Chronic rejection of concordant aortic xenografts in the hamster-to-rat model

Abstract

Several groups have demonstrated that it is possible to obtain long-term graft survival of concordant xenografts. One of the important questions that remains is whether xenografts are susceptible to chronic rejection. To answer this question we used the aorta transplantation model. One centimetre of hamster aorta was interposed in the abdominal aorta of Lewis rat recipients. The recipients were either untreated (group 1), or treated with 10 mg/kg cyclosporine (CsA), given intramuscularly three times a week (group 2). Rats were sacrificed at day 7, 14, 21, 28, 56 and 84 and the thickness of the intima, the media and the adventitia was measured. Furthermore, the cellularity of the media and the adventitia was assessed by counting the number of nuclei per 0.05 mm2 and immunohistochemistry of the aortic grafts was performed. Graft arteriosclerosis developed in aortic xenografts of both group 1 and group 2. In group 1, intimal lesions were already present from day 21 onwards in all rats, whereas in group 2 they were present only in 33% (2/6) of the rats. At day 84 all the grafts in group 1 were totally occluded, while those in group 2 were still open. The thickness of the media was slightly increased in both groups during the whole observation period, mainly due to edema. Although a few infiltrating macrophages could be seen, the number of nuclei per 0.05 mm2 of the media remained constant during the first 21 days, but declined sharply from day 21 onwards, as a consequence of disappearing myocytes. Thickness of the adventitia in both groups increased after transplantation due to infiltrating macrophages and T cells, reaching a peak at day 14. After day 14 the adventitial thickness in group 1 decreased rapidly to reach values comparable to group 2 from day 28 onwards. In conclusion, graft arteriosclerosis, as a sign of chronic rejection, occurs in concordant aortic xenografts. The lesions in the xenografts develop extremely rapidly, and compared to data from the literature, faster than in aortic allografts. The process of chronic rejection in aortic xenografts can be reduced by CsA.

Isolation of mouse‐to‐rat cardiac xenograft‐infiltrating cells by ex vivo propagation

“…In all transplants the cellular infiltration was dominated by macrophages, with the T lymphocyte as the next most abundant cell type. Similar findings have been described in several xenogeneic experimental models, vascularized as well as non‐vascularized [3, 4, 13–15].…”

Histological and immunological characteristics of, and the effect of immunosuppressive treatment on, xenograft vasculopathy

“…Aortic transplantation has long been accepted as a relevant small animal model for the investigation of chronic allograft vasculopathy. Scheringa et al [21] used the same model that we have, i.e. hamster aortas transplanted into Lewis rats, and have found neointimal proliferation does take place in his model and that the lesion is inhibited by cyclosporin.…”

FK778 in Experimental Xenotransplantation: A Detailed Analysis of Drug Efficacy

“…Because intimal proliferation, collagen deposition and SMC proliferation do not occur in this model until 2 weeks after transplantation, chronic rejection features were not found. 28,31 As recently suggested, lymphocyte surface antigen expression reflects the host cellular responsiveness and can thus be used to monitor the pharmacodynamic effects of immunosuppressive agents. 32 A significantly decreased upregulation of CD25 could be demonstrated for FK778 HD and tacrolimus HD and their combination regimen at times of 24-hour trough levels.…”