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We have previously shown that systemic inflammation in xenograft recipients (SIXR<\/jats:styled-content>) precedes activation of coagulation in the absence of T cell responses. Accordingly, SIXR<\/jats:styled-content> may amplify innate and adaptive immune responses against xenografts after pig\u2010to\u2010primate xenotransplantation, even with efficient immunosuppressive therapy. We evaluated the impact of anti\u2010inflammatory agents on pro\u2010inflammatory cytokines and chemokines in pig artery patch and heart xenograft recipients. Baboons received an artery patch (Group1, n=8) or heart (Group2, n=4) from genetically engineered pigs. All baboons received lymphodepletion with thymoglobulin (ATG<\/jats:styled-content>) and costimulation blockade\u2010based immunosuppression (anti\u2010CD<\/jats:styled-content>40 and\/or CTLA<\/jats:styled-content>4Ig). In Group1, baboons received either (i) no anti\u2010inflammatory agents (n=2), (ii) cobra venom factor (CVF<\/jats:styled-content>, n=2), (iii) \u03b11\u2010antitrypsin (AAT<\/jats:styled-content>, n=2), or (iv) interleukin (IL<\/jats:styled-content>)\u20106 receptor antagonist (IL<\/jats:styled-content>\u20106RA<\/jats:styled-content>, n=2). In Group2, all baboon received corticosteroids, either without (n=2) or with (n=2) IL<\/jats:styled-content>\u20106RA<\/jats:styled-content>. Serum IFN<\/jats:styled-content>\u2010\u03b3, TNF<\/jats:styled-content>\u2010\u03b1, IL<\/jats:styled-content>\u20101\u03b2, IL<\/jats:styled-content>\u201017, IL<\/jats:styled-content>\u20106, IL<\/jats:styled-content>\u20108, MCP<\/jats:styled-content>\u20101, and sCD<\/jats:styled-content>40L levels were measured by Luminex. Fibrinogen, D\u2010dimers, and C\u2010reactive protein (C\u2010RP<\/jats:styled-content>) were also measured. Recipient baboon T cell proliferation was evaluated by mixed lymphocyte reaction (MLR<\/jats:styled-content>) before and after transplantation. Pig and baboon tissue factor (TF<\/jats:styled-content>) mRNA<\/jats:styled-content> levels in heart xenografts were measured by RT<\/jats:styled-content>\u2010PCR. In no recipient was a marked increase in T cell response to pig cells observed after transplantation. In Groups 1 and 2, post\u2010transplantation levels of IFN<\/jats:styled-content>\u2010\u03b3, TNF<\/jats:styled-content>\u2010\u03b1, IL<\/jats:styled-content>\u20101\u03b2, and IL<\/jats:styled-content>\u201017 remained comparable to or lower than pre\u2010transplant levels, except in one heart recipient that succumbed to CMV<\/jats:styled-content> infection. In Group1, when no anti\u2010inflammatory agent was administered, post\u2010transplant levels of IL<\/jats:styled-content>\u20106, IL<\/jats:styled-content>\u20108, and MCP<\/jats:styled-content>\u20101 were elevated. After CVF<\/jats:styled-content>, IL<\/jats:styled-content>\u20106, IL<\/jats:styled-content>\u20108, and MCP<\/jats:styled-content>\u20101 remained low. After IL<\/jats:styled-content>\u20106RA<\/jats:styled-content>, IL<\/jats:styled-content>\u20106 and MCP<\/jats:styled-content>\u20101 were elevated. After AAT<\/jats:styled-content>, IL<\/jats:styled-content>\u20108 was elevated. sCD<\/jats:styled-content>40L became elevated intermittently in most recipients irrespective of the administered anti\u2010inflammatory agent. In Group2, IL<\/jats:styled-content>\u20106 was transiently elevated, particularly after IL<\/jats:styled-content>\u20106RA<\/jats:styled-content> administration. MCP<\/jats:styled-content>\u20101 gradually increased by 2\u00a0months in Group2 recipients. sCD<\/jats:styled-content>40L generally remained low except in one recipient. In Group1 and Group2 recipients, C\u2010RP<\/jats:styled-content> levels were elevated except after IL<\/jats:styled-content>\u20106RA<\/jats:styled-content> administration, while D\u2010dimers were elevated regardless of administration of anti\u2010inflammatory agent. In Group2, pig TF mRNA<\/jats:styled-content> levels were increased in heart xenografts compared to naive pig hearts, irrespective of IL<\/jats:styled-content>\u20106 receptor antagonist administration. Additionally, baboon TF mRNA<\/jats:styled-content> levels were detectable in heart xenografts, but not in naive pig hearts. Some pro\u2010inflammatory cytokines and chemokines are elevated in xenograft recipients, even with efficient T cell\u2010directed immunosuppressive therapy. Persistent elevation of D\u2010dimers, and individual cytokines and chemokines suggest a continuous inflammatory response, despite administration of anti\u2010inflammatory agents. Systemic administration of combined anti\u2010inflammatory agents as well as complement regulation may be essential to prevent SIXR<\/jats:styled-content> after xenotransplantation.<\/jats:p>","DOI":"10.1111\/xen.12296","type":"journal-article","created":{"date-parts":[[2017,3,14]],"date-time":"2017-03-14T15:18:50Z","timestamp":1489504730000},"source":"Crossref","is-referenced-by-count":48,"title":["Therapeutic regulation of systemic inflammation in xenograft recipients"],"prefix":"10.1111","volume":"24","author":[{"given":"Hayato","family":"Iwase","sequence":"first","affiliation":[{"name":"Thomas E. Starzl Transplantation Institute University of Pittsburgh Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Liu","sequence":"additional","affiliation":[{"name":"Thomas E. Starzl Transplantation Institute University of Pittsburgh Pittsburgh PA USA"},{"name":"Department of General Surgery First Hospital of Shanxi Medical University Taiyuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Li","sequence":"additional","affiliation":[{"name":"Thomas E. Starzl Transplantation Institute University of Pittsburgh Pittsburgh PA USA"},{"name":"Center for Kidney Transplantation Second Affiliated Hospital of the University of South China Hengyang Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongquiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Thomas E. Starzl Transplantation Institute University of Pittsburgh Pittsburgh PA USA"},{"name":"Department of General Surgery Second Xiangya Hospital of the Central South University Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingsi","family":"Gao","sequence":"additional","affiliation":[{"name":"Thomas E. Starzl Transplantation Institute University of Pittsburgh Pittsburgh PA USA"},{"name":"Center for Kidney Transplantation Second Affiliated Hospital of the University of South China Hengyang Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidetaka","family":"Hara","sequence":"additional","affiliation":[{"name":"Thomas E. Starzl Transplantation Institute University of Pittsburgh Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Wijkstrom","sequence":"additional","affiliation":[{"name":"Thomas E. Starzl Transplantation Institute University of Pittsburgh Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cassandra","family":"Long","sequence":"additional","affiliation":[{"name":"Thomas E. Starzl Transplantation Institute University of Pittsburgh Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Saari","sequence":"additional","affiliation":[{"name":"Thomas E. Starzl Transplantation Institute University of Pittsburgh Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Ayares","sequence":"additional","affiliation":[{"name":"Revivicor Blacksburg VA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8899-9431","authenticated-orcid":false,"given":"David K. C.","family":"Cooper","sequence":"additional","affiliation":[{"name":"Thomas E. 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