Systemic expression of heme oxygenase-1 ameliorates type 1 diabetes in NOD mice.
Heme oxygenase-1 (HO-1) is an enzyme with potent immunoregulatory capacity. To evaluate the effect of HO-1 on autoimmune diabetes, female NOD mice at 9 weeks of age received a single intravenous injection of a recombinant adeno-associated virus bearing HO-1 gene (AAV-HO-1; 0.5 x 10(10)-2.5 x 10(10) viruses/mouse). In a dose-dependent manner, HO-1 transduction reduced destructive insulitis and the incidence of overt diabetes examined over a 15-week period. HO-1-mediated protection was associated with a lower type 1 T-helper cell (Th1)-mediated response. Adaptive transfer experiments in NOD.scid mice demonstrated that splenocytes isolated from AAV-HO-1-treated mice were less diabetogenic. Flow cytometry analysis revealed no significant difference in the percentages of CD4(+)CD25(+) regulatory T-cells between saline-treated and AAV-HO-1-treated groups. However, the CD11c(+) major histocompatibility complex II(+) dendritic cell population was much lower in the AAV-HO-1-treated group. A similar protective effect against diabetes was observed in NOD mice subjected to carbon monoxide (CO) gas (250 ppm CO for 2 h, twice per week). These data suggest that HO-1 slows the progression to overt diabetes in pre-diabetic NOD mice by downregulating the phenotypic maturity of dendritic cells and Th1 effector function. CO appears to mediate at least partly the beneficial effect of HO-1 in this disease setting.
Hu
Chien-Ming
CM
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China.
Lin
Heng-Huei
HH
Chiang
Ming-Tsai
MT
Chang
Pi-Fei
PF
Chau
Lee-Young
LY
D019264:Adoptive Transfer; D000818:Animals; D003208:Concanavalin A / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D017931:DNA Primers; D018076:DNA, Complementary / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology; D000229:Dependovirus / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000517:prevention & control*; D005260:Female; D005822:Genetic Vectors; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010179:Pancreas / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology
D016207:Cytokines; D017931:DNA Primers; D018076:DNA, Complementary; D003208:Concanavalin A; D051547:Heme Oxygenase-1