Date of Award

8-1-2011

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

Abstract

Adjuvants are used widely in vaccine formulations. However for humans, choices are very limited. Since they are selected empirically, it is not expected that any two adjuvants would influence immune mechanisms the same way. However they all influence host microenvironment, antigen presentation, and retention of immunological memory. This study focuses on new terpenoid adjuvants based on phytol derivatives. We previously observed that phytol and one of its derivatives PHIS-01 (a phytol-based immunostimulant, phytanol) are excellent adjuvants. To gain an understanding of the structural features important for adjuvanticity, we further studied compounds derived from a diterpene Phytol. We designed two new phytol derivatives, PHIS-02 and PHIS-03 (aminated and mannosylated compounds respectively). In this study we investigated their relative safety and efficacy compared to PHIS-01 (phytanol) and other commonly used adjuvants that include alum, Freunds’ adjuvants and SIS (extra-cellular matrix). In addition, we examined how changes at the polar terminus affect adjuvanticity of PHIS-01, PHIS-02, PHIS-03 in term of host microenvironment and safety profile. Using these adjuvants as emulsions with different soluble protein antigens, ovalbumin and a hapten-protein conjugate phthalate-KLH, we evaluated in both autoimmune resistant and susceptible murine models. The following immunological parameters were studied: 1) effects on antibody responses in terms of titers, specificities and isotypic profiles; 2) effects on T-helper cells, cytokines, and chemokines milieu; 3) involvements of apoptotic and/or necrotic activity and inflammasome pathways as their primary modes of action. Our results indicate that: 1) Adjuvants are used widely in vaccine formulations. However for humans, choices are very limited. Since they are selected empirically, it is not expected that any two adjuvants would influence immune mechanisms the same way. However they all influence host microenvironment, antigen presentation, and retention of immunological memory. This study focuses on new terpenoid adjuvants based on phytol derivatives. We previously observed that phytol and one of its derivatives PHIS-01 (a phytol-based immunostimulant, phytanol) are excellent adjuvants. To gain an understanding of the structural features important for adjuvanticity, we further studied compounds derived from a diterpene Phytol. We designed two new phytol derivatives, PHIS-02 and PHIS-03 (aminated and mannosylated compounds respectively). In this study we investigated their relative safety and efficacy compared to PHIS 01 (phytanol) and other commonly used adjuvants that include alum, Freunds’ adjuvants and SIS (extra-cellular matrix). In addition, we examined how changes at the polar terminus affect adjuvanticity of PHIS-01, PHIS-02, PHIS-03 in term of host microenvironment and safety profile. Using these adjuvants as emulsions with different soluble protein antigens, ovalbumin and a hapten-protein conjugate phthalate-KLH, we evaluated in both autoimmune resistant and susceptible murine models. The following immunological parameters were studied: 1) effects on antibody responses in terms of titers, specificities and isotypic profiles; 2) effects on T-helper cells, cytokines, and chemokines milieu; 3) involvements of apoptotic and/or necrotic activity and inflammasome pathways as their primary modes of action. Our results indicate that: 1)

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