title: CD26/dipeptidylpeptidase IV-targeted therapy of acute lung rejection in rats.
abstract: BACKGROUND
  CD26 is a T-cell co-stimulator, and interacts with adenosine deaminase, human immunodeficiency virus (HIV) Tat-1 protein and extracellular matrix. It possesses dipeptidylpeptidase IV (DPP IV) catalytic activity, which is linked to its co-stimulatory efficacy. We investigated the effect of specific DPP IV systemic activity inhibition on acute pulmonary rejection.
  
  
  METHODS
  Rat single-lung transplantation (Tx) was performed (LBNF1/LEW donor/recipient) in two groups (n = 12). Group I (n = 6) received daily treatment with a Pro-Pro-diphenylphosphonate derivative (AB197), and Group II served as an untreated control. At Day 5 post-Tx, ventilatory parameters, cytotoxicity and mixed lymphocyte reaction were analyzed and staining for ISHLT rejection grade and proliferating cell nuclear antigen (PCNA) was performed.
  
  
  RESULTS
  Treatment with AB192 abrogated acute rejection and preserved pulmonary function up to Day 5 post-Tx for PO2 (Group II: 24.9 +/- 6.9 mm Hg; Group I: 149.5 +/- 24.3 mm Hg; p < 0.001), PCO2 (Group II: 53.3 +/- 13.6 mm Hg; Group I: 39.0 +/- 9.8 mm Hg; p < 0.05) and peak airway pressure (Group II: 50.7 +/- 17.2 mm Hg; Group I: 20.2 +/- 10.0 mm Hg; p < 0.01). Controls showed moderate/severe rejection (ISHLT Grade A2 or 3), grafts from inhibited hosts revealed no/mild rejection (Grade A0 to 2: Group II: 2.8 +/- 0.3; Group I: 1.25 +/- 1.0; p < 0.005). Proliferating cell nuclear antigen (PCNA) staining of rejection-associated cellular infiltrates showed a significant reduction in positivity in perivascular infiltrates (34 +/- 11.5%; p < 0.05) and bronchial surface epithelium (31.7 +/- 10.6%; p < 0.05) in Group I vs Group II (55.9 +/- 8.4% and 57.2 +/- 4.5%).
  
  
  CONCLUSIONS
  Irreversible enzymatic inhibition of DPP IV has been shown to abrogate acute pulmonary rejection, maintain pulmonary function, and preserve histomorphologic architecture. These results extend earlier findings and illustrate the role of CD26/DPP IV in alloantigen-mediated immune responses.
authors.affiliation: Department of Thoracic Surgery, University Hospital Zurich, Switzerland.
authors.forename: Florian Johannes
authors.initials: FJ
authors.lastname: Jung
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.forename: Ingrid
authors.initials: I
authors.lastname: De Meester
authors.forename: Koen
authors.initials: K
authors.lastname: Augustyns
authors.forename: Markus
authors.initials: M
authors.lastname: Cardell
authors.forename: Sven
authors.initials: S
authors.lastname: Hillinger
authors.forename: Peter
authors.initials: P
authors.lastname: Vogt
authors.forename: Didier
authors.initials: D
authors.lastname: Lardinois
authors.forename: Simon
authors.initials: S
authors.lastname: Scharpé
authors.forename: Walter
authors.initials: W
authors.lastname: Weder
authors.forename: Stephan
authors.initials: S
authors.lastname: Korom
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology; D018819:Dipeptidyl Peptidase 4 / Q000097:blood / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006084:Graft Rejection / Q000188:drug therapy* / Q000201:enzymology* / Q000517:prevention & control; D007519:Isoantigens / Q000502:physiology; D008168:Lung / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D016040:Lung Transplantation / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: C514208:AB197 compound; D004151:Dipeptides; D004791:Enzyme Inhibitors; D007519:Isoantigens; D018819:Dipeptidyl Peptidase 4