Abstract 17956: Serpin Treatment Reduces Inflammation in Transplanted Temporal Artery Biopsy Specimens from Patients with Suspected Giant Cell Arteritis in Immunodeficient Mice

Abstract

Background - Giant cell / temporal arteritis (GCTA) is a severe inflammatory vasculitic syndrome (IVS), which causes arterial occlusion and sudden loss of vision. Treatment for IVS remains limited. Intra-aortic full thickness implants of human TA biopsy and left internal mammary artery (LIMA) specimens were surgically engrafted into the abdominal aorta of immunodeficient SCID mice as a new model for analyzing development of vascular inflammation, as well as response to new treatments. Serp-1 is a myxomaviral-derived serine protease inhibitor (serpin) that blocks thrombotic and thrombolytic protease pathways, arterial inflammation, and plaque growth. Serp-1 was recently tested in acute coronary syndromes (ACS), where reduced markers of myocardial damage were detected after stent implant. Objective - We assessed the effects of Serp-1 or saline treatment on inflammatory cell invasion and plaque growth after TA and LIMA engraftment in NOD-SCID mice. Results - Normal arterial (LIMA) specimens were harvested during bypass surgery and implanted into 24 SCID mice. Half the mice had saline (N=12) and half had Serp-1 treatment (N=12). In each group 6 mice had 5x106 peripheral blood mononuclear cells (PBMCs) infusions from the same patient as the donor LIMA graft, given immediately postop by tail vein and 6 had no cell infusion. TA grafts from patients with suspected GCA were implanted into a separate group of 24 SCID mice - 12 mice had saline (100µl) and 12 Serp-1 (100ng/g/100µl) treatment (one i.v. injection followed by daily i.p. injection for 10 days). in each treatment group 4 mice had infusion of non-matched PBMCs. At 4 weeks LIMA (P < 0.034) or TA (P < 0.0001) grafts, had significantly reduced plaque growth with Serp-1 treatment when human PBMC were also infused (p<0.05). In the absence of PBMC, Serp-1 had minimal effect. Mononuclear cell invasion was reduced in Serp-1 treated mice with PBMCs. Flow cytometry did not detect significant changes in splenocytes. Conclusions - Aortic implant of human LIMA or TA xenografts in SCID mice provides a physiological model for investigating inflammatory vasculitis. With PBMC infusion, treatment with the myxomaviral Serp-1, reduced inflammatory cell invasion and plaque growth in arterial xenografts.