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C. Esmon, Jun Xu, Florea Lupu (2011)
Innate immunity and coagulationJournal of Thrombosis and Haemostasis, 9
D. Goldstein (2011)
Inflammation and transplantation toleranceSeminars in Immunopathology, 33
I. Ikonomidis, G. Athanassopoulos, J. Lekakis, K. Venetsanou, M. Marinou, K. Stamatelopoulos, D. Cokkinos, P. Nihoyannopoulos (2005)
Myocardial Ischemia Induces Interleukin-6 and Tissue Factor Production in Patients With Coronary Artery Disease: A Dobutamine Stress Echocardiography StudyCirculation, 112
M. Koulmanda, R. Sampathkumar, Manoj Bhasin, A. Qipo, Zhigang Fan, Gurbakhshish Singh, Babak Movahedi, M. Duggan, Vaja Chipashvili, Terry Strom (2014)
Prevention of Nonimmunologic Loss of Transplanted Islets in MonkeysAmerican Journal of Transplantation, 14
M. Ezzelarab, B. Ekser, A. Azimzadeh, C. Lin, Yuming Zhao, R. Rodriguez, G. Echeverri, H. Iwase, Cassandra Long, H. Hara, D. Ayares, R. Pierson, A. Thomson, D. Cooper (2015)
Systemic inflammation in xenograft recipients precedes activation of coagulationXenotransplantation, 22
H. Iwase, B. Ekser, V. Satyananda, J. Bhama, H. Hara, M. Ezzelarab, E. Klein, R. Wagner, Cassandra Long, J. Thacker, Jiang Li, Hao Zhou, Mao-lin Jiang, S. Nagaraju, Huidong Zhou, M. Veroux, P. Bajona, M. Wijkstrom, Yi Wang, C. Phelps, N. Klymiuk, E. Wolf, D. Ayares, D. Cooper (2015)
Pig‐to‐baboon heterotopic heart transplantation – exploratory preliminary experience with pigs transgenic for human thrombomodulin and comparison of three costimulation blockade‐based regimensXenotransplantation, 22
R. Christenson, C. deFilippi, D. Kreutzer (2005)
Biomarkers of ischemia in patients with known coronary artery disease: do interleukin-6 and tissue factor measurements during dobutamine stress echocardiography give additional insight?Circulation, 112 21
J. Qi, S. Goralnick, Donald Kreutzer (1997)
Fibrin regulation of interleukin-8 gene expression in human vascular endothelial cells.Blood, 90 9
C. Labarrere, J. Woods, J. Hardin, B. Jaeger, M. Zembala, M. Deng, G. Kassab (2014)
Early Inflammatory Markers Are Independent Predictors of Cardiac Allograft Vasculopathy in Heart-Transplant RecipientsPLoS ONE, 9
H. Iwase, B. Ekser, Huidong Zhou, Hong Liu, V. Satyananda, Rishab Humar, Pooja Humar, H. Hara, Cassandra Long, J. Bhama, P. Bajona, Yi Wang, M. Wijkstrom, D. Ayares, M. Ezzelarab, D. Cooper (2015)
Further evidence for sustained systemic inflammation in xenograft recipients (SIXR)Xenotransplantation, 22
A. Azimzadeh, S. Kelishadi, M. Ezzelarab, Avneesh Singh, T. Stoddard, H. Iwase, Tianshu Zhang, L. Burdorf, E. Sievert, C. Avon, Xiangfei Cheng, D. Ayares, K. Horvath, P. Corcoran, M. Mohiuddin, R. Barth, D. Cooper, R. Pierson (2015)
Early graft failure of GalTKO pig organs in baboons is reduced by expression of a human complement pathway‐regulatory proteinXenotransplantation, 22
Takaaki Kobayashi, S. Taniguchi, F. Neethling, Alan Rose, Wayne Hancock, Y. Ye, M. Niekrasz, Stanley Kosanke, L. Wright, David White, David Cooper (1997)
Delayed xenograft rejection of pig-to-baboon cardiac transplants after cobra venom factor therapy.Transplantation, 64 9
D. Cooper, B. Ekser, J. Ramsoondar, C. Phelps, D. Ayares (2016)
The role of genetically engineered pigs in xenotransplantation researchThe Journal of Pathology, 238
C. Lin, M. Ezzelarab, Ron Shapiro, B. Ekser, Cassandra Long, H. Hara, G. Echeverri, Corine Torres, Hiroshi Watanabe, D. Ayares, Anthony Dorling, D. Cooper (2010)
Recipient Tissue Factor Expression Is Associated With Consumptive Coagulopathy in Pig‐to‐Primate Kidney XenotransplantationAmerican Journal of Transplantation, 10
Strukova Sm (2006)
Blood coagulation-dependent inflammation. Coagulation-dependent inflammation and inflammation-dependent thrombosis.Frontiers in Bioscience, 11
C. Phelps, C. Koike, T. Vaught, J. Boone, K. Wells, Shu-Hung Chen, S. Ball, S. Specht, I. Polejaeva, Jeff Monahan, P. Jobst, Sugandha Sharma, Ashley Lamborn, A. Garst, M. Moore, A. Demetris, W. Rudert, R. Bottino, S. Bertera, M. Trucco, T. Starzl, Yifan Dai, D. Ayares (2003)
Production of alpha 1,3-galactosyltransferase-deficient pigs.Science, 299 5605
W. Baldwin, R. Fairchild (2017)
Inflammation and Transplantation
M. Ezzelarab, B. Ekser, G. Echeverri, H. Hara, Corin Ezzelarab, Cassandra Long, P. Bajona, B. Garcia, N. Murase, D. Ayares, D. Cooper (2012)
Costimulation blockade in pig artery patch xenotransplantation – a simple model to monitor the adaptive immune response in nonhuman primatesXenotransplantation, 19
A. Chong, M. Alegre (2012)
The impact of infection and tissue damage in solid-organ transplantationNature Reviews Immunology, 12
M. Ezzelarab, B. Ekser, K. Isse, H. Iwase, A. Morelli, D. Ayares, D. Cooper (2014)
Increased Soluble CD154 (CD40 Ligand) Levels in Xenograft Recipients Correlate With the Development of De Novo Anti-Pig IgG AntibodiesTransplantation, 97
Carol Phelps, Chihiro Koike, T. Vaught, J. Boone, Kevin Wells, Shu-Hung Chen, S. Ball, S. Specht, I. Polejaeva, Jeff Monahan, P. Jobst, Sugandha Sharma, Ashley Lamborn, A. Garst, Marilyn Moore, A. Demetris, W. Rudert, R. Bottino, S. Bertera, Massimo Trucco, Thomas Starzl, Yifan Dai, D. Ayares (2002)
Production of α1,3-Galactosyltransferase-Deficient PigsScience, 299
M. Ezzelarab, B. Garcia, A. Azimzadeh, Hongtao Sun, C. Lin, H. Hara, S. Kelishadi, Tianshu Zhang, Y. Lin, H. Tai, R. Wagner, J. Thacker, N. Murase, K. McCurry, R. Barth, D. Ayares, R. Pierson, D. Cooper (2009)
The Innate Immune Response and Activation of Coagulation in α1,3-Galactosyltransferase Gene-Knockout Xenograft RecipientsTransplantation, 87
B. Wung, M. Hsu, C. Wu, C. Hsieh (2005)
Resveratrol suppresses IL-6-induced ICAM-1 gene expression in endothelial cells: effects on the inhibition of STAT3 phosphorylation.Life sciences, 78 4
Inflammation is known to preclude tolerance after transplantation. We have previously shown that systemic inflammation in xenograft recipients (SIXR) precedes activation of coagulation in the absence of T cell responses. Accordingly, SIXR may amplify innate and adaptive immune responses against xenografts after pig‐to‐primate xenotransplantation, even with efficient immunosuppressive therapy. We evaluated the impact of anti‐inflammatory agents on pro‐inflammatory 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) and costimulation blockade‐based immunosuppression (anti‐CD40 and/or CTLA4Ig). In Group1, baboons received either (i) no anti‐inflammatory agents (n=2), (ii) cobra venom factor (CVF, n=2), (iii) α1‐antitrypsin (AAT, n=2), or (iv) interleukin (IL)‐6 receptor antagonist (IL‐6RA, n=2). In Group2, all baboon received corticosteroids, either without (n=2) or with (n=2) IL‐6RA. Serum IFN‐γ, TNF‐α, IL‐1β, IL‐17, IL‐6, IL‐8, MCP‐1, and sCD40L levels were measured by Luminex. Fibrinogen, D‐dimers, and C‐reactive protein (C‐RP) were also measured. Recipient baboon T cell proliferation was evaluated by mixed lymphocyte reaction (MLR) before and after transplantation. Pig and baboon tissue factor (TF) mRNA levels in heart xenografts were measured by RT‐PCR. In no recipient was a marked increase in T cell response to pig cells observed after transplantation. In Groups 1 and 2, post‐transplantation levels of IFN‐γ, TNF‐α, IL‐1β, and IL‐17 remained comparable to or lower than pre‐transplant levels, except in one heart recipient that succumbed to CMV infection. In Group1, when no anti‐inflammatory agent was administered, post‐transplant levels of IL‐6, IL‐8, and MCP‐1 were elevated. After CVF, IL‐6, IL‐8, and MCP‐1 remained low. After IL‐6RA, IL‐6 and MCP‐1 were elevated. After AAT, IL‐8 was elevated. sCD40L became elevated intermittently in most recipients irrespective of the administered anti‐inflammatory agent. In Group2, IL‐6 was transiently elevated, particularly after IL‐6RA administration. MCP‐1 gradually increased by 2 months in Group2 recipients. sCD40L generally remained low except in one recipient. In Group1 and Group2 recipients, C‐RP levels were elevated except after IL‐6RA administration, while D‐dimers were elevated regardless of administration of anti‐inflammatory agent. In Group2, pig TF mRNA levels were increased in heart xenografts compared to naive pig hearts, irrespective of IL‐6 receptor antagonist administration. Additionally, baboon TF mRNA levels were detectable in heart xenografts, but not in naive pig hearts. Some pro‐inflammatory cytokines and chemokines are elevated in xenograft recipients, even with efficient T cell‐directed immunosuppressive therapy. Persistent elevation of D‐dimers, and individual cytokines and chemokines suggest a continuous inflammatory response, despite administration of anti‐inflammatory agents. Systemic administration of combined anti‐inflammatory agents as well as complement regulation may be essential to prevent SIXR after xenotransplantation.
Xenotransplantation – Wiley
Published: Mar 1, 2017
Keywords: ; ; ; ; ;
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