title: TNF-α Antibody Therapy in Combination With the T-Cell-Specific Antibody Anti-TCR Reverses the Diabetic Metabolic State in the LEW.1AR1-iddm Rat.
abstract: Anti-tumor necrosis factor-α (TNF-α) therapy (5 mg/kg body weight), alone or combined with the T-cell-specific antibody anti-T-cell receptor (TCR) (0.5 mg/kg body weight), was performed over 5 days immediately after disease manifestation to reverse the diabetic metabolic state in the LEW.1AR1-iddm rat, an animal model of human type 1 diabetes. Only combination therapy starting at blood glucose concentrations below 15 mmol/L restored normoglycemia and normalized C-peptide. Increased β-cell proliferation and reduced apoptosis led to a restoration of β-cell mass along with an immune cell infiltration-free pancreas 60 days after the end of therapy. This combination of two antibodies, anti-TCR/CD3, as a cornerstone compound in anti-T-cell therapy, and anti-TNF-α, as the most prominent and effective therapeutic antibody in suppressing TNF-α action in many autoimmune diseases, was able to reverse the diabetic metabolic state. With increasing blood glucose concentrations during the disease progression, however, the proapoptotic pressure on the residual β-cell mass increased, ultimately reaching a point where the reservoir of the surviving β-cells was insufficient to allow a restoration of normal β-cell mass through regeneration. The present results may open a therapeutic window for reversal of diabetic hyperglycemia in patients, worthwhile of being tested in clinical trials.
authors.affiliation: Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany Centre for Anatomy, Hannover Medical School, Hannover, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Jörns
authors.affiliation: Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany.
authors.forename: Ümüs Gül
authors.initials: ÜG
authors.lastname: Ertekin
authors.affiliation: Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Arndt
authors.affiliation: Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany.
authors.forename: Taivankhuu
authors.initials: T
authors.lastname: Terbish
authors.affiliation: Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Wedekind
authors.affiliation: Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany lenzen.sigurd@mh-hannover.de.
authors.forename: Sigurd
authors.initials: S
authors.lastname: Lenzen
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000097:blood; D049109:Cell Proliferation / Q000187:drug effects; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D004195:Disease Models, Animal; D007328:Insulin / Q000097:blood; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin; D014409:Tumor Necrosis Factor-alpha