A20 Haploinsufficiency Aggravates Transplant Arteriosclerosis in Mouse Vascular Allografts: Implications for Clinical Transplantation

作者：Moll Herwig P; Lee Andy; Peterson Clayton R; Cervantes Jesus Revuelta; Wojcik Brandon M; Parulkar Anshul; Mele Alessandra; LoGerfo Philip J; Siracuse Jeffrey J; Csizmadia Eva; da Silva Cleide G; Ferran Christiane^*

来源：Transplantation, 2016, 100(11): E106-E116.

DOI：10.1097/TP.0000000000001407

Background. Inflammation is central to the pathogenesis of transplant arteriosclerosis (TA). We questioned whether physiologic levels of anti-inflammatory A20 influence TA severity. Methods. We performed major histocompatibility complex mismatched aorta to carotid artery interposition grafts, using wild type (WT) or A20 heterozygote (HET) C57BL/6 (H-2(b)) donors and BALB/c (H-2(d)) recipients, and conversely BALB/c donors and WT/HET recipients. We analyzed aortic allografts by histology, immunohistochemistry, immunofluorescence, and gene profiling (quantitative real-time reverse-transcriptase polymerase chain reaction). We validated select in vivo A20 targets in human and mouse smooth muscle cell (SMC) cultures. Results. We noted significantly greater intimal hyperplasia in HET versus WT allografts, indicating aggravated TA. Inadequate upregulation of A20 in HET allografts after transplantation was associated with excessive NF-kappa B activation, gauged by higher levels of IkB alpha, p65, VCAM-1, ICAM-1, CXCL10, CCL2, TNF, and IL-6 (mostly localized to SMC). Correspondingly, cytokine-induced upregulation of TNF and IL-6 in human and mouse SMC cultures inversely correlated with A20 expression. Aggravated TA in HET versus WT allografts correlated with increased intimal SMC proliferation, and a higher number of infiltrating IFN gamma(+) and Granzyme B+ CD4(+) Tcells and natural killer cells, and lower number of FoxP3(+) regulatory Tcells. A20 haploinsufficiency in allograft recipients did not influence TA. Conclusions. A20 haploinsufficiency in vascular allografts aggravates lesions of TA by exacerbating inflammation, SMC proliferation, and infiltration of pathogenic Tcells. A20 single nucleotide polymorphisms associating with lower A20 expression or function in donors of vascularized allografts may inform risk and severity of TA, highlighting the clinical implications of our findings.

• 出版日期2016-11