Histopathologic insights into the mechanism of anti-non-Gal antibody-mediated pig cardiac xenograft rejection.
Bottom Line: The histopathology of cardiac xenograft rejection has evolved over the last 20 yr with the development of new modalities for limiting antibody-mediated injury, advancing regimens for immune suppression, and an ever-widening variety of new donor genetics.These new technologies have helped us progress from what was once an overwhelming anti-Gal-mediated hyperacute rejection to a more protracted anti-Gal-mediated vascular rejection to what is now a more complex manifestation of non-Gal humoral rejection and coagulation dysregulation.This review summarizes the changing histopathology of Gal- and non-Gal-mediated cardiac xenograft rejection and discusses the contributions of immune-mediated injury, species-specific immune-independent factors, transplant and therapeutic procedures, and donor genetics to the overall mechanism(s) of cardiac xenograft rejection.
Affiliation: Institute of Cardiovascular Science, University College London, London, UK; Department of Surgery, Mayo Clinic, Rochester, MN, USA.Show MeSH
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Mentions: The initial barrier to xenotransplantation was hyperacute rejection (HAR) caused by complement-mediated endothelial cell (EC) destruction directed by preformed anti-Gal antibody. The histopathology of HAR is predominantly characterized by rapid graft failure and widespread intravascular hemorrhage (Fig. 1A,C, Table 1). This is accompanied by vascular antibody, complement, and fibrin deposition with the formation of platelet-rich thrombi (not shown) [23–27]. Improved xenograft survival was not reliably achieved until methods were developed to block the effects of complement and anti-Gal antibody. Early attempts depleted anti-Gal antibody through pig-specific organ perfusion [10,23,24], plasmapheresis, or affinity immunoadsorption [11–14,28,29]. These studies demonstrated the dominant role of anti-Gal antibody in graft rejection [14,28–30], but provided only temporary antibody reduction. An induced anti-Gal antibody response led to delayed xenograft rejection (DXR) also characterized by interstitial hemorrhage, vascular antibody and complement deposition with diffuse platelet-rich fibrin thrombosis (Fig. 1B, Table 1). Unlike HAR, DXR occurs over the course of days to weeks, and vascular antibody and complement deposition, nearly universal in HAR, is more variable in DXR. This is due in part to the efficacy of different modalities (hCRP transgenic organs, cobra venom factor, plasmapheresis, or soluble complement inhibitors) used to limit antibody-dependent complement-mediated injury.
Affiliation: Institute of Cardiovascular Science, University College London, London, UK; Department of Surgery, Mayo Clinic, Rochester, MN, USA.