Modulating mucosal immune responses to HIV

Abstract

Development of a successful vaccine against HIV is likely to require the induction of strong and long-lasting humoral immune responses at the mucosal portals of virus entry. One approach to achieve this is the direct immunisation of mucosal sites. However, there is a need for potent and safe adjuvants that work at mucosal surfaces. A number of cytokines have recently been identified that specifically activate B-cells including BAFF, APRIL and TSLP. The hypothesis of this thesis is that these cytokines will act as adjuvants to boost antibody responses to mucosally delivered HIV antigen. Following immunisation of mice, serum and vaginal samples were tested for gp140-specific IgA and IgG responses. Splenocytes were assessed for T-cell proliferation and gp140-specific IgA and IgG antibody secreting cells. Cytokine production by T-cells after in vitro stimulation with CN54gp140 peptides was also assessed. TSLP, but not APRIL or BAFF, induced strong immune responses after nasal " immunisation, comparable to those seen with cholera toxin. Responses were still detected 4 months after the last boost, indicating a long lasting response. TSLP also induced T -cell proliferative responses to gp 140 after nasal immunisation and induced a T H2 type immune response but without induction of an allergic response. Due to cost limitations on the mass production of protein for use as an adjuvant, it was also tested whether TSLP could be delivered in the form of a plasmid DNA adjuvant. These studies demonstrated limited efficacy. In conclusion, the study demonstrated that B-cell activating cytokine TSLP, but not BAFF and APRIL can work as a mucosal adjuvant. It is notable that there was no significant development of allergic responses following administration of TSLP. This is 4 , the first time that TSLP has been demonstrated to have a positive effect as a mucosal adjuvant, and specifically promoting mucosal and systemic responses to HIV gp140.EThOS - Electronic Theses Online ServiceGBUnited Kingdo