Objective: Stress, either physical or psychological, can modulate immune function. However, the mechanisms associated with stress-induced immune suppression remain to be elucidated. β-Arrestin 2 serves as adaptor, scaffold, and/or signal transducer. The role of β-arrestin 2 in stress-induced immune suppression is not known yet. Methods/Results: Here, we demonstrate that β-arrestin 2 deficiency in mice increases the sensitivity to the chronic stress-induced reduction in the number of splenocytes. Interestingly, the stress-induced suppression of T helper-type (Th) 1 cytokines and the increased production of Th2 cytokines were greatly enhanced in β-arrestin 2-deficient mice compared with wild-type mice. Moreover, inhibition of PI3K in β-arrestin 2-deficient mice exerts an additive effect on the stress-induced reduction in the number of splenocytes. Conclusion: Our study demonstrates that a deficiency in β-arrestin 2 augments stress-induced immune suppression.

Skin is the largest immune organ and an ideal site to administer vaccines. However, by nature, skin is not permeable to antigens, which are macromolecules. The major hurdle in skin permeation is the outermost stratum corneum layer. Microneedles have proven feasible to create micron-sized channels in the epidermis of the skin, through which protein and plasmid DNA antigens can penetrate into the viable skin epidermis and dermis. However, the immune responses induced by microneedle-mediated transcutaneous immunization with protein or plasmid DNA alone are generally weak, and a vaccine adjuvant is often required to induce strong immune responses. Data from numerous previous studies have shown that nanoparticles as a vaccine carrier can significantly enhance the immunogenicity of antigens, but the feasibility of utilizing nanoparticles as a vaccine carrier to enhance the immune responses induced by microneedle-mediated transcutaneous immunization has rarely been studied. In this dissertation, using protein antigen (OVA) chemically conjugated onto the surface of solid-lipid nanoparticles and plasmid DNA (pCMV-beta, pVax/opt-BoNT/C-Hc50, and pCI-neo-sOVA) physically coated on the surface of cationic polymeric nanoparticles, we showed that the immune responses induced by microneedle-mediated transcutaneous immunization with protein antigens or plasmid DNA vaccines are significantly enhanced by delivering the proteins and plasmid DNA with nanoparticles. Importantly, microneedle-mediated transcutaneous immunization with proteins or plasmid DNA induces not only systemic immune responses, but also mucosal immune responses. In addition, it is generally believed that microneedles are safe. However, it remained unclear whether the micropores created by microneedles on the skin will also facilitate the permeation of microbes such as bacteria into the skin. In this dissertation, we also designed an unique ex vivo model to evaluate the permeation of live bacteria through mouse skin pretreated with microneedles. The results demonstrated that the risk of potential bacterial infection associated with microneedle treatment is not greater than that associated with a hypodermic needle injection. / text