Coagulation, platelet activation and thrombosis in xenotransplantation

Schmelzle, Moritz; Esch, Jan Schulte Am; Robson, Simon C.

doi:10.1097/mot.0b013e3283373ccc

Cited by 36 publications

(29 citation statements)

References 65 publications

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“…Hepatocyte xenografts could be performed as planned procedures, using well-characterized sources that are uniform (inbred or even cloned) and potentially engineered genetically to enhance key functions or address important hurdles. Although biological incompatibility and heightened immunity pose barriers [41], those barriers might potentially be overcome by repeated transplants, an approach rarely if ever possible for hepatocyte allografts, and by improvements in immunosuppression that make immunity to xenografts more tractable than previously thought [41-43]. Unlike organ transplants, hepatocyte xenografts are not susceptible to antibody-mediated rejection [22, 44] and currently used immunosuppressive agents can usually control cell-mediated rejection of xenografts, at least for weeks to months [22, 45].…”

Section: Discussionmentioning

confidence: 99%

Host conditioning and rejection monitoring in hepatocyte transplantation in humans

Soltys

Setoyama

Tafaleng

et al. 2017

Journal of Hepatology

103

115

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Background Hepatocyte transplantation partially corrects genetic disorders and has been associated anecdotally with reversal of acute liver failure. Monitoring for graft function and rejection has been difficult, and has contributed to limited graft survival. Methods Preparative hepatic irradiation was examined in non-human primates as a strategy to improve engraftment of donor hepatocytes, and was then applied in human subjects. T-cell immune monitoring was also examined in human subjects to assess adequacy of immunosuppression. Results Porcine hepatocyte transplants engrafted and expanded to comprise up to 15% of irradiated segments in immunosuppressed monkeys preconditioned with 10Gy liver-directed irradiation. Two patients with urea cycle deficiencies had early graft loss following hepatocyte transplantation; retrospective immune monitoring suggested the need for additional immunosuppression. Preparative radiation, anti-lymphocyte induction, and frequent immune monitoring were instituted for hepatocyte transplantation in a 27-year old female with classical phenylketonuria. Post-transplant liver biopsies demonstrated multiple small clusters of transplanted cells, multiple mitoses, and Ki67+ hepatocytes. Mean peripheral blood phenylalanine (PHE) level fell from pre-transplant levels of 1343 ± 48μM (normal 30-119μM) to 854 ± 25μM (treatment goal ≤360μM) after transplant (36% decrease; p<0.0001), despite transplantation of only half the target number of donor hepatocytes. PHE levels remained below 900 μM during supervised follow-up, but graft loss occurred after follow-up became inconsistent. Conclusions Radiation preconditioning and serial rejection-risk assessment may produce better engraftment and long-term survival of transplanted hepatocytes. Hepatocyte xenografts engraft for a period of months in non-human primates and may provide effective therapy for patients with acute liver failure.

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Section: Discussionmentioning

confidence: 99%

Host conditioning and rejection monitoring in hepatocyte transplantation in humans

Soltys

Setoyama

Tafaleng

et al. 2017

Journal of Hepatology

103

115

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“…Activation of the coagulation cascade is a consequence of the inflammatory responses described above, leading to disseminated intravascular coagulation and thrombosis, rapid loss of platelet and clotting factors, decreased blood flow and ischemia/infarction (Schmelzle et al 2010;Ezzelarab et al 2015b). As with inflammation, coagulation is rapidly amplified after initiation and difficult to regulate once widespread.…”

Section: Coagulationmentioning

confidence: 99%

Synthetic Biology in Cell and Organ Transplantation

Stevens

2016

Cold Spring Harb Perspect Biol

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The transplantation of cells and organs has an extensive history, with blood transfusion and skin grafts described as some of the earliest medical interventions. The speed and efficiency of the human immune system evolved to rapidly recognize and remove pathogens; the human immune system also serves as a barrier against the transplant of cells and organs from even highly related donors. Although this shows the remarkable effectiveness of the immune system, the engineering of cells and organs that will survive in a host patient over the long term remains a steep challenge. Progress in the understanding of host immune responses to donor cells and organs, combined with the rapid advancement in synthetic biology applications, allows the rational engineering of more effective solutions for transplantation.

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“…Dysregulation of the coagulation system is common in baboon recipients after pig organ xenotransplantation, where platelets play an important role in the development of thrombotic microangiopathy in the graft and of consumptive coagulopathy in the recipient (1). Platelets are known to be a rich source of soluble (s)CD154 (CD40 ligand), which is released following platelet activation.…”

mentioning

confidence: 99%