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Diabetes Publish Ahead of Print published online ahead of print February 15, 2007
DOI: 10.2337/db06-0495
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Original Research

SYSTEMIC EXPRESSION OF HEME OXYGENASE-1 AMELIORATES TYPE 1 DIABETES IN NOD MICE

Chien-Ming Hu1, Heng-Huei Lin1, Ming-Tsai Chiang1, Pi-Fei Chang1, and Lee-Young Chau1

1Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China

Correspondence: lyc{at}ibms.sinica.edu.tw

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 1010 - 2.5 x 1010 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-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 and AAV-HO-1-treated groups. However, the CD11c+ MHC 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 CO gas (250 ppm CO for 2 h, twice per week). These data suggest that HO-1 slows the progression to overt diabetes in prediabetic NOD mice by down-regulating 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.


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