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
Related in: MedlinePlus
Mentions: α1,3-galactosyltransferase gene knockout pigs heart xenografts have also been reported to undergo early immune injury from preformed anti-non-Gal antibody, which did not result in HAR [34,41]. In these studies, GTKO graft survival was <1 day in the absence of immune suppression, but was extended to 2 to 12 days with “partial” immune suppression and up to 8 weeks with a “full” regimen. Xenograft rejection was complex, as the grafts, regardless of the efficiency of immune suppression, showed evidence of both humoral rejection, in the form of vascular antibody and complement deposition, and recipient innate immune cell activation. The innate cell activation was manifested as CC (defined by thrombocytopenia, low fibrinogen levels, prolongation of prothrombin and activated partial thromboplastin times, bleeding) and as a significantly increased level of intragraft neutrophil infiltration with a marked increase in recipient baboon tissue factor (bTF) expression from intragraft and graft adherent intravascular monocytes and macrophages (Fig. 4A–D, Table 1). Activation of recipient innate immune cells and induction of bTF expression have also been reported in kidney xenograft recipients subject to CC .
Affiliation: Institute of Cardiovascular Science, University College London, London, UK; Department of Surgery, Mayo Clinic, Rochester, MN, USA.