Prevention of autoimmune diabetes by immunogene therapy using recombinant vaccinia virus expressing glutamic acid decarboxylase

• Published in: Diabetologia Vol. 45; no. 5; pp. 668 - 676
• Main Authors: JUN, H.-S, CHUNG, Y.-H, HAN, J, KIM, A, YOO, S. S, SHERWIN, R. S, YOON, J.-W
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01.05.2002
• Subjects: Adoptive Transfer - methods; Animals; Base Sequence; Biological and medical sciences; Diabetes Mellitus, Type 1 - prevention & control; Diabetes. Impaired glucose tolerance; DNA Primers; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Genetic Therapy; Genetic Vectors; Glutamate Decarboxylase - immunology; Hypoxanthine Phosphoribosyltransferase - genetics; Isoenzymes - immunology; Lymphocytes - immunology; Medical sciences; Mice; Mice, Inbred NOD; Recombination, Genetic; Spleen - immunology; Vaccines, DNA - therapeutic use; Vaccinia virus; Endocrinopathy; Animal model; Recombinant virus; Autoimmune disease; Lyases; Prevention; Carboxy-lyases; Immunopathology; Chordopoxvirinae; Immune response; Enzyme; Orthopoxvirus; Rodentia; Glutamate decarboxylase; Virus; Vaccinia virus; Carbon-carbon lyases; Vertebrata; Mammalia; Mouse; Poxviridae; Excitatory aminoacid; Neurotransmitter; Insulin dependent diabetes; Gene therapy
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-002-0806-9

Type I (insulin-dependent) diabetes mellitus results from T-cell-mediated autoimmune destruction of pancreatic beta cells. Among the beta-cell autoantigens that have been implicated in triggering of beta-cell-specific autoimmunity, glutamic acid decarboxylase (GAD) is a strong candidate in both humans and the NOD mouse. We aimed to determine whether treatment with a recombinant vaccinia virus expressing GAD (rVV-GAD65) could prevent the development of diabetes in NOD mice. Three-eight-to-nine-week-old female NOD mice were injected with various doses of rVV-GAD65 or rVV-MJ601as a control. We then examined the incidence of diabetes, T-cell proliferative response to GAD, amounts of anti-GAD IgGs, cytokine production and generation of regulatory cell populations. Administration of rVV-GAD65 to NOD mice prevented diabetes in an age-dependent and dose-dependent manner. Splenic T cells from rVV-GAD65-treated mice did not proliferate in response to GAD65. The amount of IgG1 was increased, whereas IgG2a amounts did not change in rVV-GAD65-treated NOD mice. The production of interleukin-4 increased, whereas the production of interferon-gamma decreased in rVV-GAD65-treated mice after stimulation with GAD. Furthermore, splenocytes from rVV-GAD65-treated NOD mice prevented the transfer of diabetes by splenocytes from acutely diabetic NOD mice in NOD. scid recipients. Immunogene therapy using a recombinant vaccinia virus expressing GAD results in the prevention of autoimmune diabetes in NOD mice by the induction of immunological tolerance through active suppression of effector T cells, and this treatment might have therapeutic value for the prevention of Type I diabetes.