title: CD26 costimulatory blockade improves lung allograft rejection and is associated with enhanced interleukin-10 expression.
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.
authors.affiliation: Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland; Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Jae-Hwi
authors.initials: JH
authors.lastname: Jang
authors.affiliation: Department of Medical Biochemistry, University of Antwerp, Antwerp, Belgium.
authors.forename: Ingrid
authors.initials: I
authors.lastname: De Meester
authors.affiliation: Department of Medical Biochemistry, University of Antwerp, Antwerp, Belgium.
authors.forename: Lesley
authors.initials: L
authors.lastname: Baerts
authors.affiliation: Department of Medical Biochemistry, University of Antwerp, Antwerp, Belgium.
authors.forename: Gwendolyn
authors.initials: G
authors.lastname: Vliegen
authors.affiliation: Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Ilhan
authors.initials: I
authors.lastname: Inci
authors.affiliation: Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Yoshino
authors.affiliation: Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Walter
authors.initials: W
authors.lastname: Weder
authors.affiliation: Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland. Electronic address: wolfgang.jungraithmayr@usz.ch.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jungraithmayr
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D064591:Allografts; D000818:Animals; D004247:DNA / Q000235:genetics*; D018819:Dipeptidyl Peptidase 4 / Q000187:drug effects* / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics*; D016040:Lung Transplantation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009570:Nitriles / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D000077597:Vildagliptin
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D009570:Nitriles; D011759:Pyrrolidines; D016753:Interleukin-10; D004247:DNA; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse; D000077597:Vildagliptin; D000218:Adamantane
keywords: CD26/DPP4; IL-10; Th17; acute rejection; mouse lung transplantation