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 PS166. Loss of Function Studies Highlight the Vasculoprotective Effect of A20 in Transplant Arteriosclerosis (TA)

Andy Lee1, Clayton Peterson1, Herwig Moll1, Eva Csizmadia1, Ashley Rogers1, Alon Neidich2, Victor Chien1, Cleide da Silva1, Christiane Ferran1
1Surgery, BIDMC, Boston, MA; 2Tufts Medical School, Boston, MA.

OBJECTIVES: Transplant arteriosclerosis (TA) is an accelerated form of atherosclerosis largely driven by the immune response to the allograft. As for all atherosclerotic disease, inflammation is central to vascular remodeling associated with TA. We have shown that the potent NF-kB inhibitory protein A20 exerts atheroprotective effects, in part through its anti-inflammatory and antiapoptotic functions in endothelial cells (EC), its anti-inflammatory, and anti-proliferative functions in smooth muscles cells (SMC), and its specific pro-apoptotic function in neointimal SMC. In this work, we wanted to check the physiologic role that A20 plays in the vascular remodeling associated with transplant arteriosclerosis by performing loss of function experiments in a mouse model of TA.
METHODS: We used a murine vascular transplant model, implanting aortae of 8-12-week-old C57bL/6 mice into the carotid arteries of fully HLA mismatched Balb/c mice. For our donors, we used aortic grafts from C57bL/6 A20 heterozygote mice (HET) or from their wild-type littermates (WT). Aortic allografts were harvested after 10 days and 4 weeks.
RESULTS: Partial loss of A20 in aortic allografts caused significantly greater TA lesions, measured by intima over media ratios in wild type allografts. This was associated with higher inflammation as evaluated by VCAM-1 immunostaining and granulocyte infiltration, lower expression of the anti-inflammatory and tolerogenic cytokine IL-10, and greater incidence of thrombosis in HET allografts.
CONCLUSIONS: We conclude that A20 plays an important physiologic role in vascular remodeling, and propose that tailored A20-based vascular therapies could decrease incidence and severity of TA, and synergize with or minimize use of immunosuppression in solid organ transplantation. These results are particularly relevant to newly discovered A20 single nucleotide polymorphisms that are less effective in inhibiting inflammation, and have been associated with a number of auto-immune and inflammatory diseases.
AUTHOR DISCLOSURES: V. Chien: Nothing to disclose; E. Csizmadia: Nothing to disclose; C. da Silva: Nothing to disclose; C. Ferran: Nothing to disclose; A. Lee: Nothing to disclose; H. Moll: Nothing to disclose; A. Neidich: Nothing to disclose; C. Peterson: Nothing to disclose; A. Rogers: Nothing to disclose.
Posted April 2013

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