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: This change in histopathology was attributed to sustained depletion of anti-Gal antibody. A recent histopathology comparison of cardiac xenografts under conditions where pre-transplant anti-Gal antibody was uniformly depleted and post-transplant induction of anti-Gal antibody was either partially muted by immunoapheresis, blocked by in vivo Gal polymers, or made irrelevant using GTKO donor hearts supports this conclusion . Under these conditions, the major histopathologic features of developing and terminal xenograft rejection were the same for each group (Fig. 3A). Early evidence of rejection included vascular antibody deposition at 30 min after organ reperfusion and, at later time points, consistent myocyte vacuolization in the absence of appreciable microvascular thrombosis (Fig. 3B). As rejection progressed, based on the systemic release of cardiac troponin, diffuse microvascular thrombosis developed, eventually leading to myocardial coagulative necrosis and ischemic changes (Fig. 3C). At the time of graft failure, all three groups showed prominent microvascular thrombosis and coagulative necrosis with minimal interstitial hemorrhage or lymphocytic infiltration (Fig. 3D). Taken together, these results suggest that muting or elimination of the acute effects of preformed anti-Gal antibody reduced the intensity of humoral rejection, which likely limited the extent of interstitial hemorrhage. Gene expression analysis of these transplants suggested that a chronic state of antibody-mediated EC activation likely contributed to the development of TM .
Affiliation: Institute of Cardiovascular Science, University College London, London, UK; Department of Surgery, Mayo Clinic, Rochester, MN, USA.