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

Interdepartmental Program in Vascular Biology and Transplantation, Department of Surgery, Yale University School of Medicine, New Haven, CT 06510, USA.
The Journal of Immunology (Impact Factor: 4.92). 11/2007; 179(8):5246-54. DOI: 10.4049/jimmunol.179.8.5246
Source: PubMed


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-gamma-induced IDO expression and activity in cultured human VSMCs was considerably greater than in endothelial cells (ECs) or T cells. IFN-gamma-treated VSMCs, but not untreated VSMCs nor ECs with or without IFN-gamma 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-gamma-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.

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    • "A fine-tuned balance between effector and regulatory immune responses also controls the development of atherosclerosis (Tedgui and Mallat, 2006), an inflammatory vascular disease responsible for the first cause of death worldwide. In this setting, Ido1 is also seen as a potentially important regulator of the immune response, limiting pathogenic adaptive T cell activation (Cuffy et al., 2007; Daissormont et al., 2011; Nakajima et al., 2011). However, those studies were based on incomplete and probably nonselective pharmacologic inhibition of Ido activity (Nakajima et al., 2011; Polyzos et al., 2015), or involved supplementation with supraphysiologocial levels of Ido metabolites (Polyzos et al., 2015; Zhang et al., 2012). "
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    Cell metabolism 07/2015; 22(3). DOI:10.1016/j.cmet.2015.07.004 · 17.57 Impact Factor
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    • "The circumferential distribution along the elastin sheets suggests that lymphoid and myeloid cell infiltrates follow the weakening of the wall due to the disappearance of smooth muscle cells and the degradation of ECM. Indeed, the arterial media is an immune-privileged tissue because the survival and activation of leucocytes are actively inhibited by healthy smooth muscle cells, largely through consumption of tryptophan.64 "
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