Abstract 878: The Cxcr3 Antagonist Nbi-74330 Attenuates Atherosclerotic Plaque Formation In Ldl Receptor Deficient Mice
Migration of leukocytes into the vessel wall is an essential step in atherosclerotic lesion formation and progression, and chemokines are regarded as key regulators of this process. The chemokine receptor CXCR3 is expressed on various leukocyte subsets, including monocytes, (NK)T- and B cells. CXCR3 expression is highly induced upon CD4 T cell activation and it is preferentially expressed on auto-reactive T cells. Recent publications point towards a prominent role for CXCR3 in mediating the migration of inflammatory cells into human atherosclerotic lesions, which were seen to express high levels of CXCR3 ligands. In this study the effect of the CXCR3 antagonist NBI-74330 on leukocyte migration and atherogenesis was determined. NBI-74330 administration (100 mg/kg, daily, s.c., 6 days) in a murine thioglycollate based peritonitis model resulted in a 56% reduced (P = 0.02) cellular migration of especially CD4+ T-cells (30.8 ± 2.1% vs. 24.0 ± 1.6% in NBI treated; P = 0.03) and macrophages (33.0 ± 1.4 compared to 26.8 ± 1.9 in NBI treated; P = 0.03). Successive Ex vivo migration studies with peritoneal leukocytes showed that the reduced migration was completely CXCR3 dependent as its ligand CXCL10 did not induce chemotaxis (P = 0.001). Subsequently western type diet fed LDL receptor knockout mice were treated with NBI-74330 (100 mg/kg, daily, s.c.) for 8 weeks during atherogenesis. Atherosclerotic lesion formation in both the aortic valve leaflet area (5.4 ± 0.4*105 μm2 vs. 3.9 ± 0.5*105 μm2 in treated mice; P = 0.03) as well as the entire aorta (0.18 ± 0.03% compared to 0.09 ± 0.02% plaque area in treated animals; P = 0.01) was significantly inhibited in NBI-74330 treated mice. Furthermore lymph nodes draining from the aorta were smaller in treated mice (P = 0.01), were particularly enriched in regulatory T cells 45.2 ± 14.6% compared to 80.3 ± 4.6% in treated; P < 0.04 and contained more naive T cells (CD4 ± CD62Llow, 12.4 ± 1.3% vs. 29.2 ± 2.0% in treated animals; P < 0.001). In conclusion, we show for the first time that treatment with a CXCR3 antagonist results in attenuation of atherosclerotic lesion formation, not only by directly blocking effector cells migration from the circulation into the atherosclerotic plaque, but also by beneficially modulating the local immune response.