Further evidence for sustained systemic inflammation in xenograft recipients (<scp>SIXR</scp>)

Iwase, Hayato; Ekser, Burçin; Zhou, Huidong; Liu, Hong; Satyananda, Vikas; Humar, Rishab; Humar, Pooja; Hara, Hidetaka; Long, Cassandra; Bhama, Jay K.; Bajona, Pietro; Wang, Yi; Wijkstrom, Martin; Ayares, David; Ezzelarab, Mohamed; Cooper, David K.C.

doi:10.1111/xen.12182

Cited by 55 publications

(98 citation statements)

References 42 publications

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“…For example, a beneficial effect of tocilizumab (IL-6 receptor blockade) has been documented. 26,31 In the present study, when baboons received tocilizumab, the levels of serum histone and CRP were reduced, and the level of fT3 and the platelet count were increased. The mechanisms by which tocilizumab results in a reduction in histone release is uncertain, but the prevention or suppression of an inflammatory response is likely to play a role.…”

Section: Discussionsupporting

confidence: 49%

“…26,27 Therefore, anti-inflammatory agents have been administered. For example, a beneficial effect of tocilizumab (IL-6 receptor blockade) has been documented.…”

Section: Discussionmentioning

confidence: 99%

“…25 There is increasing evidence that a systemic inflammatory response is associated with the presence of a pig xenograft. 26,27 Furthermore, this response precedes the onset of features of coagulation dysfunction. 28,29 Inflammation, coagulation, and the immune response have a complex inter-relationship.…”

Section: Introductionmentioning

confidence: 99%

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An Investigation of Extracellular Histones in Pig-To-Baboon Organ Xenotransplantation

Lee

Hara

et al. 2017

Transplantation

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Background Serum (extracellular) histone levels are increased in inflammatory states and in the presence of coagulation dysfunction, eg, 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. Methods 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 ELISA. 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. Results Serum histones increased when baboons developed consumptive coagulopathy (CC) (eg, thrombocytopenia) or infection. CRP levels tended to be higher and fT3 levels lower when CC 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-kB pathway inhibitor, parthenolide. Conclusions 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.

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Section: Discussionsupporting

confidence: 49%

“…26,27 Therefore, anti-inflammatory agents have been administered. For example, a beneficial effect of tocilizumab (IL-6 receptor blockade) has been documented.…”

Section: Discussionmentioning

confidence: 99%

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An Investigation of Extracellular Histones in Pig-To-Baboon Organ Xenotransplantation

Lee

Hara

et al. 2017

Transplantation

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“…We attribute this relative success to the combination of (i) transplantation of a kidney from a pig with multiple genetic modifications directed to prevent injury from the primate immune response and from the effects of coagulation dysfunction between pig and baboon (8), (ii) an immunosuppressive regimen that has been demonstrated to prevent a T cell response to pig cardiac xenografts (9, 10), and (iii) a regimen that reduces the inflammatory response (11). …”

Section: Discussionmentioning

confidence: 99%

Myroides Infection in a Baboon After Prolonged Pig Kidney Graft Survival

Liu

Iwase

Wijkstrom

et al. 2015

Transplantation Direct

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Background Immunosuppressed patients and experimental nonhuman primates are at risk of opportunistic infection. We report a Myroides spp infection in an immunosuppressed baboon that had received a life-supporting kidney from a genetically-engineered pig. Case report The baboon received a costimulation blockade-based immunosuppressive regimen as well as two anti-inflammatory agents (tocilizumab and etanercept). Although the pig kidney functioned well, approximately four months after the transplant the baboon became less active and ate and drank poorly. On day 136, it collapsed and died despite inotropic and fluid support. A blood culture drawn before death grew Myroides spp. Discussion and conclusions To our knowledge, Myroides spp has not been reported as a cause of opportunistic infection in either patients with organ allotransplants or experimental animals. We summarize what is known about this rare organism, and suggest it should be considered in any immunocompromised patient or animal. In the present case, we suggest the baboon died of circulatory shock following infection through an indwelling intravenous catheter.

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“…Increasing attention is being paid to an inflammatory response that develops after the transplantation of a pig organ into a NHP [48-50]. The inflammatory response can augment the immune response and the coagulation discrepancies [51].…”

Section: Pig-to-primate Organ Transplantationmentioning

confidence: 99%

Recent advances in understanding xenotransplantation: implications for the clinic

Cooper

Bottino

2015

Expert Review of Clinical Immunology

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Summary The results of organ and cell allotransplantation continue to improve, but the field remains limited by a lack of deceased donor organs. Xenotransplantation, e.g., between pig and human, offers unlimited organs and cells for clinical transplantation. The immune barriers include a strong innate immune response in addition to the adaptive T cell response. The innate response has largely been overcome by the transplantation of organs from pigs with genetic modifications that protect their tissues from this response. T cell-mediated rejection can be controlled by immunosuppressive agents that inhibit costimulation. Coagulation dysfunction between the pig and primate remains problematic but is being overcome by the transplantation of organs from pigs that express human coagulation-regulatory proteins. The remaining barriers will be resolved by the introduction of novel genetically-engineered pigs. Limited clinical trials of pig islet and corneal transplantation are already underway.

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Further evidence for sustained systemic inflammation in xenograft recipients (SIXR)

Cited by 55 publications

References 42 publications

An Investigation of Extracellular Histones in Pig-To-Baboon Organ Xenotransplantation

An Investigation of Extracellular Histones in Pig-To-Baboon Organ Xenotransplantation

Myroides Infection in a Baboon After Prolonged Pig Kidney Graft Survival

Recent advances in understanding xenotransplantation: implications for the clinic

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