title: Anti-TCR therapy combined with fingolimod for reversal of diabetic hyperglycemia by β cell regeneration in the LEW.1AR1-iddm rat model of type 1 diabetes.
abstract: The therapeutic capacity of an antibody directed against the T cell receptor (anti-TCR) of the TCR/CD3 complex alone or in combination with fingolimod (FTY720) to reverse the diabetic metabolic state through suppression of autoimmunity and stimulation of β cell regeneration was analyzed in the LEW.1AR1-iddm (IDDM) rat, an animal model of human type 1 diabetes. Animals were treated with anti-TCR (0.5 mg/kg body weight for 5 days) monotherapy or in combination with fingolimod (1 mg/kg body weight for 40 days). Metabolic changes and β cell morphology were analyzed before, immediately after, and 60 days after end of therapy. Both therapies were started early after disease manifestation and led to normoglycemia in parallel with an increase of the C-peptide concentration. Combination therapy increased the β cell mass reaching a range of normoglycemic controls, decreased the apoptosis rate fivefold, and increased the proliferation rate threefold. Additionally, at 60 days after therapy, islets were virtually free of T cells, macrophages, and cytokine expression. In contrast, after anti-TCR monotherapy, β cell mass remained low with an activated immune cell infiltrate. A concomitant fivefold increased β cell apoptosis rate resulted in a complete loss of β cells. Only combination therapy yielded sustained normoglycemia with full reversal of islet infiltration and restoration of pancreatic β cell mass.
  
  
  CONCLUSIONS
  Combination therapy of anti-TCR and fingolimod was effective in the reversal of T1D. Combination therapy increased the pancreatic β cell mass to normoglycemic control levels. Combination therapy leads to a full reversal of pancreatic islet infiltration. Anti-TCR monotherapy did not abolish islet infiltration. Combination therapy was successful only immediately after diabetes manifestation.
authors.affiliation: Institute of Clinical Biochemistry, Hannover Medical School, 30623, Hannover, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Jörns
authors.forename: Muharrem
authors.initials: M
authors.lastname: Akin
authors.forename: Tanja
authors.initials: T
authors.lastname: Arndt
authors.forename: Taivankhuu
authors.initials: T
authors.lastname: Terbish
authors.forename: Andreas Meyer
authors.initials: AM
authors.lastname: Zu Vilsendorf
authors.forename: Dirk
authors.initials: D
authors.lastname: Wedekind
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Hedrich
authors.forename: Sigurd
authors.initials: S
authors.lastname: Lenzen
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage*; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D000068876:Fingolimod Hydrochloride; D006943:Hyperglycemia / Q000188:drug therapy* / Q000276:immunology; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000648:ultrastructure; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D046529:Microscopy, Electron, Transmission; D011409:Propylene Glycols / Q000008:administration & dosage*; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D000906:Antibodies; D016207:Cytokines; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D011948:Receptors, Antigen, T-Cell; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine