All About Multiple Sclerosis

More MS news articles for November 2003

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
Sytwu HK, Lin WD, Roffler SR, Hung JT, Sung HS, Wang CH, Cheng TL, Tsou SC, Hsi SC, Shen KL.
Department of Microbiology and Immunology, National Defense Medical Center, 161, Section 6, MinChuan East Road, Neihu, 114, Taipei, Taiwan

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.