Intravenous administration of proinsulin 1 or 2-expressing fiber-mutant recombinant adenovirus vector protects against the development of diabetes in NOD mice.
Insulin has been reported as a major autoantigen in both human and murine type 1 diabetes (T1D). Insulin1-knockout NOD mice with only insulin2 are protected against the development of autoimmune diabetes, suggesting that insulin1 has strong immunogenicity and insulin2 has weak immunogenicity or a possible protective role in the pathogenesis of type 1 diabetes. In this study, we have developed fiber-mutant adenovirus vectors that express murine proinsulin1 or proinsulin2 (named Ad.Pins1-RGD/Ad.Pins2-RGD) and administered those virus vectors to the NOD mouse to evaluate modulation of autoimmune responses. The intravenous administration of either Ad.Pins1-RGD or Ad.Pins2-RGD at 3 and 5 weeks of age strongly suppressed the development of overt diabetes, accompanied by a significant reduction of insulin autoantibody (IAA), and suppression of disease was similar between administration of Ad.Pins1-RGD and that of Ad.Pins2-RGD. Our study suggests that systemic administration of fiber-mutant adenovirus vectors, which induce transient expression of proinsulin, may be applicable to a gene therapy inducing tolerance to insulin.
Yamada
Katsumi
K
Department of Internal and Geriatric Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
Moriyama
Hiroaki
H
Okumachi
Yasuyo
Y
Arai
Takashi
T
Kameno
Mami
M
Kishi
Minoru
M
Yasuda
Hisafumi
H
Hara
Kenta
K
Yokono
Koichi
K
Nagata
Masao
M
D000256:Adenoviridae / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D036022:Capsid Proteins / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage*; D007275:Injections, Intravenous; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000235:genetics; D011384:Proinsulin / Q000235:genetics*; D019076:Transgenes; D014779:Virus Replication / Q000235:genetics
D036022:Capsid Proteins; D050505:Mutant Proteins; D011384:Proinsulin