title: Inhibition of T-cell activation by the CTLA4-Fc Abatacept is sufficient to ameliorate proteinuric kidney disease.
abstract: Diabetic nephropathy (DN) remains an unmet medical challenge as its prevalence is projected to continue to increase and specific medicines for treatment remain undeveloped. Activation of the immune system, in particular T-cells, is emerging as a possible mechanism underlying DN disease progression in humans and animal models. We hypothesized that inhibition of T-cell activation will ameliorate DN. Interaction of B7-1 (CD80) on the surface of antigen presenting cells with its binding partners, CTLA4 (CD152) and CD28 on T-cells, is essential for T-cell activation. In this study we used the soluble CTLA4-Fc fusion protein Abatacept to block cell surface B7-1, preventing the cellular interaction and inhibiting T-cell activation. When Abatacept was dosed in an animal model of diabetes-induced albuminuria, it reduced albuminuria in both prevention and intervention modes. The number of T-cells infiltrating the kidneys of DN animals correlated with the degree of albuminuria, and treatment with Abatacept reduced the number of renal T-cells. As B7-1 induction has been recently proposed to underlie podocyte damage in DN, Abatacept could be efficacious in DN by protecting podocytes. However, this does not appear to be the case as B7-1 was not expressed in1) kidneys of DN animals;2) stimulated human podocytes in culture; or3) glomeruli of DN patients. We conclude that Abatacept ameliorates DN by blocking systemic T-cell activation and not by interacting with podocytes.
authors.affiliation: Cardiovascular & Metabolic Diseases, MedImmune, Cambridge, United Kingdom; herreramari@medimmune.com.
authors.forename: Marcela
authors.initials: M
authors.lastname: Herrera
authors.affiliation: Drug Safety and Metabolism, AstraZeneca, Gothenburg, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Söderberg
authors.affiliation: Cardiovascular & Metabolic Diseases, AstraZeneca, Gothenburg, Sweden.
authors.forename: Alan
authors.initials: A
authors.lastname: Sabirsh
authors.affiliation: Cardiovascular & Metabolic Diseases, AstraZeneca, Gothenburg, Sweden.
authors.forename: Barbara
authors.initials: B
authors.lastname: Valastro
authors.affiliation: Sahlgrenska University, Gothenburg, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Mölne
authors.affiliation: Institute for Biomedical Research Alberto Sols, CSIC, UAM, Madrid, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM, ISCIII), Madrid, Spain; and.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Santamaria
authors.affiliation: Institute for Biomedical Research Alberto Sols, CSIC, UAM, Madrid, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM, ISCIII), Madrid, Spain; and.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Valverde
authors.affiliation: Cardiovascular & Metabolic Diseases, MedImmune, Cambridge, United Kingdom.
authors.forename: Silvia
authors.initials: S
authors.lastname: Guionaud
authors.affiliation: Cardiovascular & Metabolic Diseases, MedImmune, Cambridge, United Kingdom.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Heasman
authors.affiliation: Drug Safety and Metabolism, AstraZeneca, Cheshire, United Kingdom.
authors.forename: Alison
authors.initials: A
authors.lastname: Bigley
authors.affiliation: Cardiovascular & Metabolic Diseases, MedImmune, Cambridge, United Kingdom.
authors.forename: Lutz
authors.initials: L
authors.lastname: Jermutus
authors.affiliation: Cardiovascular & Metabolic Diseases, MedImmune, Cambridge, United Kingdom.
authors.forename: Cristina
authors.initials: C
authors.lastname: Rondinone
authors.affiliation: Cardiovascular & Metabolic Diseases, MedImmune, Cambridge, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Coghlan
authors.affiliation: Cardiovascular & Metabolic Diseases, MedImmune, Cambridge, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Baker
authors.affiliation: Cardiovascular & Metabolic Diseases, MedImmune, Cambridge, United Kingdom.
authors.forename: Carol Moreno
authors.initials: CM
authors.lastname: Quinn
mesh_terms: D000069594:Abatacept / Q000494:pharmacology*; D000419:Albuminuria / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D024141:Collagen Type IV / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000276:immunology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D059305:Diet, High-Fat; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008810:Mice, Inbred C57BL; D050199:Podocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013311:Streptozocin; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D013997:Time Factors
chemical_list: D018122:B7-1 Antigen; D024141:Collagen Type IV; D007166:Immunosuppressive Agents; D013311:Streptozocin; D000069594:Abatacept
keywords: Abatacept; B7-1; CD80; CTLA4-Fc; T-cells; albuminuria; diabetic nephropathy