Abstract 561: Serpin Suppression of Macrophage and T Helper Cell Response in Temporal Artery Biopsy Xenograft Implants from Patients with Giant Cell Inflammatory Arteritis
Background Glucocorticoids are a principal treatment for giant cell arteritis (GCA), with some studies reporting predominate effect on T helper17 (Th17) cell activity in GCA, with lesser effects on other inflammatory cells. Serp-1 is a 55kDa myxomaviral serpin that modifies macrophage, Th1, and Th17 responses in aortic transplants in animal models.
Objectives We have analyzed the effects of a virus-derived anti-inflammatory serine protease inhibitor (serpin) on human temporal artery (TA) biopsies isolated from patients with suspected GCA.
Methods Using a newly developed “Aortic Window Xenopatch” model, human TA biopsy sections were divided implanted as full thickness grafts into the abdominal aorta of SCID mice in parallel and tested for response to Serp-1, with and without human PBMC infusion (N = 32).
Results TA sections positive for arteritis (GCApos) displayed significantly increased inflammatory plaque when compared to negative sections (GCAneg). Serp-1 reduced plaque in GCApos sections (<0.01) with concommitant reduction in Th1, and Th17 splenocytes on flow cytometry (P < 0.01), with decreased IFNγ and IL-17 gene expression by RT-PCR array analysis. Serp-1 also reduced arterial CD11b+ cells after PBMC infusion with reduced TNF-α expression in spleen, but not CD3+, CCR6+, nor CD86+. Splenocytes from mice with GCApos grafts had increased interleukin-1beta (Il-1β), IL-17, and CD25 expression, while IL-1β was significantly reduced by Serp-1.Serp-1 also markedly reducedt gene expression for the FII, FXa-PAR2, tPA, uPA in splenocytes (P <0.05).
Conclusions Treatment with a virus-derived serpin, significantly reduces inflammation and plaque thickness in human GCApos TA xenograft implants with associated reductions in macrophage and Th1 and Th17 responses in mice.
- © 2013 by American Heart Association, Inc.