CD26/dipeptidylpeptidase IV-targeted therapy of acute lung rejection in rats.
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.
Jung
Florian Johannes
FJ
Department of Thoracic Surgery, University Hospital Zurich, Switzerland.
Yang
Lin
L
De Meester
Ingrid
I
Augustyns
Koen
K
Cardell
Markus
M
Hillinger
Sven
S
Vogt
Peter
P
Lardinois
Didier
D
Scharpé
Simon
S
Weder
Walter
W
Korom
Stephan
S
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
C514208:AB197 compound; D004151:Dipeptides; D004791:Enzyme Inhibitors; D007519:Isoantigens; D018819:Dipeptidyl Peptidase 4