Thrombotic Microangiopathy Associated with Humoral Rejection of Cardiac Xenografts from α1,3-Galactosyltransferase Gene-Knockout Pigs in Baboons

Shimizu, Akira; Hisashi, Yosuke; Kuwaki, Kenji; Tseng, Yau‐Lin; Dor, Frank J. M. F.; Houser, Stuart L.; Robson, Simon C.; Schuurman, Henk Jan; Cooper, David K. C.; Sachs, David H.; Yamada, Kazuhiko; Colvin, Robert B.

doi:10.2353/ajpath.2008.070672

Cited by 137 publications

(130 citation statements)

References 36 publications

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“…After the transplantation of GalT-KO kidneys, AHXR is characterized histologically by a thrombotic microangiopathic glomerulopathy with increasing IgM, IgG, C4d, and C5b-9 deposition in the glomeruli, with thrombi forming inside the injured glomeruli, loss of capillaries, and endothelial cell death (Shimizu et al 2012). A similar picture can be seen after heart xenotransplantation (Shimizu et al 2008), in which case, AHXR is characterized by antibody and complement deposition on the capillary walls, multiple microthrombi in the capillaries, myocardial ischemia, and necrosis. The pathogenesis of AHXR is assumed to be multifactorial, but preformed and induced antibodies directed against the endothelium are believed to be the primary factors triggering AHXR, resulting in endothelial activation and orienting the anticoagulative properties of the endothelium toward a procoagulative phenotype favoring thrombosis (Crikis et al 2006).…”

Section: Antibody-mediated Xenograft Rejectionmentioning

confidence: 86%

Immunological Challenges and Therapies in Xenotransplantation

Vadori

2014

Cold Spring Harbor Perspectives in Medicine

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Section: Antibody-mediated Xenograft Rejectionmentioning

confidence: 86%

Immunological Challenges and Therapies in Xenotransplantation

Vadori

2014

Cold Spring Harbor Perspectives in Medicine

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“…The development of thrombosis in rejecting porcine xenografts begins in the microvasculature before progressing to larger vessels (27)(28)(29). This pattern suggests that failure to control coagulation in the microcirculation, which is the major source of anticoagulant activity in the body because of its high endothelium-to-blood ratio (30), is a trigger for the injury process.…”

Section: Discussionmentioning

confidence: 99%

Protective Effects of Transgenic Human Endothelial Protein C Receptor Expression in Murine Models of Transplantation

Lee

Lü

Roussel

et al. 2012

American Journal of Transplantation

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†Equal senior authors.Thrombosis and inflammation are major obstacles to successful pig-to-human solid organ xenotransplantation. A potential solution is genetic modification of the donor pig to overexpress molecules such as the endothelial protein C receptor (EPCR), which has anticoagulant, anti-inflammatory and cytoprotective signaling properties. Transgenic mice expressing human EPCR (hEPCR) were generated and characterized to test this approach. hEPCR was expressed widely and its compatibility with the mouse protein C pathway was evident from the anticoagulant phenotype of the transgenic mice, which exhibited a prolonged tail bleeding time and resistance to collagen-induced thrombosis. hEPCR mice were protected in a model of warm renal ischemia reperfusion injury compared to wild type (WT) littermates (mean serum creatinine 39.0 ± 2.3 lmol/L vs. 78.5 ± 10.0 lmol/L, p < 0.05; mean injury score 31 ± 7% vs. 56 ± 5%, p < 0.05). Heterotopic cardiac xenografts from hEPCR mice showed a small but significant prolongation of survival in C6-deficient PVG rat recipients compared to WT grafts (median graft survival 6 vs. 5 days, p < 0.05), with less hemorrhage and edema in rejected transgenic grafts. These data indicate that it is possible to overexpress EPCR at a sufficient level to provide protection against transplantrelated thrombotic and inflammatory injury, without detrimental effects in the donor animal.

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“…16 Recently, however, with the use of xenografts deriving from αGalT -/-pigs and the introduction of novel immunosuppressive strategies, the pattern of AHXR is changing towards a picture compatible with a prominent thrombotic microangiopathy. 25 As for HAR, the identification of specific targets of intervention for AHXR should allow scientists to overcome this immune barrier, ultimately further extending xenograft survival. To this end, at least three different approaches are currently being explored.…”

Section: Xenotransplantation: the Need For An Integrated Multidiscipmentioning

confidence: 99%

Xenotransplantation as a model of integrated, multidisciplinary research

Cozzi

Bosio

Seveso³

et al. 2009

Organogenesis

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However it has also become apparent that if xenotransplantation has to enter the clinical arena, a multidisciplinary approach will be needed to comprehensively tackle the different issues related to the use of a xenograft to cure human disease.In this regard, the safety, ethics and regulatory aspects of xenotransplantation are currently being aggressively addressed to enable the initiation of xenotransplantation with a favourable risk/benefit ratio.

show abstract

Thrombotic Microangiopathy Associated with Humoral Rejection of Cardiac Xenografts from α1,3-Galactosyltransferase Gene-Knockout Pigs in Baboons

Cited by 137 publications

References 36 publications

Immunological Challenges and Therapies in Xenotransplantation

Immunological Challenges and Therapies in Xenotransplantation

Protective Effects of Transgenic Human Endothelial Protein C Receptor Expression in Murine Models of Transplantation

Xenotransplantation as a model of integrated, multidisciplinary research

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