Rantes Production During Development of Cardiac Allograft Vasculopathy

Abstract

We present evidence that other cell types in addition to CD4+, CD8+ T lymphocytes, and CD11b+ macrophages contribute significantly to RANTES production in CAV. In this MHC II-mismatched murine model of CAV, sustained RANTES production requires CD4+ lymphocytes, correlates with mononuclear cell recruitment, and precedes intimal thickening. In experimental and human CAV, vessel wall cells may also produce RANTES. Interventions aimed at inhibiting RANTES production in CAV may need to target several types of cells, and neutralization of RANTES bioactivity may reduce mononuclear cell recruitment and CAV development.

Heterogeneity of Endothelial Cells from Different Organ Sites in T-Cell Subset Recruitment

“…Most interesting was the finding that TNF-␣-activated MHECs express high levels of RANTES mRNA. This finding is consistent with previous studies that have immunolocalized expression of RANTES protein to vessel walls of intramyocardial arterioles and capillaries in rejected heart allografts, 3,4 suggesting that our in vitro-expanded MHECs have retained their ability to produce RANTES on stimulation with inflammatory cytokines. By comparison, MLECs cultured and stimulated with TNF-␣ under similar conditions were unable to up-regulate RANTES mRNA.…”

“…3,4,46,47 Our present findings that TNF-␣-induced RANTES in MHECs and the VCAM-1-VLA-4 pathway are important for the arrest and subsequent transmigration of Th1 cells across the MHEC monolayer in vitro provides insight to the molecular mechanisms that mediate the recruitment of T cells into the heart during the development of graft rejection. A better understanding of the roles of these molecules and the signaling pathways involved will provide the knowledge necessary for the design of novel immunomodulatory interventions that may prevent chronic graft rejections.…”

“…[1][2][3] In murine models, as well as in rejected human heart transplants, expression of the RANTES gene and protein has been localized to the graft-infiltrating cells (T cells and macrophages), within the intimal lesions, and in the vessel walls of intramyocardial arterioles and capillaries. 3,4 Similarly, chemokines such as MIP-1␤ and MIP-2 produced in the lungs are believed to be major chemotactic factors responsible for the recruitment of neutrophils into the alveolar spaces during infection and inflammation. 1,5,6 In most cases, the cellular source of these chemokines remained undefined and it was unclear whether endothelial cells were significant contributors.…”

Direct Anti-Inflammatory Mechanisms Contribute to Attenuation of Experimental Allograft Arteriosclerosis by Statins

“…22 RANTES expression correlated with mononuclear cell infiltration and preceded the development of GAD. 23 Several basic studies suggest a beneficial effect on organ transplant rejection by RANTES blockade. 24,25 MCP-1 is an important chemokine in the progression of atherosclerosis and the pathogenesis of GAD.…”

Genetic control of chemokines in severe human internal carotid artery stenosis

“…RANTES is a potent chemoattractant for monocytes, lymphocytes, eosinophilis, and basophilis [9]. RANTES interacts with the chemokine receptors CCR1, CCR3, and CCR5, and has been implicated in cardiac inflammatory disorder after organ transplantation [10,11]. Systemic blockage of RANTES receptors inhibits neointima formation and macrophage infiltration in carotid arteries of ApoEÀ/À mice [11].…”