Therapeutic effects of IL-12 combined with benzoylmesaconine, a non-toxic aconitine-hydrolysate, against herpes simplex virus type 1 infection in mice following thermal injury

IL-12 is an inducer of type 1 T cell responses, which are essential in host defense against herpes simplex virus type 1 (HSV-1) infection. However, type 1 T cell responses are not elicited by IL-12 in thermally injured mice (TI-mice) that routinely have a predominance of burn-associated type 2 T cell responses. In our previous studies, benzoylmesaconine (BEN, an aconitine derivative extracted from heated-Aconiti tuber) induced the generation of CD4⁺ T cells antagonistic to type 2 T cells (BEN-CD4⁺ T cells). In the present study, the effects of a combination therapy using IL-12 and BEN to treat severe HSV-1 infection in TI-mice were investigated. When TI-mice were treated with either IL-12 (500U per mouse) or BEN (1μg/kg) alone, they did not resist HSV-1 infection. However, 60-80% of TI-mice exposed to HSV-1 survived after they received IL-12 and BEN or BEN-CD4⁺ T cells in combination. After stimulation with anti-CD3 mAb in vitro, IFN-γ was not produced in cultures of splenic T cells from TI-mice exposed to HSV-1 and treated with either IL-12, BEN or BEN-CD4⁺ T cell alone. However, IFN-γ production was induced by the mAb stimulation in the cultures of T cells from infected mice treated with IL-12 and BEN or BEN-CD4⁺ T cells in combination. These results suggest that the combination therapy of IL-12 (an inducer of type 1 T cell responses) and BEN (an inhibitor of type 2 T cell responses) may protect TI-mice from severe HSV-1 infection.