Suppression of hyperglycemia in NOD mice after inoculation with recombinant vaccinia viruses |
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Authors: | Béla Dénes Jie Yu Nadja Fodor Zsuzsanna Takátsy István Fodor William H R Langridge |
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Institution: | (1) Center for Molecular Biology and Gene Therapy, Department of Biochemistry and Microbiology, Loma Linda University, 92350 Loma Linda, CA;(2) Central Vererirary Institute, Tábomok u. 2, 1149 Budapest, Hungary |
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Abstract: | In autoimmune (type 1) diabetes, autoreactive lymphocytes destroy pancreatic β-cells responsible for insulin synthesis. To
assess the feasibility of gene therapy for type 1 diabetes, recombinant vaccinia virus (rVV) vectors were constructed expressing
pancreatic islet autoantigens proinsulin (INS) and a 55-kDa immunogenic peptide from glutamic acid decarboxylase (GAD), and
the immunomodulatory cytokine interleukin (IL)-10. To augment the beneficial effects of recombinant virus therapy, the INS
and GAD genes were fused to the C terminus of the cholera toxin B subunit (CTB). Five-week-old non-obese diabetic (NOD) mice
were injected once with rVV. Humoral antibody immune responses and hyperglycemia in the infected mice were analyzed.
Only 20% of the mice inoculated with rVV expressing the CTB::INS fusion protein developed hyperglycemia, in comparison to
70% of the mice in the uninoculated animal group. Islets from pancreatic tissues isolated from euglycemic mice from this animal
group showed no sign of inflammatory lymphocyte invasion. Inoculation with rVV producing CTB::GAD or IL-10 was somewhat less
effective in reducing diabetes. Humoral antibody isotypes of hyperglycemic and euglycemic mice from all treated groups possessed
similar IgG1/IgG2c antibody titer ratios from 19 to 32 wk after virus inoculation. In comparison with uninoculated mice, 11-wk-old
NOD mice injected with virus expressing CTB::INS were delayed in diabetes onset by more than 4 wk. The experimental results
demonstrate the feasibility of using rVV expressing CTB::INS fusion protein to generate significant protection and therapy
against type 1 diabetes onset and progression. |
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Keywords: | Choleratoxin B subunit autoimmunity type 1 diabetes IDDM GAD insulin vaccinia virus |
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