title: A20 Haploinsufficiency Aggravates Transplant Arteriosclerosis in Mouse Vascular Allografts: Implications for Clinical Transplantation.
abstract: 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) donors and BALB/c (H-2) 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-кB activation, gauged by higher levels of IkBα, 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 IFNγ and Granzyme B CD4 T cells and natural killer cells, and lower number of FoxP3 regulatory T cells. 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 T cells. 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.
authors: 1 Frank W. LoGerfo Division of Vascular and Endovascular Surgery, Center for Vascular Biology Research and the Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. 2 Center of Physiology and Pharmacology, Medical University of Vienna, Waehringerstrasse, Vienna, Austria. 3 Division of Vascular and Endovascular Surgery, Stanford University Medical Center, Stanford, CA. 4 Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors: Herwig P
authors: HP
authors: Moll
authors: Andy
authors: A
authors: Lee
authors: Clayton R
authors: CR
authors: Peterson
authors: Jesus
authors: J
authors: Revuelta Cervantes
authors: Brandon M
authors: BM
authors: Wojcik
authors: Anshul
authors: A
authors: Parulkar
authors: Alessandra
authors: A
authors: Mele
authors: Philip J
authors: PJ
authors: LoGerfo
authors: Jeffrey J
authors: JJ
authors: Siracuse
authors: Eva
authors: E
authors: Csizmadia
authors: Cleide G
authors: CG
authors: da Silva
authors: Christiane
authors: C
authors: Ferran
mesh_terms: D000818:Animals; D001011:Aorta / Q000637:transplantation*; D001161:Arteriosclerosis / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D057895:Haploinsufficiency; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D011183:Postoperative Complications / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D014184:Transplantation, Homologous; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3 / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D017539:Tunica Intima / Q000473:pathology
chemical_list: D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; C513261:Tnfaip3 protein, mouse