Anti-4-1BB-based immunotherapy for autoimmune diabetes: lessons from a transgenic non-obese diabetic (NOD) model

J Autoimmun. 2003 Nov;21(3):247-54. doi: 10.1016/s0896-8411(03)00112-4.

Abstract

Various therapeutic strategies have been developed to tolerize autoreactive T cells and prevent autoimmune pathology in type 1 diabetes. 4-1BB, a member of the tumor necrosis factor receptor (TNFR) superfamily, is a costimulatory receptor primarily expressed on activated T cells. The administration of an agonistic anti-4-1BB antibody (2A) dramatically reduced the incidence and severity of experimental autoimmune encephalomyelitis (EAE). Treatment with the same antibody in Fas-deficient MRL/lpr mice blocked lymphadenopathy and lupus-like autoimmune processes. Paradoxically, transgenic non-obese diabetic (NOD) mice overexpressing membrane-bound agonistic single-chain anti-4-1BB Fv in pancreatic beta cells developed more severe diabetes than their non-transgenic littermates, with earlier onset, faster diabetic processes, and higher mortality. Forty percent of transgenic mice developed diabetes by 4 weeks of age, compared with their control littermates, which first exhibited diabetes at 14 weeks. The frequency of diabetes in female transgenics reached 70% by 8 weeks of age. Most female transgenic mice died around 12 weeks. Consistent with this, transgenic mice developed earlier and more severe insulitis and showed stronger GAD-specific T-cell responses, compared with age-matched control littermates. Our results indicate an adverse effect of transgenic anti-4-1BB scFv in NOD mice and suggest a potential risk of this anti-4-1BB-based immunotherapy for autoimmune diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / therapeutic use*
  • Antigens, CD
  • BALB 3T3 Cells
  • Blood Glucose / analysis
  • Blotting, Southern
  • Diabetes Mellitus, Type 1 / drug therapy*
  • Diabetes Mellitus, Type 1 / etiology
  • Diabetes Mellitus, Type 1 / pathology
  • Disease Models, Animal
  • Female
  • Gene Expression
  • Genetic Carrier Screening
  • Genetic Vectors / genetics
  • Glutamate Decarboxylase / immunology
  • Glycosuria / urine
  • Humans
  • Immunoglobulin Fragments / genetics
  • Immunoglobulin Fragments / pharmacology
  • Immunoglobulin Variable Region / genetics
  • Immunotherapy / adverse effects*
  • Insulin / genetics
  • Isoenzymes / immunology
  • Lymphocyte Activation / immunology
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Pancreas / pathology
  • Peptide Fragments / immunology
  • Peptide Fragments / pharmacology
  • Promoter Regions, Genetic / genetics
  • Receptors, Cell Surface / genetics
  • Receptors, Nerve Growth Factor / agonists
  • Receptors, Nerve Growth Factor / immunology*
  • Receptors, Tumor Necrosis Factor / agonists
  • Receptors, Tumor Necrosis Factor / immunology*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / pharmacology
  • Sex Factors
  • Spleen / cytology
  • Transfection
  • Tumor Necrosis Factor Receptor Superfamily, Member 9

Substances

  • Antibodies, Monoclonal
  • Antigens, CD
  • Blood Glucose
  • Immunoglobulin Fragments
  • Immunoglobulin Variable Region
  • Insulin
  • Isoenzymes
  • Peptide Fragments
  • Receptors, Cell Surface
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor
  • Recombinant Fusion Proteins
  • TNFRSF9 protein, human
  • Tnfrsf9 protein, mouse
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Glutamate Decarboxylase
  • glutamate decarboxylase 2