The pathogeneses of chronic allograft nephropathy (CAN), a leading cause of allograft failure, and one of its complications, transplant glomerulopathy (TGP), are unknown. Immunohistologic analysis of human renal transplant biopsies showed expression of inducible costimulator (ICOS), the chemokine receptor CXCR3, and its ligands, Mig and IP-10, by intraglomerular and periglomerular leukocytes in biopsies with CAN and TGP but not CAN alone. ICOS and CXCR3 are both characteristics of activated, effector T cells, suggesting different pathogenetic mechanisms underlying TGP vs. CAN. We conclude that targeting of specific chemokine and chemokine receptor pathways and/or ICOS may have clinical application in the prevention and treatment of TGP.