title: Immunological characterization and therapeutic activity of an altered-peptide ligand, NBI-6024, based on the immunodominant type 1 diabetes autoantigen insulin B-chain (9-23) peptide.
abstract: The nonobese diabetic (NOD) mouse is a good model for human type 1 diabetes, which is characterized by autoreactive T-cell-mediated destruction of insulin-producing islet beta-cells of the pancreas. The 9-23 amino acid region of the insulin B-chain [B((9-23))] is an immunodominant T-cell target antigen in the NOD mouse that plays a critical role in the disease process. By testing a series of B((9-23)) peptide analogs with single or double alanine substitutions, we identified a set of altered peptide ligands (APLs) capable of inhibiting B((9-23))-induced proliferative responses of NOD pathogenic T-cell clones. These APLs were unable to induce proliferation of these clones. However, vaccinations with the APLs induced strong cellular responses, as measured by in vitro lymphocyte proliferation and Th2 cytokine production (i.e., interleukin [IL]-4 and IL-10, but not gamma-interferon [IFN-gamma]). These responses were cross-reactive with the native antigen, B((9-23)), suggesting that the APL-induced Th2 responses may provide protection by controlling endogenous B((9-23))-specific Th1 (i.e., IFN-gamma-producing) pathogenic responses. One of these APLs that contained alanine substitutions at residues 16 and 19 (16Y-->A, 19C-->A; NBI-6024) was further characterized for its therapeutic activity because it consistently induced T-cell responses (e.g., T-cell lines and clones) that were of the Th2 type and that were cross-reactive with B((9-23)). Subcutaneous injections of NBI-6024 to NOD mice administered either before or after the onset of disease substantially delayed the onset and reduced the incidence of diabetes. This study is the first to report therapeutic activity of an APL derived from an islet beta-cell-specific antigen in type 1 diabetes.
authors.affiliation: Neurocrine Biosciences, Inc., 10555 Science Center Drive, San Diego, CA 92121-1102, USA. dalleva@neurocrine.com
authors.forename: David G
authors.initials: DG
authors.lastname: Alleva
authors.forename: Amitabh
authors.initials: A
authors.lastname: Gaur
authors.forename: Liping
authors.initials: L
authors.lastname: Jin
authors.forename: Dale
authors.initials: D
authors.lastname: Wegmann
authors.forename: Peter A
authors.initials: PA
authors.lastname: Gottlieb
authors.forename: Anil
authors.initials: A
authors.lastname: Pahuja
authors.forename: Eric B
authors.initials: EB
authors.lastname: Johnson
authors.forename: Theresa
authors.initials: T
authors.lastname: Motheral
authors.forename: Amy
authors.initials: A
authors.lastname: Putnam
authors.forename: Paul D
authors.initials: PD
authors.lastname: Crowe
authors.forename: Nicholas
authors.initials: N
authors.lastname: Ling
authors.forename: Stefen A
authors.initials: SA
authors.lastname: Boehme
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Conlon
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001324:Autoantigens / Q000097:blood*; D002478:Cells, Cultured; D002999:Clone Cells; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy* / Q000276:immunology*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000276:immunology / Q000494:pharmacology*; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D016688:Mice, Inbred NOD; D010446:Peptide Fragments / Q000276:immunology / Q000494:pharmacology*; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D001324:Autoantigens; D007004:Hypoglycemic Agents; D007328:Insulin; D008024:Ligands; C460599:NBI6024; D010446:Peptide Fragments; C097877:insulin B (9-23)