kdkd mice, a mutant subline of CBA/Ca mice, develop a progressive, T cell-mediated, autoimmune interstitial nephritis which leads to renal failure and death of all mice at 20-28 weeks of age. This disease is inherited in an autosomal recessive manner, with complete penetrance, and has been linked to grizzled and waltzer on mouse chromosome 10. Immunologic evaluation of this lesion has demonstrated that histologic disease is initiated by a population of CD8+, H-2Kk-restricted T cells, which recognize an antigen in collagenase-solubilized syngeneic renal tubules. These nephritogenic effector cells can also be demonstrated in non-disease prone CBA/Ca mice. Susceptibility to autoimmune nephritis correlates with distinct expression of regulatory, rather than effector, T cells. Interstitial nephritis in kdkd mice can be inhibited by protein-calorie restriction, infusions of CBA/Ca CD8+ T cells, or monoclonal antibodies of ICAM-1. This murine model most closely resembles medullary cystic disease in humans, which has not historically been considered an autoimmune disease. Mapping of the genes for both medullary cystic disease and the defect in kdkd mice should augment our understanding of mechanisms of organ-specific autoimmunity.