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Induction of Indoleamine 2,3-Dioxygenase in Vascular Smooth Muscle Cells by Interferon- Contributes to Medial Immunoprivilege¹

Madison C. Cuffy^*, Amanda M. Silverio^*, Lingfeng Qin^*, Yinong Wang^*, Raymond Eid^*, Gerald Brandacher, Fadi G. Lakkis^2,,, Dietmar Fuchs^¶, Jordan S. Pober and George Tellides^3,*

^* Interdepartmental Program in Vascular Biology and Transplantation and the Departments of Surgery, Internal Medicine, and Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510 and the Department of General and Transplant Surgery and ^¶ Division of Biological Chemistry, Biocentre, Innsbruck Medical University, Innsbruck, Austria

Atherosclerosis and graft arteriosclerosis are characterized by leukocytic infiltration of the vessel wall that spares the media. The mechanism(s) for medial immunoprivilege is unknown. In a chimeric humanized mouse model of allograft rejection, medial immunoprivilege was associated with expression of IDO by vascular smooth muscle cells (VSMCs) of rejecting human coronary artery grafts. Inhibition of IDO by 1-methyl-tryptophan (1-MT) increased medial infiltration by allogeneic T cells and increased VSMC loss. IFN--induced IDO expression and activity in cultured human VSMCs was considerably greater than in endothelial cells (ECs) or T cells. IFN--treated VSMCs, but not untreated VSMCs nor ECs with or without IFN- pretreatment, inhibited memory Th cell alloresponses across a semipermeable membrane in vitro. This effect was reversed by 1-MT treatment or tryptophan supplementation and replicated by the absence of tryptophan, but not by addition of tryptophan metabolites. However, IFN--treated VSMCs did not activate allogeneic memory Th cells, even after addition of 1-MT or tryptophan. Our work extends the concept of medial immunoprivilege to include immune regulation, establishes the compartmentalization of immune responses within the vessel wall due to distinct microenvironments, and demonstrates a duality of stimulatory EC signals versus inhibitory VSMC signals to artery-infiltrating T cells that may contribute to the chronicity of arteriosclerotic diseases.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Institutes of Health (PO1 HL70295) and by the government of the State of the Austrian Tyrol. M.C.C. received a fellowship award from the Thoracic Surgery Foundation for Research and Education.

² Current address: Thomas E. Starzl Transplantation Institute, University of Pittsburgh, BST-W1542, 200 Lothrop Street, Pittsburgh, PA 15261

³ Address correspondence and reprint requests to Dr. George Tellides, 295 Congress Avenue, Boyer Center for Molecular Medicine 454, New Haven, CT 06510. E-mail address: george.tellides{at}yale.edu

⁴ Abbreviations used in this paper: 1-MT, 1-methyl-tryptophan; -SMA, -smooth muscle actin; EC, endothelial cell; TrpRS, tryptophanyl-tRNA synthetase; VSMC, vascular smooth muscle cell.