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

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...

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Published in:Journal of autoimmunity 2003-11, Vol.21 (3), p.247-254
Main Authors: Sytwu, Huey-Kang, Lin, Wen-Der, Roffler, Steve R, Hung, Jung-Tung, Sung, Hsiang-Sheng, Wang, Chi-Hsien, Cheng, Tian-Lu, Tsou, Shey-Cherng, Hsi, Sheng-Chuan, Shen, Kuo-Liang
Format: Article
Language:English
Subjects:
4-1BB
Animals
Antibodies, Monoclonal - therapeutic use
Antigens, CD
Autoimmune diabetes
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
Human insulin promoter (pIns)
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
Non-obese diabetic mice
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
Single-chain anti-4-1BB Fv (anti-4-1BB scFv)
Spleen - cytology
Transfection
Transgenic mice
Tumor Necrosis Factor Receptor Superfamily, Member 9
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Summary: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 β 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.
ISSN:0896-8411
1095-9157
DOI:10.1016/S0896-8411(03)00112-4