CYTOKINES, ADHESION MOLECULES, AND THE PATHOGENESIS OF CHRONIC REJECTION OF RAT RENAL-ALLOGRAFTS

Little is known of the host immune mechanisms responsible for initiati on and progression of chronic rejection. We describe immunopathologic features associated with progressively deteriorating function of kidne y allografts in the F344-to-Lewis rat strain combination, which differ at MHC and non-MHC loci. Initial rejection in untreated recipients wa s controlled by a brief course of CsA (5 mg/kg/day, for 10 days), resu lting in >80% of recipients surviving up to a year despite declining r enal function. In contrast to controls (isografts placed in untreated or CsA-treated Lewis rats), allografts from 12-16 weeks post-Tx showed segmental or global glomerulosclerosis, increasing tubular atrophy, i nterstitial fibrosis, and intimal proliferation leading ultimately to vascular occlusion. By flow cytometry, IgM and IgG alloantibodies peak ed at 2-4 weeks, with a gradual decline to baseline thereafter. Immuno histology showed early and progressive deposition of IgM, IgG, C3, and fibrin in vessel walls and glomeruli. In addition, by 12 weeks, exten sive infiltration by activated (IL-2R+) macrophages and CD4+ T cells w ere noted in glomeruli and blood vessels, in conjunction with staining for the cytokines TNF-alpha, IL-1, and IL-6. The persistent and dense intraglomerular expression of IL-6 was of particular interest, given its potent mitogenic effects for mesangial cells in vitro, and suggest s a role for this cytokine as a mediator of mesangial expansion, advan ced glomerular injury, and glomerulosclerosis in chronic rejection. Pa rallel timing of IL-6 and TNF-alpha expression was shown in serum samp les by ELISA and bioassays. In vitro binding studies showed increased binding of naive host lymphocytes to allograft versus isografts, corre lating with upregulation (peaking at week 16) of intercellular adhesio n molecule-1 expression by graft endothelium. We conclude that cytokin e production and upregulation of adhesion molecules occurring as part of a cellular immune response may be as important to the etiology of c hronic rejection as the hitherto widely emphasized antibody-mediated h ost responses.