title: Antibody combination therapy targeting CD25, CD70 and CD8 reduces islet inflammation and improves glycaemia in diabetic mice.
abstract: Destruction of pancreatic islets in type 1 diabetes is caused by infiltrating, primed and activated T cells. In a clinical setting this autoimmune process is already in an advanced stage before intervention therapy can be administered. Therefore, an effective intervention needs to reduce islet inflammation and preserve any remaining islet function. In this study we have investigated the role of targeting activated T cells in reversing autoimmune diabetes. A combination therapy consisting of CD25-, CD70- and CD8-specific monoclonal antibodies was administered to non-obese diabetic (NOD) mice with either new-onset diabetes or with advanced diabetes. In NOD mice with new-onset diabetes antibody combination treatment reversed hyperglycaemia and achieved long-term protection from diabetes (blood glucose <13·9 mmol/l) in >50% of mice. In contrast, in the control, untreated group blood glucose levels continued to increase and none of the mice were protected from diabetes (P < 0·0001). Starting therapy early when hyperglycaemia was relatively mild proved critical, as the mice with advanced diabetes showed less efficient control of blood glucose and shorter life span. Histological analysis (insulitis score) showed islet preservation and reduced immune infiltration in all treated groups, compared to their controls. In conclusion, antibody combination therapy that targets CD25, CD70 and CD8 results in decreased islet infiltration and improved blood glucose levels in NOD mice with established diabetes.
authors.affiliation: Medical Research Council (MRC) Centre for Transplantation, King's Health Partners Department of Immunobiology, King's College London, Guy's Hospital Barts Cancer Institute, Queen Mary, University of London, London, UK.
authors.forename: T
authors.initials: T
authors.lastname: Alkhamis
authors.forename: J
authors.initials: J
authors.lastname: Barbic
authors.forename: T
authors.initials: T
authors.lastname: Crnogorac-Jurcevic
authors.forename: R E
authors.initials: RE
authors.lastname: Greenlaw
authors.forename: M
authors.initials: M
authors.lastname: Peakman
authors.forename: S
authors.initials: S
authors.lastname: Jurcevic
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D000918:Antibody Specificity; D015703:Antigens, CD / Q000276:immunology*; D001786:Blood Glucose / Q000276:immunology; D053282:CD27 Ligand / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000276:immunology / Q000628:therapy*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000276:immunology / Q000628:therapy*; D005260:Female; D006943:Hyperglycemia / Q000097:blood / Q000276:immunology / Q000628:therapy*; D007249:Inflammation / Q000097:blood / Q000276:immunology / Q000628:therapy*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D001786:Blood Glucose; D053282:CD27 Ligand; D016827:CD8 Antigens; D053645:Interleukin-2 Receptor alpha Subunit