Effect of soluble form CTLA‐4 on spontaneous IgA nephropathy in ddY mice

Abstract

The aim of the present study was to examine the role of CD28‐B7 signalling in the development of glomerulonephritis in ddY mice, an animal model for IgA nephropathy. To achieve this aim, we investigated whether the CTLA‐4 (CD152) fusion protein, which binds to B7.1 (CD80) and B7.2 (CD86), affects glomerular pathological changes (including IgA deposition), or functional parameters (such as serum creatinine and proteinuria). Each group (n = 4) was given either human CTLA‐4 fused with human IgG (CTLA4Ig) or control human IgG1. All treated groups of mice were injected intraperitoneally at a dose of 0.1 mg twice a week for the duration of the study. Mice given control human IgG1 progressively developed typical mesangioproliferative glomerulonephritis, with remarkable glomerular IgA deposits. In contrast, mice treated with CTLA4Ig showed a significant reduction in proteinuria and mesangioproliferative change, with an expansion of the mesangial matrix at 40 weeks of age. The serum IgA levels of these mice were considerably lower than those in mice given the control human IgG1. A direct immunofluorescence study showed the reduction of glomerular IgA deposits in CTLA4Ig‐treated mice. We have demonstrated for the first time that the development of spontaneously occurring IgA nephropathy can be prevented in ddY mice by blocking the CD28‐B7 interaction using a soluble form of CTLA4Ig. These results suggest that a costimulatory signal via CD28‐B7 may play a crucial role in the development and progression of IgA nephropathy.