Vliegen, Gwendolyn; Inci, Ilhan; Yoshino, Ichiro; Weder, Walter; Jungraithmayr, Wolfgang (2016). CD26 costimulatory blockade improves lung allograft rejection and is associated with enhanced interleukin-10 expression. Journal of Heart and Lung Transplantation, 35(4):508-517.

Abstract

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 μg). 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.

Abstract

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 μg). 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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Thoracic Surgery
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:April 2016
Deposited On:14 Feb 2017 15:17
Last Modified:14 Feb 2017 15:17
Publisher:Elsevier
ISSN:1053-2498
Publisher DOI:https://doi.org/10.1016/j.healun.2015.11.002
PubMed ID:26755203

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