Background: A critical role for the terminal components of complement (C5b-C9) has been demonstrated previously in acute allograft rejection with the use of C6-deficient PVG congenic rat strains. The C6 deficiency prevents the formation of membrane attack complex (MAC) by C5b-C9. Hearts transplanted from PVG.1A (RT1a) rats are rejected acutely (7-9 days) by fully MHC-incompatible C6-sufficient PVG.1L (RT11) recipients, but they survive significantly longer in untreated C6-deficient PVG.1L recipients (19 to >60 days).
Methods: To investigate the contribution of MAC to chronic rejection and accelerated graft arteriosclerosis (AGA) in long-term cardiac allografts, hearts were transplanted heterotopically from PVG.1A donors to C6-sufficient and C6-deficient PVG.1L hosts that were treated with cyclosporine 15 mg/kg/day for 14 days after cardiac grafting. Alloantibody responses in hosts were measured by flow cytometry at 4, 8, 12, and 16 weeks after transplantation. Vigorously contracting grafts were removed at 60 days (n=5) and at 90-128 days (n=12) after surgery for morphological evaluation. Computerized planimetry measurements were made in complete cross-sections of grafts on all assessable arteries larger than 16 microns in diameter.
Results: The survival of most (six of seven) cardiac allografts in C6-deficient recipients was prolonged by cyclosporine treatment to greater than 90 days. In contrast, 14 of 25 hearts that were transplanted to C6-sufficient recipients were rejected between 21 and 84 days with severe vascular injury. AGA, defined as smooth muscle cells forming a neointima inside the internal elastic lamina and luminal compromise, affected a greater percentage of arteries in C6-sufficient than in C6-deficient recipients. AGA developed earlier and more frequently in arteries of medium (<100 micron) diameter than those of large diameter in both C6-sufficient and C6-deficient recipients. Serial sections demonstrated the lesions in medium arteries to be located adjacent to the smooth muscle sphincters at the junction of arteriolar branches.
Conclusions: These results demonstrate that MAC promotes the pathogenesis of AGA in long-term cardiac allografts.