Insulin dependent diabetes mellitus (IDDM Type I) is the result of autoimmune destruction of insulin producing beta cells. Disease progression is evidenced by multiple autoantibodies responding in a cascade mechanism, wherein the first antigen induces the activation of the immune system, leading to destruction of beta cells and consequently, exposure of other antigens and autoantibodies. Glutamic acid decarboxylase (GAD) is a primary autoantigen involved in the cascade. One underlying hypothesis of this study is that injected anti-GAD derivatives and conjugates will bind to the GAD antigen, blocking the antigenic determinant and preventing immune recognition by lymphocytes. The applicants' laboratory routinely isolates anti-GAD-IgG and has tested it to prevent IDDM onset in nonobese diabetic (NOD) mice. At 32 weeks of age, a significant decrease in the incidence of diabetes was observed in the anti-GAD treatment group (<35 percent) compared to control mice (>85 percent) (p<0.05). Treatment efficacy was correlated to the age of initial treatment. The extent of lymphocyte cell infiltration (insulitis) in the test group was less than controls, indicating the therapeutic benefit of anti-GAD-IgG in delaying diabetes. Other data supports the fact that anti-GAD has a direct effect on the immune system by inducing lymphocyte proliferation in vitro. The proposal will also investigate the effect of chemically coupled poly(ethylene glycol) (PEG) to anti-GAD. PEGylated proteins and antibodies are well recognized for their improved pharmacokinetic, pharmacodynamic, and immunological properties. Anti-GAD-PEGs representing different degrees of PEG modification will be synthesized. Anti-GAD-IgG and Anti-GAD-PEG conjugates will be compared in their pharmacological actions, their role in immune regulation, and ultimately in their ability to delay the onset of diabetes. These compounds will be compared and correlated to the previous results to produce an optimal molecule for the prevention of diabetes in NOD mice.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG7-SAT (01))
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Harmon, Joan T
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University of Utah
Schools of Pharmacy
Salt Lake City
United States
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Larson, R S; Menard, V; Jacobs, H et al. (2001) Physicochemical characterization of poly(ethylene glycol)-modified anti-GAD antibodies. Bioconjug Chem 12:861-9
Lee, M; Han, S O; Ko, K S et al. (2001) Repression of GAD autoantigen expression in pancreas beta-Cells by delivery of antisense plasmid/PEG-g-PLL complex. Mol Ther 4:339-46
Menard, V; Jacobs, H; Jun, H S et al. (1999) Anti-GAD monoclonal antibody delays the onset of diabetes mellitus in NOD mice. Pharm Res 16:1059-66