Oral QS-21 requires early IL-4 help for induction of mucosal and systemic immunity

The highly purified saponin derivative, QS-21, from the Quillaja saponaria Molina tree has been proved to be safe for parenteral administration and re presents a potential alternative to bacterial enterotoxin derivatives as a mucosal adjuvant, Here we report that p.o. administration of QS-21 with the vaccine protein tetanus toroid elicited strong serum IgM and IgG Ab respon ses, which were only slightly enhanced by further oral immunization. The Ig G Ab subclass responses were predominantly IgG1 followed by IgG2b for the 5 0-mug p.o. dose of QS-21, whereas the 250-mug p.o. dose also induced IgG2a and IgG3 Abs. Low oral QS-21 doses induced transient IgE Ab responses 7 day s after the primary immunization, whereas no IgE Ab responses were seen in mice given the higher QS-21 dose. Further, low but not high p.o. QS-21 dose s triggered Ag-specific secretory IgA (S-IgA) Ab responses. Th cell respons es showed higher IFN-gamma (Th1-type) and lower IL-5, IL-6, and IL-10 (Th2- type) secretion after the high QS-21 p.o, dose than after low doses. Intere stingly, the mucosal adjuvant activity of low oral QS-21 doses was diminish ed in IL-4(-/-) mice, suggesting a role for this cytokine in the initiation of mucosal immunity by oral QS-21. In summary, our results show that oral QS-21 enhances immunity to coadministered Ag and that different doses of QS -21 lead to distinct patterns of cytokine and serum Ab responses. We also s how that an early IL-4 response is required for the induction of mucosal im munity by oral QS-21 as adjuvant.