Abstract

Dendritic cells (DCs) classically promote immune responses but can be manipulated to induce antigen-specific hyporesponsiveness. It has been shown that phenotypically "immature" DCs, defined by low levels of costimulatory molecules at the cell surface, are involved in the induction of peripheral immune tolerance in autoimmunity. Paecilomyces hepiali Chen (PHC) mycelium, as a substitute for Cordyceps, has been used extensively as an immunomodulator to treat numerous diseases. In this study, the effects of an ethanol extract of PHC (EEPHC) on the phenotypic and functional maturation of bone marrow-derived DCs (BM-DCs) from NOD mice were evaluated. EEPHC significantly suppressed the expression of major histocompatibility complex (MHC) class II molecules and the costimulatory molecules CD40 and CD86 in NOD BM-DCs. These DCs also exhibited impaired production of the proinflammatory cytokine interleukin-12 (IL-12) and poor stimulatory capacity in the presence of EEPHC. Moreover, inhibition of the activation and differentiation of cultured DCs was associated with reduced DNA binding activity of nuclear factor kappa B (NF- kappaB), a transcription factor recently shown to be responsible for DC maturation. Administration of 3x10(5) EEPHC-treated DCs into NOD mice aged 3-4 weeks effectively prevented the onset of diabetes. Furthermore, splenocytes from the protected mice produced high amounts of IL-4 and IL-10 and low levels of IL-2 and interferon gamma, suggesting that these DCs deficient in NF- kappaB activity are responsible for the apparent shift in type 2 helper T cells. These novel results showed that EEPHC could specifically inhibit NF- kappaB activity and maintain DCs in a potentially tolerogenic state, permitting their use in strategies to induce immune tolerance in type 1 diabetes.

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