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The effect of organ-specific CD26/DPP IV enzymatic activity inhibitor-preconditioning on acute pulmonary allograft rejection


Jungraithmayr, W; Oberreiter, B; De Meester, I; Wiedl, T; Inci, I; Bain, M; Augustyns, K; Hillinger, S; Scharpé, S; Weder, W; Korom, S (2009). The effect of organ-specific CD26/DPP IV enzymatic activity inhibitor-preconditioning on acute pulmonary allograft rejection. Transplantation, 88(4):478-485.

Abstract

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. CONCLUSION: 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.

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. CONCLUSION: 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.

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6 citations in Web of Science®
7 citations in Scopus®
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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
04 Faculty of Medicine > University Hospital Zurich > Division of Surgical Research
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2009
Deposited On:12 Feb 2010 14:50
Last Modified:05 Apr 2016 13:54
Publisher:Lippincott Wiliams & Wilkins
ISSN:0041-1337
Publisher DOI:https://doi.org/10.1097/TP.0b013e3181b08e77
PubMed ID:19696630

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