Antagonism of RANTES receptors reduces atherosclerotic plaque formation in mice.

Increasing evidence supports the involvement of inflammation in the early phases of atherogenesis. Recruitment of leukocytes within the vascular wall, controlled by chemokines, is an essential process in the development of this common disease. In this study, we report that blocking a chemokine pathway in vivo with the CC chemokine antagonist Met-RANTES reduces the progression of atherosclerosis in a hypercholesterolemic mouse model. The reduction of lesions was correlated with a diminution of expression of several major chemokines and chemokine receptors, a decrease in leukocyte infiltration, and an increase of collagen-rich atheroma, features associated with stable atheroma. Treatment was well tolerated and serum lipid profiles were not affected. Whereas genetically engineered mice with deletion of either a CC chemokine or its receptor have demonstrated resistance to disease, to our knowledge, this is the first demonstration that treatment with a chemokine receptor antagonist limits the progression of atherosclerosis in vivo. Thus, our findings indicate that blockade of chemokine receptor/ligand interactions might become a novel therapeutic strategy to reduce the evolution of this common disease.

Veillard NR ，Kwak B ，Pelli G ，Mulhaupt F ，James RW ，Proudfoot AE ，Mach F ... -  《-》

Combined blockade of the chemokine receptors CCR1 and CCR5 attenuates chronic rejection.

Chemokine-chemokine receptor interaction and the subsequent recruitment of T-lymphocytes to the graft are early events in the development of chronic rejection of transplanted hearts or cardiac allograft vasculopathy (CAV). In this study, we sought to determine whether blockade of chemokine receptors CCR1 and CCR5 with Met-RANTES affects the development of CAV in a murine model. B6.CH-2(bm12) strain donor hearts were transplanted heterotopically into wild-type C57BL/6 mice (myosin heavy chain II mismatch). Recipients were treated daily with either Met-RANTES or vehicle starting on postoperative day 4 and were euthanized on postoperative days 24 and 56. We found that Met-RANTES significantly reduced intimal thickening in this model of chronic rejection and that Met-RANTES markedly decreased the infiltration of CD4 and CD8 T lymphocytes and MOMA-2+ monocytes/macrophages into transplanted hearts. Met-RANTES also suppressed the ex vivo and in vitro proliferative responses of recipient splenocytes to donor antigens. Finally, Met-RANTES treatment was associated with a marked reduction in RANTES/CCL5 and monocyte chemoattractant protein-1 gene transcript levels in the donor hearts. Antagonism of the chemokine receptors CCR1 and CCR5 with Met-RANTES attenuates CAV development in vivo by reducing mononuclear cell recruitment to the transplanted heart, proliferative responses to donor antigens, and intragraft RANTES/CCL5 and monocyte chemoattractant protein-1 gene transcript levels. These findings suggest that chemokine receptors CCR1 and CCR5 play significant roles in the development of chronic rejection and may serve as potential therapeutic targets.

Yun JJ ，Whiting D ，Fischbein MP ，Banerji A ，Irie Y ，Stein D ，Fishbein MC ，Proudfoot AE ，Laks H ，Berliner JA ，Ardehali A ... -  《-》

A novel RANTES antagonist prevents progression of established atherosclerotic lesions in mice.

Braunersreuther V ，Steffens S ，Arnaud C ，Pelli G ，Burger F ，Proudfoot A ，Mach F ... -  《-》

CCR5 chemokine receptor mediates recruitment of MHC class II-positive Langerhans cells in the mouse corneal epithelium.

Yamagami S ，Hamrah P ，Miyamoto K ，Miyazaki D ，Dekaris I ，Dawson T ，Lu B ，Gerard C ，Dana MR ... -  《INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE》

Differential influence of chemokine receptors CCR2 and CXCR3 in development of atherosclerosis in vivo.

Veillard NR ，Steffens S ，Pelli G ，Lu B ，Kwak BR ，Gerard C ，Charo IF ，Mach F ... -  《-》