Suppression of Acute Rejection Prevents Graft Arteriosclerosis After Allogeneic Aorta Transplantation in the Rat

Geerling, Rob A.; Bruin, Ron W. F. de; Scheringa, Marcel; Bonthuis, Fred; Jeekel, J; IJzermans, Jan N.M.; Marquet, R. L.

doi:10.1097/00007890-199412150-00021

Cited by 5 publications

(2 citation statements)

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“…However, despite this remarkable accomplishment, delayed graft loss due to chronic rejection still poses a formidable barrier to prolonged organ survival. 1,2 Although amelioration of acute rejection has been shown to partially obviate the development of chronic rejection, 3 it is still indeterminate as to why the prolonged use of immunosuppressive therapy fails to avert the subsequent evolvement of this disease.…”

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confidence: 99%

Improved surgical technique for the establishment of a murine model of aortic transplantation

et al. 1998

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Aortic allotransplantation is a reliable procedure to study the evolvement of chronic rejection in mice. The progressive nature of this process in mice is characterized by diffuse and concentric myointimal proliferation which is inevitably associated with variable degrees of luminal constriction. These vascular changes are comparable to those that are witnessed in organ allografts undergoing chronic rejection in humans, underscoring its utility as a model of choice for the study of the development of this lesion. Whilst improved surgical technique has resulted in markedly enhanced graft survival, the results are far from being acceptable. Realizing this limitation, we embarked on developing a modified technique for aortic transplantation which would allow for improved graft survival in mice. A bypass conduit was created by end-to-side anastomosis of a segment of the donor's thoracic aorta into the infrarenal portion of the recipient's abdominal aorta. Using this technique, the graft survival was >98% with evidence in allotransplanted aorta of morphological changes pathognomonic of chronic rejection. On the contrary, no histopathological anomalies were discerned in aortic grafts transplanted across syngeneic animals. This modified surgical approach ameliorates the unacceptably high graft loss associated with earlier techniques, further extending the utility of this model as a tool to study the molecular and cellular mechanisms rudiment to the evolvement of chronic rejection.

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confidence: 99%

Improved surgical technique for the establishment of a murine model of aortic transplantation

et al. 1998

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“…In the rat aortic allograft model, a dose of 3 mg/kg three times per week effectively prevented both acute rejection and graft arteriopathy and was as effective as high-dose cyclosporin therapy. 35 Not only has rapamycin been shown to reduce allograft vasculopathy, but reversal has also been demonstrated. In an inbred rat model, delayed administration of cyclosporin had no effect on graft vascular disease score (histological grade dependent on degree of vessel involvement), while administration of rapamycin (3 mg/kg per day) resulted in a significant reduction in score compared to control animals.…”

Section: Cardiac Transplantationmentioning

confidence: 99%

Rapamycin in cardiovascular medicine

Ruygrok

Muller

Serruys

2003

Internal Medicine Journal

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The cellular action of rapamycin (sirolimus), a natural fermentation product produced by Streptomyces hygroscopicus, is mediated by binding to the FK506 binding protein. By inhibiting a kinase known as the target of rapamycin, it restricts the proliferation of smooth-muscle cells by blocking cell-cycle progression at the G1/S transition. The finding that rapamycin possesses both anti-proliferative and antimigratory activity suggests that it could contribute to the control of arterial re-narrowing after percutaneous intervention and control the vascular manifestations of chronic rejection in transplanted hearts. The first clinical trials of implantation of rapamycin- coated stents in obstructive coronary artery lesions have been reported and, in selected patient groups, it appears that the restenosis process has been abolished. Studies are underway to establish the benefits of rapamycin-coated stents in day-to-day interventional practice, including small vessels, long lesions and patients with multivessel disease. With the addition of novel antiplatelet agents and delivery systems, it is possible that the two major limitations of percutaneous coronary intervention - restenosis and stent thrombosis - will be overcome. Cardiac graft loss due to intimal hyperplasia and accelerated atherosclerosis remains the major limitation to long-term survival following cardiac transplantation. Animal studies of rapamycin have suggested that this process can be reduced or abolished. Human studies of the efficacy of rapamycin in preventing both acute rejection and allograft arterial disease are in progress. Concerns regarding toxicity, carcinogenicity, delayed healing and endothelialization remain. As with any new agent or technology, we must remain vigilant to late adverse side-effects.

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Prevention of neointimal proliferation by immunosuppression in synthetic vascular grafts

Walpoth

Pavlicek

Çelik

et al. 2001

European Journal of Cardio-Thoracic Surgery

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Local or systemic administration of rapamycins has no effect on intimal hyperplasia in synthetic vascular grafts. In contrast, toxic signs with weight loss were observed in animals treated with high dose rapamycins, but not in those treated with MMF. Thus, in the rat model, immunosuppression with rapamycins or MMF cannot be recommended for the prevention of intimal hyperplasia in the synthetic vascular graft model.

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Suppression of Acute Rejection Prevents Graft Arteriosclerosis After Allogeneic Aorta Transplantation in the Rat

Cited by 5 publications

References 0 publications

Improved surgical technique for the establishment of a murine model of aortic transplantation

Improved surgical technique for the establishment of a murine model of aortic transplantation

Rapamycin in cardiovascular medicine

Prevention of neointimal proliferation by immunosuppression in synthetic vascular grafts

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