Systemic Expression of Heme Oxygenase-1 Ameliorates Type 1 Diabetes in NOD Mice

  1. Chien-Ming Hu,
  2. Heng-Huei Lin,
  3. Ming-Tsai Chiang,
  4. Pi-Fei Chang and
  5. Lee-Young Chau
  1. From the Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China
  1. Address correspondence and reprint requests to Lee-Young Chau, PhD, Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan, Republic of China. E-mail: lyc{at}


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 × 1010-2.5 × 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 (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.


  • Published ahead of print at on 15 February 2007. DOI: 10.2337/db06-0495.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted January 31, 2007.
    • Received April 13, 2006.
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  1. Diabetes vol. 56 no. 5 1240-1247
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