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Active Tolerance Induction and Prevention of Autoimmune Diabetes by Immunogene Therapy Using Recombinant Adenoassociated Virus Expressing Glutamic Acid Decarboxylase 65 Peptide GAD_500–585¹

Gencheng Han^*, Yan Li^*, Jianan Wang^*, Renxi Wang^*, Guojiang Chen^*, Lun Song^*, Ruonan Xu^*, Ming Yu^*, Xiaobing Wu, Jiahua Qian and Beifen Shen^2,*

^* Department of Molecular Immunology, Institute of Basic Medical Sciences, and National Lab of Molecular Virology and Genetic Engineering, Beijing, People’s Republic of China; and National Cancer Institute, Vaccine Branch, Bethesda, MD 20889

Tolerance induction of autoreactive T cells against pancreatic cell-specific autoantigens such as glutamic acid decarboxylase 65 (GAD65) and insulin has been attempted as a method to prevent autoimmune diabetes. In this study, we investigate whether adenoassociated virus (AAV) gene delivery of multiple immunodominant epitopes expressing GAD_500–585 could induce potent immune tolerance and persistently suppress autoimmune diabetes in NOD mice. A single muscle injection of 7-wk-old female NOD mice with rAAV/GAD_500–585 (3 x 10¹¹ IU/mouse) quantitatively reduced pancreatic insulitis and efficiently prevented the development of overt type I diabetes. This prevention was marked by the inactivation of GAD_500–585-responsive T lymphocytes, the enhanced GAD_500–585-specific Th2 response (characterized by increased IL-4, IL-10 production, and decreased IFN- production; especially elevated anti-GAD_500–585 IgG1 titer; and relatively unchanged anti-GAD_500–585 IgG2b titer), the increased secretion of TGF-, and the production of protective regulatory cells. Our studies also revealed that peptides 509–528, 570–585, and 554–546 in the region of GAD_500–585 played important roles in rAAV/GAD_500–585 immunization-induced immune tolerance. These data indicate that using AAV, a vector with advantage for therapeutic gene delivery, to transfer autoantigen peptide GAD_500–585, can induce immunological tolerance through active suppression of effector T cells and prevent type I diabetes in NOD mice.

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