title: Abatacept Treatment Does Not Preserve Renal Function in the Streptozocin-Induced Model of Diabetic Nephropathy.
abstract: Diabetic nephropathy (DN) is one of the most severe complications of diabetes and remains the largest cause of end-stage renal disease in the Western world. Treatment options are limited and novel therapies that effectively slow disease progression are warranted. Previous work suggested that treatment with CTLA4-Ig (abatacept), a molecule that binds and blocks B7-1 and is licensed for the treatment of rheumatoid arthritis, could ameliorate DN. This study was designed to assess whether B7-1 signalling constitutes a promising therapeutic pathway for DN. Mice injected with streptozotocin (STZ) were treated with abatacept and glycemia and renal function were assessed. No differences were found in diabetes progression, albumin excretion rates or albumin/creatine ratios, while mesangial expansion was unaltered at endpoint. Except for increased renal CCL5, treatment did not affect a panel of gene expression endpoints reflecting early fibrotic changes, inflammation and kidney injury. Finally, abatacept treatment effectively reduced the accumulation of activated CD4+ T cells in the kidney, suggesting that renal T cell inflammation is not a driving factor in the pathology of the STZ model. In conjunction with the recent data discounting the expression of B7-1 on podocytes, our present data do not support a role for abatacept in DN treatment.
authors.affiliation: Novo Nordisk A/S, Måløv, Denmark.
authors.forename: Jenny
authors.initials: J
authors.lastname: Norlin
authors.affiliation: Novo Nordisk A/S, Måløv, Denmark.
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Nielsen Fink
authors.affiliation: Novo Nordisk A/S, Måløv, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Helding Kvist
authors.affiliation: Novo Nordisk A/S, Måløv, Denmark.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Douglas Galsgaard
authors.affiliation: Novo Nordisk A/S, Måløv, Denmark.
authors.forename: Ken
authors.initials: K
authors.lastname: Coppieters
mesh_terms: D000069594:Abatacept / Q000494:pharmacology*; D000818:Animals; D018122:B7-1 Antigen / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018946:Chemokine CCL5 / Q000276:immunology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D005920:Glomerular Mesangium / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D050199:Podocytes / Q000276:immunology* / Q000473:pathology
chemical_list: D018122:B7-1 Antigen; C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D000069594:Abatacept