title: Trials in type 1 diabetes: Antigen-specific therapies.
abstract: Type 1 diabetes (T1D) results from an aberrant immunological response against the insulin-producing beta cells in the islets of the pancreas. The ideal therapy would restore immune balance in a safe and lasting fashion, stopping the process of beta cell decay. The efficacy of immune suppressive agents such as cyclosporin underscores the notion that T1D can in principle be prevented, albeit at an unacceptable long-term safety risk. Immune modulatory drugs such as monoclonal anti-CD3 antibody, on the other hand, have recently had rather disappointing results in phase 3 trials, possibly due to inadequate dosing or choice of inappropriate endpoints. Therefore, it is argued that striking the right balance between safety and efficacy, together with careful trial design, will be paramount in preventing T1D. Here we outline the concept of antigen-specific tolerization as a strategy to safely induce long-term protection against T1D, focusing on available clinical trial data, key knowledge gaps and potential future directions.
authors.affiliation: Type 1 Diabetes R&D Center, Novo Nordisk Inc., Seattle, WA, USA.
authors.forename: Ken T
authors.initials: KT
authors.lastname: Coppieters
authors.forename: Leonard C
authors.initials: LC
authors.lastname: Harrison
authors.forename: Matthias G
authors.initials: MG
authors.lastname: von Herrath
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D018834:Chaperonin 60 / Q000627:therapeutic use; D017326:Clinical Trials, Phase III as Topic; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D005968:Glutamate Decarboxylase / Q000627:therapeutic use; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007108:Immune Tolerance; D007328:Insulin / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D010446:Peptide Fragments / Q000627:therapeutic use; D011498:Protein Precursors / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D001324:Autoantigens; D017252:CD3 Complex; D018834:Chaperonin 60; C447781:DiaPep 277; D007004:Hypoglycemic Agents; D007328:Insulin; D010446:Peptide Fragments; D011498:Protein Precursors; C013737:preproinsulin; D005968:Glutamate Decarboxylase
keywords: Antigen-specific therapies; Clinical trials; Immune intervention; Type 1 diabetes