An ultrastructural analysis of concordant and discordant cardiac xenografts in unmodified recipients

Abstract

Ultrastructural changes in endothelial cells in a hamster‐to‐rat and guinea pig‐to‐rat heart transplantation model are described. In the hamster‐to‐rat model, changes were minimal with an increase in cytoplasmic vesicles 4–6 h after transplantation. 16–24 h after transplantation larger vesicles appeared and the basement and cell membranes were less well defined. 42–48 h after transplantation the changes had progressed with destruction of cell membranes and the appearance of extravasated erythrocytes. At the time of complete rejection, changes had further progressed with widespread endothelial cell destruction and infiltration of neutrophilic granulocytes and macrophages, and large amounts of fibrin were present. In the guinea pig‐to‐rat model, changes were characterized by the appearance of platelets in close contact with the endothelium of the capillaries 1–3 min after transplantation. 4–6 min after transplantation the basement membranes as well as the cell membranes were affected with indistinct borders and interruption. Occasionally fusion of platelets and endothelial cell membranes was demonstrated. In the grafts examined 7–9 min after transplantation, changes had further progressed. Massive aggregation of platelets now appeared in relation to remnants of endothelical cells. Signs of microvascular damage appeared in both models, but with different morphology. In hamster grafts, endothelial cell activation is indicated by gradual changes in the cell membranes resulting in vascular damage and infiltration of the grafts by macrophages and neutrophilic granulocytes. In the guinea pig grafts, activation of endothelial cells results in platelet aggregation, formation of microthrombi, and subsequent tissue damage. Even though antibody and complement are involved in both types of rejection the basic mechanisms are different.

Acute xenograft rejection, late xenograft rejection and long term survival xenografts in the hamster‐to‐rat heart transplantation model: histological characterisation under low‐dose of FK506

“…Unmodified recipients show a pattern classically defined as humoral but there is no consensus between the different studies, as a number of variants of the same rejection mechanism have been described (5, 19). Like Brouard et al (20), we observed severe alterations of the interstitium, with extensive edema, coagulative necrosis, haemorrhage, and with no cellular infiltration of any type.…”

High-Dose Stabilized Chlorite Matrix WF10 Prolongs Cardiac Xenograft Survival in the Hamster-to-Rat Model without Inducing Ultrastructural or Biochemical Signs of Cardiotoxicity

“…Samples of left ventricular tissue were removed immediately after sacrifice and fixed in 2.5% glutaraldehyde. The tissue was then treated after standard procedure (Nielsen et al 1994) and examined with a 208 Philips electron microscope by two of us (ABH, TH), unaware of treatment conditions. Serum analysis.…”

High‐Dose Stabilized Chlorite Matrix WF10 Prolongs Cardiac Xenograft Survival in the Hamster‐to‐Rat Model without Inducing Ultrastructural or Biochemical Signs of Cardiotoxicity

“…Although our results exclude a cardiotoxic side effect of WF10, serial biochemical or contractile functional measurements might have shown the opposite. However, electron microscopy has been shown to be a valuable method, both to evaluate cardiac xenotransplant rejection (Nielsen et al 1994;Rose 1997;Kemp et al 2000) and druginduced cardiotoxicity (Billingham 1983). Correlational studies using ejection fraction indices and/or 31P nuclear magnetic resonance spectroscopy will be of great value in the future (Zandt et al 1999).…”

“…Samples of left ventricular tissue were removed immediately after sacrifice and fixed in 2.5% glutaraldehyde. The tissue was then treated after standard procedure (Nielsen et al 1994) and examined with a 208 Philips electron microscope by two of us (ABH, TH), unaware of treatment conditions.…”

“…Cardiotoxic damage was defined by the presence of one or more of the following features: myofibrillar loss or disorganization, T-tubulus or sacroplasmatic reticulum dilatation or vacuolization, degenerative mitochondria, destruction of membranes, chromatin changes, dilated endoplasmatic reticulum, electron dense vesicles or reduced matrix density (Billingham 1983;Rose 1997;Kemp et al 2000). Endothelial cell damage was defined according to Nielsen et al (1994), including degenerative organelle changes. Fig.…”