The Japanese
herbal medicines,
Juzen-taiho-to (JTT) and
Hochu-ekki-to (HET), have been shown to enhance humoral immune responses to
vaccine antigen when used as adjuvants for prophylactic
vaccines. However, their adjuvant effect on mucosal cellular immune responses remains unstudied. The precursor lesion of
cervical cancer, high-grade CIN that expresses HPV E7
oncoprotein ubiquitously is a target for HPV therapeutic
vaccines that elicit mucosal E7-specific type 1 T cell responses. We have demonstrated that oral immunization with recombinant Lactobacillus casei expressing HPV16 E7 (LacE7) is more effective in eliciting mucosal E7-specific IFNγ-producing cells than subcutaneous or intramuscular
antigen delivery. Here we report the synergistic effect of an oral Lactobacillus-based
vaccine and Japanese
herbal medicines on mucosal immune responses. Oral immunization of mice with LacE7 plus either a Japanese herbal medicine (JTT or HET) or a mucosal adjuvant, heated-labile
enterotoxin T subunit (LTB), promotes systemic E7-specific type 1 T cell responses but not mucosal responses. Administration of LacE7 plus either Japanese herbal medicine and LTB enhanced mucosal E7-specific type 1 T cell response to levels approximately 3-fold higher than those after administration of LacE7 alone. Furthermore, secretion of IFNγ and
IL-2 into the intestinal lumen was observed after
oral administration of LacE7 and was enhanced considerably by the addition of Japanese
herbal medicines and LTB. Our data indicated that Japanese
herbal medicines, in synergy with Lactobacillus and LTB, enhance the mucosal type 1 immune responses to orally immunized
antigen. Japanese
herbal medicines may be excellent adjuvants for oral Lactobacillus-based
vaccines and oral immunization of LacE7, HET and LTB may have the potential to elicit extremely high E7-specific mucosal cytotoxic immune response to HPV-associated neoplastic lesions.