Immunomodulation in Type 1 Diabetes by NBI-6024, an Altered Peptide Ligand of the Insulin B Epitope

Scand J Immunol. 2006 Jan;63(1):59-69. doi: 10.1111/j.1365-3083.2005.01705.x.

Abstract

NBI-6024 is an altered peptide ligand (APL) corresponding to the 9-23 amino acid region of the insulin B chain (B(9-23)), an epitope recognized by inflammatory interferon-gamma-producing T helper (Th)1 lymphocytes in type 1 diabetic patients. Immunomodulatory effects of NBI-6024 administration in recent-onset diabetic patients in a phase I clinical trial (NBI-6024-0003) were measured in peripheral blood mononuclear cells using the enzyme-linked immunosorbent spot assay. Analysis of the mean magnitude of cytokine responses to B(9-23) and NBI-6024 for each cohort showed significant increases in interleukin-5 responses (a Th2 regulatory phenotype) in cohorts that received APL relative to those receiving placebo. A responder analysis showed that Th1 responses to B(9-23) and NBI-6024 were observed almost exclusively in the placebo-treated diabetic population but not in nondiabetic control subjects and that APL administration (five biweekly subcutaneous injections) significantly and dose-dependently reduced the percentage of patients with these Th1 responses. The results of this phase I clinical study strongly suggest that NBI-6024 treatment shifted the Th1 pathogenic responses in recent-onset type 1 diabetic patients to a protective Th2 regulatory phenotype. The significance of these findings on the clinical outcome of disease is currently under investigation in a phase II multidose study.

Publication types

  • Clinical Trial, Phase I
  • Controlled Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Cytokines / metabolism*
  • Diabetes Mellitus, Type 1 / immunology*
  • Female
  • Humans
  • Immunodominant Epitopes / administration & dosage
  • Immunologic Factors / administration & dosage*
  • Insulin / administration & dosage*
  • Interferon-gamma / metabolism*
  • Male
  • Peptide Fragments / administration & dosage*
  • Th1 Cells / immunology
  • Th2 Cells / immunology

Substances

  • Cytokines
  • Immunodominant Epitopes
  • Immunologic Factors
  • Insulin
  • NBI6024
  • Peptide Fragments
  • insulin B (9-23)
  • Interferon-gamma