Viral chemokine-binding proteins inhibit inflammatory responses and aortic allograft transplant vasculopathy in rat models

Abstract

Background: Both CC and CXC chemokines direct monocyte and T-cell migration and activation at sites of vascular injury, but the relative contributions of each chemokine class to transplant vasculopathy development have not been defined. The nonselective C, CC, and CXC chemokine binding protein, M-T7, inhibits vasculopathy development after angioplasty and after renal transplant. We have assessed the effects of three viral chemokine-binding proteins with differing ranges of chemokine inhibition on plaque growth in rats after aortic allograft transplant.

Methods: One of two myxomaviral chemokine binding proteins, (1). M-T1, a selective CC chemokine inhibitor, or (2). M-T7, a nonselective chemokine-binding protein, was given immediately after transplant. A separate group was treated with the gamma68-herpesvirus protein, M3, a C, CC, CXC, and CX3C binding protein, with preferential CC binding.

Results: Intimal hyperplasia was significantly reduced at late times posttransplant after infusion of each chemokine-binding protein (P <0.05). Early inhibition of macrophage and T-cell invasion was associated with a late decrease in vasculopathy development. Infusion of an inactive myxomavirus protein did not inhibit plaque growth. Combined high-dose M-T1 and M-T7 did not reduce plaque growth or early cell invasion to a greater extent than either protein alone. Coinfusion of the CC chemokines macrophage chemoattractant protein-1 and macrophage inflammatory protein-1alpha neutralized M-T1 and M-T7 inhibition of monocyte invasion, respectively, suggesting a key role for CC chemokine-mediated cellular influx.

Conclusion: Viral chemokine-modulating proteins effectively reduce aortic allograft vasculopathy, acting predominantly through inhibition of a CC chemokine-mediated response.