PREVENTION OF CHRONIC REJECTION AND GRAFT ARTERIOSCLEROSIS BY TOLERANCE INDUCTION

Chronic rejection is a major cause of graft failure in solid organ tra nsplants after the first year. A characteristic lesion in a variety of chronically rejecting organs is a fibrointimal proliferative arterios clerosis. It has been speculated that approaches to tolerance inductio n may be effective in obviating not only acute, but also chronic, reje ction. A picture of chronic rejection develops naturally in heart graf ts transplanted from the Lewis-to-F-344 strain of rat. We examined whe ther tolerance induction by bone marrow transplantation and developmen t of hematopoietic chimerism or tolerance induction by intrathymic ino culation of alloantigen could effectively prevent chronic rejection in an established model of chronic rejection. Bone marrow chimeras were developed in F-344 hosts by transplantation of T cell-depleted allogen eic marrow (TCD A BRIT). Another set of F-344 hosts was inoculated wit h intrathymic allogeneic bone marrow cells. Heart grafts in these anim als demonstrated tolerance for 120 days after transplantation. Control F-344 animals treated with a short course of cyclosporine consistentl y developed chronic rejection by 120 days following heart transplantat ion. Strikingly absent from the tolerant animals was any sign of graft arteriosclerosis, which was demonstrated in the vast majority of cont rol animals. Analysis of cytokine mRNA profiles at 30 days following h eart transplantation demonstrated differences between control and tole rant animals. These results suggest that tolerance induction can effec tively prevent chronic rejection.