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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Jun
H-S
HS
Laboratory of Viral Immunopathogenesis of Diabetes, Julia McFarlane Diabetes Research Centre, Faculty of Medicine, The University of Calgary, Alberta, Canada.
Chung
Y-H
YH
Han
J
J
Kim
A
A
Yoo
S S
SS
Sherwin
R S
RS
Yoon
J-W
JW
D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D005968:Glutamate Decarboxylase / Q000276:immunology*; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D007527:Isoenzymes / Q000276:immunology*; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D011995:Recombination, Genetic; D013154:Spleen / Q000276:immunology; D019444:Vaccines, DNA / Q000627:therapeutic use*; D014616:Vaccinia virus
D017931:DNA Primers; D007527:Isoenzymes; D019444:Vaccines, DNA; D007041:Hypoxanthine Phosphoribosyltransferase; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2