Little is known of the host immune mechanisms responsible for initiation and progression of chronic rejection. We describe immunopathologic features associated with progressively deteriorating function of kidney allografts in the F344-to-Lewis rat strain combination, which differ at MHC and non-MHC loci. Initial rejection in untreated recipients was controlled by a brief course of CsA (5 mg/kg/day, for 10 days), resulting in > 80% of recipients surviving up to a year despite declining renal 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, interstitial fibrosis, and intimal proliferation leading ultimately to vascular occlusion. By flow cytometry, IgM and IgG alloantibodies peaked at 2-4 weeks, with a gradual decline to baseline thereafter. Immunohistology showed early and progressive deposition of IgM, IgG, C3, and fibrin in vessel walls and glomeruli. In addition, by 12 weeks, extensive infiltration by activated (IL-2R+) macrophages and CD4+ T cells were 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 suggests a role for this cytokine as a mediator of mesangial expansion, advanced glomerular injury, and glomerulosclerosis in chronic rejection. Parallel timing of IL-6 and TNF-alpha expression was shown in serum samples by ELISA and bioassays. In vitro binding studies showed increased binding of naive host lymphocytes to allograft versus isografts, correlating with upregulation (peaking at week 16) of intercellular adhesion molecule-1 expression by graft endothelium. We conclude that cytokine production and upregulation of adhesion molecules occurring as part of a cellular immune response may be as important to the etiology of chronic rejection as the hitherto widely emphasized antibody-mediated host responses.