Abstract 1361: M-T7, A Viral Chemokine Modulating Protein (vCMP) Inhibits Plaque Growth Through Interruption of Chemokine: GAG Interactions
Background: Transplant vasculopathy impedes long-term organ transplant survival. Early inflammatory cell invasion initiates progressive neointimal hyperplasia and vessel occlusion, termed chronic rejection. Chemokines direct inflammatory cell migration and activation. Glycosaminoglycans (GAGs) in the tissue matrix and on the cell surface enhance inflammatory responses. Interruption of the chemokine: GAG (CK:GAG) interaction may alter inflammatory cell invasion and plaque growth. In prior work, the viral chemokine modulating protein (vCMP), MT-7 from myxoma virus, significantly reduced inflammatory cell invasion and plaque growth in rat aortic and renal transplant models. M-T7 binds to the C terminal, GAG-binding domain of human and mouse C, CC, and CXC chemokines. To determine the role of CC chemokine receptor and GAG in M-T7 anti-inflammatory activity, effects of M-T7 on plaque growth were assessed after mouse CC-Chemokine Receptor 2 deficient (CCR2−/−) aortic transplant. Mononuclear cell migration into mouse ascites was tested after M-T7 treatment in heparan sulfate (HS/GAG) deficient NDST1−/−.
Methods: Plaque growth was assessed at 28 days after allograft transplant. Donor aorta CCR2−/− or CCR2+/+ Balb/c donor aorta was transplanted to C57BL/6 (CCR2+/+) mouse recipients treated with 600pg – 6μg of M-T7, or controls. Control vCMPs, M-T1 and M3, bind the N-terminal, chemokine receptor binding domain of chemokines. NDST-1−/− mice were given MCP-1 by intra-peritoneal injection, together with intravenous M-T7 or control injections for cell migration analysis.
Results: Intimal hyperplasia was significantly reduced in the wild type CCR2+/+ aortic transplant model after M-T7 (p<0.009), M-T1 (p <0.031), and M3 (p<0.041) treatments. Aortic plaque was decreased in the CCR2−/− transplant model when compared to CCR2 +/+. M-T7 treatment further reduced plaque at 6μg doses in CCR2−/− (p<0.026), but M-T1 and M3 did not. M-T7 inhibited MCP-1 induced peritoneal cell migration in wild type mice (P<0.01), but had reduced inhibitory activity in NDST−/− mice (P=0.34).
Conclusions: The viral chemokine binding protein M-T7 inhibits inflammatory cell migration and vasculopathy through CCR2-independent, but heparan sulfate/GAG dependent mechanism.