Sequential, morphological, and antidonor antibody analysis in a hamster-to-rat heart transplantation model

Abstract

The pathogenesis and the mechanism of accelerated graft rejection in concordant xenotransplantation are unclear. The histopathological features and kinetics neither fulfill the criteria of classic hyperacute rejection nor resemble an accelerated type of first-set allograft reaction. The aim of this study was to investigate the mechanism of concordant xenograft rejection in relation to the early morphological changes in hamster hearts transplanted to unmodified rat recipients by sequential, immunohistological analysis of grafts, regional lymph nodes, and spleens and to correlate these results to the production of antidonor antibodies, as determined by a flow cytometric assay. Histopathological features were characterized by a gradually increasing myocytolysis with fragmentation and loss of myofilaments. The first slight signs were observed a few hours after transplantation. Later, vascular changes developed, evolving into a leukocytoclastic type of vasculitis, eventually with thrombosis. No significant interstitial lymphocyte infiltration was present, but neutrophilic granulocytes and macrophages appeared. In addition, a distinct increase in B cells in spleens and lymph nodes was noted. Low levels of preformed antidonor antibodies did not increase during the first 48 h; however, significant amounts of species-, but not donor-, specific antibodies were demonstrated at the time of rejection. These data, together with the morphological observations, indicate a primarily humoral xenograft rejection in this model. Minor damage to graft myocytes a few hours after transplantation, progressing to vascular changes within 24-48 h, further suggests that preformed antidonor antibodies directed against endothelial or myocyte determinants may play an initiating role in the pathogenesis of unmodified, concordant xenograft rejection.

Evidence for a primarily humoral rejection mechanism in concordant xenogeneic heart transplantation. A sequential immunohistological study in a hamster-to-rat model

“…In the present study the finding of progressive tissue damage in relation to vascular changes and subsequent infiltration with macrophages and neutrophilic granulocytes confirmed by immunohistochemistry indicates a primarily humoral rejection mechanism in this model. This is in accordance with other findings in our laboratory where significant amounts of speciesspecific cytotoxic antibodies were demonstrated (12,21).…”

“…described by Rosengard et al (1986) (19). In accordance with Rosengard et al (1986) we concluded that the type of rejection was primarily of the humoral type (12,16,21). This has also been proposed by others using different treat-ment schedules for prevention of xenograft rejection (5,8,14).…”

“…This may partly be due to the use of different concordant animal models. The mechanism of acute cardiac xenograft rejection in the hamsterto-rat model has turned out to be completely different from first-set allograft rejection (5, 16,19,21). In earlier studies we described the presence of high-titre anti-donor antibodies in a series of unmodified cardiac hamster-to-rat transplantations (12,21).…”

“…The mechanism of acute cardiac xenograft rejection in the hamsterto-rat model has turned out to be completely different from first-set allograft rejection (5, 16,19,21). In earlier studies we described the presence of high-titre anti-donor antibodies in a series of unmodified cardiac hamster-to-rat transplantations (12,21). These findings corresponded to a morphological non-lymphocytic type of acute rejection dominated by progressive infiltration with macrophages and neutrophilic granulocytes, vascular changes of leukocytoclastic-like type, and myocyte damage (16).…”

The graft content of hyaluronan is increased during xenograft rejection

“…The morphology of rejecting cardiac xenotransplants clearly shows oedema [9][10][11]; however, hyaluronan has previously not been investigated in a xenotransplantation situation. In an attempt to characterize tissue hyaluronan content and distribution during xenograft rejection, we used the concordant mouse-to-rat heart transplantation model.…”