Systemic inflammation in xenograft recipients precedes activation of coagulation

作者：Mohamed B. Ezzelarab, Burcin Ekser, Agnes M. Azimzadeh, Chih Che Lin, Yuming Zhao, Rachael Rodriguez, Gabriel J. Echeverri, Hayato Iwase, Cassandra E. Long, Hidetaka Hara, David Ayares, Richard N. Pierson, Angus W. Thomson, David K. C. Cooper · 发表于：Xenotransplantation · 年份：2014 · DOI：10.1111/xen.12133 · 被引用次数：140 · 研究领域：Xenotransplantation and immune response、T-cell and B-cell Immunology、Organ Transplantation Techniques and Outcomes

BACKGROUND: Dysregulation of coagulation is considered a major barrier against successful pig organ xenotransplantation in non-human primates. Inflammation is known to promote activation of coagulation. The role of pro-inflammatory factors as well as the relationship between inflammation and activation of coagulation in xenograft recipients is poorly understood. METHODS: Baboons received kidney (n=3), heart (n=4), or artery patch (n=8) xenografts from α1,3-galactosyltransferase gene-knockout (GTKO) pigs or GTKO pigs additionally transgenic for human complement-regulatory protein CD46 (GTKO/CD46). Immunosuppression (IS) was based on either CTLA4Ig or anti-CD154 costimulation blockade. Three artery patch recipients did not receive IS. Pro-inflammatory cytokines, chemokines, and coagulation parameters were evaluated in the circulation after transplantation. In artery patch recipients, monocytes and dendritic cells (DC) were monitored in peripheral blood. Expression of tissue factor (TF) and CD40 on monocytes and DC were assessed by flow cytometry. C-reactive protein (C-RP) levels in the blood and C-RP deposition in xenografts as well as native organs were evaluated. Baboon and pig C-RP mRNA in heart and kidney xenografts were evaluated. RESULTS: In heart and kidney xenograft recipients, the levels of INFγ, TNF-α, IL-12, and IL-8 were not significantly higher after transplantation. However, MCP-1 and IL-6 levels were significantly higher after transplantation, particularly in kid...