Treatment with total lymphoid irradiation, cyclosporin A and a monoclonal anti-T-cell antibody in a hamster-to-rat heart transplantation model: Graft survival and morphological analysis

Abstract

Treatment with preoperative total lymphoid irradiation and post-transplant cyclosporin A has been shown to have a synergistic effect on graft survival in allo- and xenotransplantation. Specific monoclonal antibodies against T cells and T cell subpopulations could offer new ways of preventing graft rejection in xenotransplantation. Graft survival and histology were examined after total lymphoid irradiation plus cyclosporin A treatment versus cyclosporin A plus a monoclonal antibody in a concordant, heterotopic, hamster-to-rat heart transplantation model. Preoperative total lymphoid irradiation was given at a dose of 1.25 Gy, 12 times over a period of 3 weeks. Cyclosporin A at a dose of 12.5 mg/kg per day was administered perorally and OX-19, a pan T cell monoclonal antibody, was given as intraperitoneal injections at doses of 100 micrograms or 500 micrograms/kg per day from day 0 until graft rejection. While total lymphoid irradiation alone prolonged graft survival to 9.4 days, total lymphoid irradiation plus cyclosporin A extended graft survival to a mean of 22 days. Cyclosporin alone or combined with the monoclonal antibody could not increase graft survival significantly when compared to untreated animals, which rejected their grafts within 3.7 days. Vascular rejection was the characteristic morphological finding, even after some weeks of excellent graft function. In conclusion, total lymphoid irradiation and cyclosporin A had a synergistic effect on graft survival in this concordant xenotransplantation model, although recent impressive results from other groups could not be reproduced. Total lymphoid irradiation combined with cyclosporin A appears to delay a primary humoral graft rejection, while the mechanism of rejection, judged by histology, stays the same.

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

“…In one recently presented study by Cramer et al (1992) (4) CD8+ and CD4+ cells were demonstrated in the early phase of xenograft rejection using a similar hamster-to-rat model. This is in disagreement with the present findings and seems difficult to explain in relation to our experience in untreated as well as treated transplantation series (20). However, different rejection mechanisms obviously occur in concordant models and the study by Marchman et al (1992) (13) using total lymphoid irradiation and 15deoxyspergualin in a hamster-to-rat model demonstrated that the initial humoral response was followed by mild cellular rejection, a finding also described by others using the same treatment (22).…”

“…Tissue available for examination came from 34 heterotopic heart-transplantated rats (outbred Sprague-Dawley rats SPF Msllegaard Breeding Center, Copenhagen, Denmark) using the albino variant of the Syrian hamster (Department of Odontological Research, Gothenburg University, Sweden) as donor. The heart transplantations were performed using a microvascular technique described by On0 & Lindsey (17) and modified by Steinbriichel et al (20). The grafts were excised and examined at the following intervals: 6 h (N = 8), 24 h (N = lo), 48 h (N = 8), and at the time of complete rejection (72-96 h, average 78 h) (N=8).…”

Xenotransplantation

“…In our laboratory, we have tried to add monoclonal antibodies and\or total lymphoid irradiation to a basic therapy of Cyclosporin [37][38][39] and obtained some prolongation of survival time, but we achieved even better results with application of the newer antiproliferative drugs such as Cyclosporin, Brequinar Sodium, Mycophenolate Mofetil, and especially, Leflunomide.…”

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

“…Hamster-to-rat heterotopic cardiac transplantation has been studied by several groups as a model of concordant xenograft rejection [2,5,9,10,12,13,18,19]. Graft survival data from these studies, including different treatment modalities, are not always consistent.…”