| Our previous study showed that paclitaxel enhance humoral and cellular immune response to OVA in mice. Docetaxel is a derivative of paclitaxel, which is more soluble and active. Docetaxel will be a valuable adjuvant candidate if adjuvant activity demonstrated. Present study was conducted to analysis the adjuvant activity of docetaxel on H1N1split influenza vaccin.1:This study was designed to investigate the adjuvant effect of docetaxel on split influenza A H1N1vaccine. Seventy-two Balb/c mice were randomly distributed into nine groups with8mice in each. All animals were subcutaneously immunized twice on weeks0and3with saline. H1N1antigen (10or100ng HA),100μg docetaxel or H1N1antigen (10ng HA) adjuvanted with docetaxel (25,50,100or200μg), or200μg aluminum hydroxide. Two weeks later, blood was collected for measurement of IgG, IgG isotypes, total IgE and HI titers; Splenocytes were separated for detection of lymphocyte proliferation, mRNA expression of IFN-γ, IL-12, IL-4, IL-10, T-bet and GATA-3. Results showed that docetaxel up-regulated Th1/Th2immune responses. When co-administered with docetaxel,10ng HA induced similar levels of IgG and IgG isotypes as well as HI titers to those induced by100ng of HA. Docetaxel promoted splenocyte responses to H1N1antigen, ConA and LPS, mRNA expressions of cytokines (IL-4, IL-10, IL-12and IFN-γ) and T-bet/GATA-3by splenocytes. Docetaxel promoted similar IgE level to but alum promoted significantly higher IgE level than the control. Considering its unique vaccine adjuvant property as well as the safe record as an antineoplastic agent clinically used in humans during a long period, docetaxel should be further studied for its use in influenza vaccine production.2:Present study was conducted to test intranasal immunization of mice with split influenza vaccine in a mixture with docetaxel, whose immune regulation function has been studied more and more recently. Forty Balb/c mice were randomly distributed into five groups with8mice in each. All animals were intranasally immunized twice on weeks0and2with saline,10ng H1N1antigen,100μg docetaxel or H1N1antigen (10ng HA) adjuvanted with docetaxel (100μg), or5μg rCTB. Two weeks after the second immunization, samples were collected for system and mucosal immune response analyzing. The treatment resulted in a marked increase of systemic (IgG, IgA, IgG subclasses and HI titer in serum) and mucosal antibody response (slgA and IgA+secretory cell). In addition, significantly increased mRNA expression of IFN-γ, IL-12, IL-4and IL-10in lungs, intraepithelial lymphocytes (IELs) in the intestinal, as well as the proliferation responses of splenocytes to ConA, LPS and HA were observed in docetaxel adjuvanted-group. In conclusion, both humoral and cellular immunity in local and systemic elicited by split influenza vaccine were enhanced by docetaxel. Considering the low dose and safety results, docetaxel may become a novel mucosal adjuvant candidate.3:In order to explore the mechanism of docetaxel adjuvant activity, lysosome maturation, co-stimulator factor expression, cytokines expression. NF-κB activity, involvement of microRNAs and danger signal analysis were conducted in vitro. Result showed that docetaxel can increase the quantity of lysosome in macrophage and change the distribution of lysosome, mRNA of co-stimulator factors CD80and CD86were enhanced by docetaxel; docetaxel promote the secretion of cytokines to a mixed Th1/Th2type. NF-κB signaling pathway are activated by low dose docetaxel. MicroRNAs detection results showed that miR-155, miR-150and miR-146a expression were enhanced by docetaxel3h after the stimulation, while there was no significant change in the expression of miR-181a and miR-125b, which means that some microRNAs play an important role in docetaxel adjuvant activity, therefore further study of microRNA regulation and adjuvant activity is needed. Present study confirmed that Hsp90seemed to mediate the adjuvant activity of docetaxel, increasment of Hsp90in serum after docetaxel adjuvanted antigen immunization prompted that Hsp90might act as the danger signal to elicit immune response. In conclusion, adjuvant activity of docetaxel may through enhancing the ability of processing and presentation of antigen by APC, and NF-κB pathway may also be involved in the stimulation of immune cell by docetaxel; immune response related microRNAs plays important roles in regulating the gene expression.In conclusion, docetaxel enhanced the immune respose elicited by subcutaneous and mucosal immunization. HA specific humoral and Thl/Th2type cellular immune response were triggered by the addition of docetaxel and no significant increasement of IgE was seen in docetaxel adjuvanted group in subcutaneous immunization model; both local mucosal and system immune response were enhanced by docetaxel in mucosal immunization model, serum IgG, IgA, IgG isotype and HI titer increased in docetaxel adjuvant group; Meanwhile slgA in nasal and bronchoalveolar lavage fluid, IgA+secreting cell in duodenum,(IFN-γ, IL-12, IL-4and IL-10) cytokine mRNA and IELs in intestinal were enhanced. NF-κB and proinflammatory cytokines were triggered by docetaxel, certain microRNAs were involved in the induction of cytokines, detail mechanism need to be further investigated. |
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