An Investigation of Extracellular Histones in Pig-To-Baboon Organ Xenotransplantation.
Serum (extracellular) histone levels are increased in inflammatory states and in the presence of coagulation dysfunction, for example, trauma, chemical/ischemic injury, infection. There is increasing evidence of a systemic inflammatory response associated with the presence of a pig xenograft in a nonhuman primate. We evaluated extracellular histone levels in baboons with various pig xenografts.



We measured serum histones in baboons with pig heterotopic heart (n = 8), life-supporting kidney (n = 5), orthotopic liver (n = 4), and artery patch (n = 9) grafts by enzyme-linked immunosorbent assay. C-reactive protein (CRP), free triiodothyronine (fT3), serum amyloid A (SAA), and platelet counts were also measured, all of which may provide an indication of an inflammatory state. We investigated the effect of histones on platelet aggregation and on cytotoxicity of pig cells in vitro.



Serum histones increased when baboons developed consumptive coagulopathy (eg, thrombocytopenia) or infection. CRP levels tended to be higher and fT3 levels lower when consumptive coagulopathy developed. Measurement of SAA correlated fairly well with CRP and indicated the state of inflammation. Treatment of the recipient with tocilizumab reduced the level of serum histones, CRP, and SAA, and increased the level of fT3 and platelet counts. In vitro, histone-induced platelet aggregation and endothelial cell apoptosis were both significantly reduced by the NF-κB pathway inhibitor, parthenolide.



These noninvasive assays may be useful for monitoring the health status of nonhuman primate recipients of pig organ grafts and may help in management after xenotransplantation. Tocilizumab and NF-κB inhibitors might prove valuable in reducing the inflammatory response to a pig xenograft.
1 Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA. 2 Center for Kidney Transplantation, Second Affiliated Hospital of the University of South China, Hengyang, Hunan, China. 3 Revivicor, Blacksburg, VA. 4 Coagulation Biology Laboratory, Oklahoma Medical Research Foundation, Oklahoma City, OK.
Tao
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Li
Whayoung
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Lee
Hidetaka
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Hara
Cassandra
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Long
Mohamed
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Ezzelarab
David
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Ayares
Hai
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Huang
Yi
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Wang
Charles T
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Esmon
David K C
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Iwase
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D001158:Arteries / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D001777:Blood Coagulation; D001792:Blood Platelets / Q000276:immunology / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D016027:Heart Transplantation / Q000009:adverse effects; D064593:Heterografts; D006657:Histones / Q000097:blood* / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007249:Inflammation / Q000097:blood* / Q000276:immunology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000097:blood; D016030:Kidney Transplantation / Q000009:adverse effects; D016031:Liver Transplantation / Q000009:adverse effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010215:Papio; D010974:Platelet Aggregation; D010976:Platelet Count; D000685:Serum Amyloid A Protein / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology; D034421:Sus scrofa; D013997:Time Factors; D014284:Triiodothyronine / Q000097:blood
D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D006657:Histones; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D016328:NF-kappa B; D000685:Serum Amyloid A Protein; D012717:Sesquiterpenes; D014284:Triiodothyronine; C002669:parthenolide; D002097:C-Reactive Protein; C502936:tocilizumab