EFFECTS OF RS61443 ON FUNCTIONAL AND MORPHOLOGICAL-CHANGES IN CHRONICALLY REJECTING RAT-KIDNEY ALLOGRAFTS

No immunosuppression agent is as yet available that prevents the proce ss of chronic allograft rejection, the most critical cause of late org an allograft loss. RS61443 (mycophenolate mofetil) inhibits de novo DN A synthesis as well as diminishes expression of cell surface molecules and antibody production. As these factors seem important in the patho physiology of the chronic phenomenon, we investigated the effects of t he agent in an established model of chronic rejection of kidney allogr afts in a F344-to-Lewis rat strain combination. Ah recipients were tre ated for the first 10 days after engraftment with low-dose cyclosporin e (1.5 mg/kg/day) to reverse an initial acute rejection episode. Since functional and morphological changes do not become manifest in this m odel until after 12 wk, treatment with RS61443 (15 mg/kg/day, p.o.) wa s either initiated at the day of grafting (Gp 1) or 8 wks thereafter ( Gp 2), and continued throughout the follow-up period. Non-RS61443-trea ted allografted rats receiving vehicle only (Gp 3) developed progressi ve proteinuria after 12 wk. Peak cellular infiltration (particularly m acrophages in glomeruli and perivascular areas) at 16 wk was associate d with densely expressed adhesion molecules (ICAM-1 on endothelium), c ytokines and growth factors (TNF-alpha and TGF-beta in glomeruli and P DGF on arterial smooth muscle cells). Interstitial fibrosis, with tubu lar atrophy, glomerulosclerosis, and varying degrees of intimal prolif eration and luminal obliteration of vessels, progressed thereafter. In vitro binding of MNC from naive animals to chronically rejecting allo grafted kidneys generally confirmed the immunohistological observation s, peaking at 12 wk; this binding was significantly inhibited by mAbs against specific adhesion molecules (CD11a, CD18, and ICAM-1). Serum-a llospecific IgG and IgM peaked at 1-2 wk after engraftment in the cont rol recipients, decreasing thereafter. Although IgM declined to baseli ne after 12 wk, low levels of allospecific IgG persisted throughout th e follow-up period. In contrast, recipient treatment with RS61443 (bot h Gp 1 and Gp 2) allowed the allografts to function normally throughou t follow-up period. Proteinuria was virtually absent, and morphologica l and immunohistological manifestations of the chronic process were ma rkedly diminished. In addition, treated recipients developed no signif icant side effects, including leukopenia, anemia, thrombopenia, nephro toxicity, and hepatotoxicity. It appears that this agent can safely pr event the changes of chronic rejection of kidney allografts in this ra t model.