The effect of organ-specific CD26/DPP IV enzymatic activity inhibitor-preconditioning on acute pulmonary allograft rejection.
BACKGROUND
Systemic inhibition of serum CD26/dipeptidylpeptidase (DPP IV) enzymatic activity abrogated acute rejection of pulmonary allografts, whereas organ-specific inhibition ameliorated ischemia/reperfusion injury in syngeneic transplants. Here, we analyze the effect of allograft-specific inhibitor preconditioning on acute rejection in the presence of cyclosporine-based immunosuppressive therapy.


METHODS
Orthotopic left single lung transplantation (Tx) in rats (LBNF1 to LEWIS). Control (n=5) grafts were flushed with Perfadex alone, whereas treated (n=5) transplants were perfused with Perfadex and AB192, a specific inhibitor of CD26/DPP IV enzymatic activity. All recipients were treated with 2.5 mg of cyclosporine A/kg per day subcutaneously after Tx. Recipients were sacrificed at day 5 after Tx, and oxygenation capacity was measured. In addition, staining for vasoactive intestinal peptide (VIP) and proliferating cell nuclear antigen (PCNA) at explantation (VIP) and at day 5 (VIP, PCNA) was performed with determination of protein levels for PCNA and mRNA for VIP.


RESULTS
Grafts from treated versus controls showed significantly increased oxygenation capacity (P<.008), correlating with significantly less acute rejection (P<.02). PCNA staining and protein expression were significantly lower in perivascular and bronchial epithelial cells (P=.001) in treated versus controls. There was significantly higher staining for VIP at the time of Tx in alveolar macrophages in treated versus controls (P=.001), which was seen up to day 5 post-Tx in both macrophages and respiratory epithelium (P=.001) with elevated mRNA expression for VIP in treated animals.


CONCLUSIONS
Perfusion with a specific inhibitor of CD26/DPP IV enzymatic activity was associated with sustained preservation of pulmonary VIP levels, correlating with an amelioration of the acute rejection cascade.
Jungraithmayr
Wolfgang
W
Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.
Oberreiter
Birgit
B
De Meester
Ingrid
I
Wiedl
Thomas
T
Inci
Ilhan
I
Bain
Martha
M
Augustyns
Koen
K
Hillinger
Sven
S
Scharpé
Simon
S
Weder
Walter
W
Korom
Stephan
S
D000208:Acute Disease; D000818:Animals; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006084:Graft Rejection / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*; D016040:Lung Transplantation / Q000276:immunology* / Q000473:pathology / Q000502:physiology; D008297:Male; D063065:Organophosphonates / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D019172:Transplantation Conditioning / Q000379:methods; D014184:Transplantation, Homologous; D014660:Vasoactive Intestinal Peptide / Q000235:genetics / Q000378:metabolism
D054873:Dipeptidyl-Peptidase IV Inhibitors; D063065:Organophosphonates; D018809:Proliferating Cell Nuclear Antigen; D011480:Protease Inhibitors; D012333:RNA, Messenger; C118220:bis(4-acetamidophenyl) 1-prolylpyrrolidine-2-phosphonate; D014660:Vasoactive Intestinal Peptide; D011392:Proline; D009195:Peroxidase