Cardiac transplantation in the rat. I. The effect of histocompatibility differences on graft arteriosclerosis

Abstract

The development of arteriosclerosis is the most serious and common complication in long-term survivors of cardiac transplantation. We have used a variety of inbred rat strains with selected histocompatibility differences to examine the influence of prolonged, mild rejection reactions on the development of pathological changes in long-term cardiac allografts. Heterotopic cardiac allografts were exchanged between rat strains that differed for MHC class I (RT1.A and/or RT1.E) antigens or groups of minor, non-MHC antigens in MHC-compatible congenic combinations. Our results demonstrate that in strain combinations in which the allograft reaction is mild and prolonged, the donor hearts exhibit pathological changes that include a diffuse, interstitial myocardial fibrosis, perivascular fibrosis, and intimal proliferation in arteries of the graft myocardium. The lesions were less prominent in animals with more active rejection and infrequent in strains that differ for class I histocompatibility antigens or syngeneic controls. These results suggest that the comparable pathological changes seen in long-term human cardiac survivors may reflect low-level, persistent allograft reactions rather than factors associated with graft anoxia or effects of immunotherapy to prevent graft rejection.

Figure 1

Histopathological changes in cardiac graft consisting of perivascular fibrosis, mild inflammatory cell infiltration, and fibrosis (A,B). Patchy areas of interstitial fibrosis with minimal numbers of inflammatory cells were also present (C,D). All sections were stained with hematoxylin and eosin (A: ×300; B: ×750; C: ×300; D: ×750).

Figure 2

Concentric myointimal proliferation in medium-to-large myocardial arteries with narrowing of the lumen (A) and irregular focal areas of proliferation (B,C). All sections were stained with hematoxylin and eosin (A: ×300; B: ×750; C: ×1200).

Figure 3

Early arterial lesions consisting of endothelial proliferation, disruption of prominently stained basement membrane (A,B,C), and infiltration of the vessel wall with macrophages (D). All sections stained with toluidine blue (A: ×750; B: ×1200; C: ×3000; D: ×3000).

Figure 4

Electron photomicrograph of the vessel illustrated in Figure 3. The internal elastic membrane (B) is irregular, electron dense and discontinuous. Macrophages (M) are present in the vessel wall and a small group of platelets (P) is associated with the endothelial surface (× 7300, moderately reduced).