title: CTLA4-Ig in B7-1-positive diabetic and non-diabetic kidney disease.
abstract: Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease in the Western world. Standard treatments have ultimately proven ineffective in blocking DKD progression, thus necessitating the design of new therapies to complement glycaemic and blood pressure control. High glucose levels upregulate the immune-related molecule B7-1 in podocytes, and such an event may play a relevant role in DKD onset, suggesting that B7-1 is a suitable therapeutic target for DKD. CTLA4-Ig is a clinically available fusion protein, approved for the treatment of some autoimmune diseases, which binds B7-1 and blocks its signalling. We have previously demonstrated that CTLA4-Ig restores the physiological structure and cellular motility of podocytes challenged with high glucose in vitro and abrogates the onset of proteinuria in murine models of DKD in vivo. Notably, these beneficial effects occurred independently of any systemic immunological effects of CTLA4-Ig. While the expression of B7-1 on podocytes raises questions regarding the very nature of the podocyte as we know it, the preliminary positive effect of CTLA4-Ig on proteinuria in preclinical models and the evidence of B7-1 expression in kidney biopsies of diabetic individuals suggest a potential novel indication for CTLA4-Ig in DKD. Nonetheless, recent reports of problems with detecting podocyte B7-1 and of inconsistent therapeutic efficacy of CTLA4-Ig in proteinuric patients highlight the necessity to establish uniformly accepted protocols for the detection of B7-1 and underline the need for randomised trials with CTLA4-Ig in kidney diseases.
authors.affiliation: Division of Nephrology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave., Enders Building, Boston, MA, 02115, USA.|Department of Transplant Medicine, IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bassi
authors.affiliation: Peggy and Harold Katz Family Drug Discovery Center, Division of Nephrology and Hypertension, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Alessia
authors.initials: A
authors.lastname: Fornoni
authors.affiliation: Section on Genetics and Epidemiology, Joslin Diabetes Center, Boston, MA, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Doria
authors.affiliation: Division of Nephrology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave., Enders Building, Boston, MA, 02115, USA. paolo.fiorina@childrens.harvard.edu.|Department of Transplant Medicine, IRCCS Ospedale San Raffaele, Milan, Italy. paolo.fiorina@childrens.harvard.edu.
authors.forename: Paolo
authors.initials: P
authors.lastname: Fiorina
mesh_terms: D000069594:Abatacept / Q000378:metabolism*; D000818:Animals; D018122:B7-1 Antigen / Q000378:metabolism*; D001706:Biopsy; D001786:Blood Glucose / Q000378:metabolism; D003920:Diabetes Mellitus / Q000097:blood*; D006801:Humans; D007107:Immune System; D007249:Inflammation; D007668:Kidney / Q000378:metabolism; D007674:Kidney Diseases / Q000097:blood*; D051379:Mice; D050199:Podocytes / Q000166:cytology / Q000276:immunology; D011507:Proteinuria / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D018122:B7-1 Antigen; D001786:Blood Glucose; D000069594:Abatacept
keywords: B7-1; CD80; CTLA4-Ig; Diabetic kidney disease; Podocytes; Review