Coagulation and the xenograft endothelium.
Acute humoral rejection remains the major barrier to long-term pig-to-primate xenograft survival, and microvascular thrombosis is a critical element of the rejection process. It appears that persistent endothelial cell activation and injury, by even low levels of anti-graft antibodies, eventually overwhelm the cellular anticoagulant defences and promote the development of thrombotic microangiopathy. Porcine endothelium may be particularly vulnerable because of cross-species molecular incompatibilities affecting the function of thrombomodulin and possibly TFPI. Recent data from small animal models suggest that transgenic overexpression of anti-thrombotic molecules on xenograft endothelium is capable of inhibiting intravascular thrombosis and preventing acute humoral rejection. In conjunction with existing genetic modifications (e.g. Gal KO, hDAF), this is a promising strategy to move xenotransplantation to the clinic.
Cowan
Peter J
PJ
Immunology Research Centre, St Vincent's Health, Department of Medicine, University of Melbourne, Melbourne, Vic., Australia. peter.cowan@svhm.org.au
D000818:Animals; D001777:Blood Coagulation; D004727:Endothelium / Q000378:metabolism*; D006801:Humans; D013927:Thrombosis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D014019:Tissue Donors; D014183:Transplantation, Heterologous