Chronic rejection in rat aortic allografts. An experimental model for transplant arteriosclerosis.

Abstract

Chronic rejection has several histological appearances, depending on the type of organ graft Common to all of them is transplant arteriosclerosis associated with an ongoing inflammatory response in the transplanted graft. To the contrary of classical atherosclerosis, in which the manifestations are mostly focal, proximal, and asymmetric, transplant arteriosclerosis is generalized, and the intimal thickening is concentric In this article, we describe an experimental animal model whereby transplant arteriosclerosis may be investigated in the inbred rat Aortic allografts were transplanted from DA (RTF) to major histocompatibility complex-incompatible WF (RTF) rats or, for control, to rats of the DA strain. Transplantation was followed by an acute inflammation episode in the aortic adventitia of the allograft, largely lacking in the syngeneic graft, with a prominence of lymphoid activation markers (Cd25) in the cells of the inflammatory infiltrate. The inflammation episode peaked at 2 months after transplantation, became attenuated, and was followed by a proliferative response of myocytes in the allograft media. An increase in the migration of myocytes to the subendothelial space (presumably through small breaks generated in the internal elastic lamina) was observed thereafter, and myocyte proliferation continued in the intima with some intermingled macrophages. Finally, necrosis and disappearance of myocytes and their replacement by fibrous tissue were observed in the media. These alterations are virtually identical with the vascular lesion of chronically rejecting parenchymal organ transplants in human subjects. We suggest that aortic allografts exchanged between histoincompatible rat strains may be used as an experimental model for transplant arteriosclerosis. (Arteriosclerosis and Thrombosis 1991;ll:671-680)

Additive and synergistic effects of a low-molecular-weight, heparin-like molecule and low doses of cyclosporin in preventing arterial graft rejection in rats.

“…The correlation between adventitial infiltration by inflammatory cells and the ratio of intimal proliferation to medial thickness in untreated allografts demonstrates one of the major features of the model, the importance of inflammation in the injury and response to chronic vascular immune aggression. Nevertheless, Mennander et al 7 reported that adventitial inflammation was predominant during the first month after arterial grafting in this model, a time when medial smooth muscle cells were still present. After this time, the adventitial inflammation decreased in parallel with the disappearance of medial smooth muscle cells.…”

“…The evidence of rejection probably decreases in untreated allografts in relation to the disappearance of smooth muscle cellular antigens 2 months after grafting. 7 In contrast, low doses of cyclosporin could delay the appearance of rejection, so that the inflammation appeared greater in cyclosporin-treated animals than in untreated allografts 2 months after grafting. This inflammation could be related to the persistence of medial cellular antigens, as suggested by the positive correlation between medial smooth muscle cell and adventitial inflammatory cell densities.…”

Treatment by Mycophenolate Mofetil of Advanced Graft Vascular Disease in Non‐Human Primate Recipients of Orthotopic Aortic Allografts

“…Our group first showed (32) that MPA is able to reduce the incidence and severity of GVD in a Brown Norway-to-Lewis transplant model. In addition, MMF reduced the obliteration of renal arteries at a dose of 15 mg/kg/day (33) that no initial immunosuppressive therapy is needed to secure graft function (34,35) and GVD can be investigated independently. In an ACI-to-Lewis model of orthotopic aortic transplantation, intimal proliferation was reduced by 76.1% with the daily treatment of 40-30 mg/kg MMF (8).…”

Strong Humoral Anti-HLA Immune Response Upon Arbitrarily Chosen Allogeneic Arterial Vessel Grafts

“…Consequently arterial allografts have generally been transplanted without considering the matching of AB0-bloodgroups and of HLA-phenotypes between donors and recipients. Furthermore, only a limited number of studies exist which have investigated the allo-specific immune response induced by arterial allografts, and the majority of them is based on animal models [12][13][14][15][16]. There are only few studies mainly of the 1990s in which the cellular and humoral immune responses as a consequence of venous and especially arterial allo-grafting in humans was investigated [8,[17][18][19][20].…”