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: Overall reported orthotopic graft survival ranges from <1 to 57 days, but with only 9 of 54 reported grafts surviving for >2 weeks . Recipient death most often occurs either within the first 48 h due to perioperative cardiac xenograft dysfunction (PCXD) or, in recipients that survive beyond 48 h, from post-operative complications. Early orthotopic transplants using CD55 transgenic organs without specific therapy to block anti-Gal antibody had graft survival of 5–39 days [80,81]. The histopathology of organ rejection included intense vascular IgM and complement deposition, thrombosis, and interstitial hemorrhage, which was consistent with anti-Gal antibody-induced DXR [96,97]. Subsequently, Gal polymer therapy was used to block anti-Gal antibody in recipients of CD55 transgenic grafts [84,85]. In this case, rejection correlated with the induction of anti-non-Gal antibody, and the histology was consistent with TM, including antibody and complement deposition, fibrin thrombosis, and myocyte necrosis. In studies using Gal-positive CD46 hearts with Gal polymer therapy, or GTKO/CD55 hearts, graft survival ranged from 14 to 57 days without apparent rejection [86,98], but with complications associated with immunosuppressive drug therapy. Explanted hearts exhibited vascular antibody binding with minimal complement deposition. There were variable levels of fibrin deposition and little evidence of CD41-stained platelet thrombi (Fig. 5A–C). Histologic injury, characterized by myocyte necrosis, varied from minimal to mild in 4 of 5 recipients.
Affiliation: Institute of Cardiovascular Science, University College London, London, UK; Department of Surgery, Mayo Clinic, Rochester, MN, USA.