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J Thorac Cardiovasc Surg 2008;136:159-167
© 2008 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Vascular allografts are resistant to methicillin-resistant Staphylococcus aureus through indoleamine 2,3-dioxygenase in a murine model

A. Saito, MD, PhDa,*, N. Motomura, MD, PhDa, K. Kakimi, MD, PhDb, K. Narui, PhDc, N. Noguchi, PhDc, M. Sasatsu, PhDc, K. Kubo, MScd, Y. Koezuka, PhDd, D. Takai, MD, PhDe, S. Ueha, PhDf, S. Takamoto, MD, PhDa

a Department of Cardiothoracic Surgery, the University of Tokyo Graduate School of Medicine, Tokyo, Japan
b Department of Immunotherapeutics (Medinet), the University of Tokyo Graduate School of Medicine, Tokyo, Japan
e Department of Respiratory Medicine, the University of Tokyo Graduate School of Medicine, Tokyo, Japan
f Department of Molecular Preventive Medicine, the University of Tokyo Graduate School of Medicine, Tokyo, Japan
c Department of Microbiology, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Tokyo, Japan
d Pharmaceutical Division, Pharmaceutical Research Laboratories, Kirin Brewery Co, Ltd, Tokyo, Japan

Received for publication October 23, 2007; revisions received December 14, 2007; accepted for publication January 17, 2008.

* Address for reprints: Aya Saito, MD, PhD, Division of Cardiac Surgery, London Health Sciences Centre, University Hospital, 339 Windermere Rd, London, Ontario, Canada N6A 5A5. (Email: ayasaitou-ths{at}umin.ac.jp).

Objective: Surgical results have shown the superiority of human heart valve and vascular allografts over artificial prostheses when used for the treatment of infectious cardiovascular diseases. However, the mechanism of infection resistance in these allografts has not been determined. In this study the contribution of the inflammatory response after allogeneic transplantation to the antimicrobial mechanism was assessed, focusing on the induction of indoleamine 2,3-dioxygenase, a tryptophan-metabolizing enzyme.

Methods: Aortic transplantation was performed with inbred rats, and aortic allografts, isografts, and control grafts were obtained for the following analyses. The extent of inflammatory-related and indoleamine 2,3-dioxygenase gene expression was measured by means of quantitative reverse transcriptase–polymerase chain reaction, and tryptophan metabolite production in the graft was measured by means of liquid chromatographic/tandem mass spectrometric analysis. The bacteriostatic effect of each graft and tryptophan metabolites was determined by using the methicillin-resistant Staphylococcus aureus proliferation assay.

Results: The inflammatory response, including interferon {gamma}, tumor necrosis factor {alpha}, and indoleamine 2,3-dioxygenase gene expression, was significant in the allografts but minimal in the isografts and control grafts. Methicillin-resistant S aureus proliferation was remarkably suppressed when cultured with the allografts but not with the control grafts. Among tryptophan metabolites, the bacteriostatic effect against methicillin-resistant S aureus was remarkable with 3-hydroxykynurenine, with a minimum inhibitory concentration of 32 mg/L. The 3-hydroxykynurenine level in the allografts was 9-fold greater than that in the control grafts.

Conclusion: The bacteriostatic effect of the allografts was acquired by inducing indoleamine 2,3-dioxygenase, which resulted in local production of 3-hydroxykynurenine as an antimicrobial agent. This is the first report to document a mechanism of the allograft's infection-resistant property against methicillin-resistant S aureus growth.

Abbreviations and Acronyms BN = Brown Norway; 3-HAA = 3-hydroxyanthranilic acid; 3-HK = 3-hydroxykynurenine; IDO = indoleamine-2,3-dioxygenase; IFN = interferon; Kyn = kynurenine; LC-MS/MS = liquid chromatography/tandem mass spectrometry; LEW = Lewis; MH = Mueller–Hinton; MRSA = methicillin-resistant Staphylococcus aureus ; PCR = polymerase chain reaction; POD = postoperative day; QA = quinolinic acid; TNF = tumor necrosis factor; Trp = tryptophan




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