We have found that protective viral-specific primary antibody responses are accelerated in naive mice in which inducible-bronchus-associated lymphatic tissues (iBALT) have formed within the mucosal epithelium of the lung in response to the administration of a protein cage nanoparticle (PCN) prior to the viral infection. Our hypothesis is that the presence of PCN-induced iBALT structures in the lung, at the time of a pulmonary viral infection, facilitates this accelerated onset of the local primary humoral immune responses as well as the establishment of antigen-specific memory and long-lived plasma B cell populations. The proposed research work of the first specific aim will determine if a correlation exists between the frequency of administration of the PCN, the profile of elicited cytokines at the mucosal surface of the lung and the isotype profile of the viral-specific antibody-mediated immune response. The information gained from these studies will enable us to design PCN treatment regimes that will favor the accelerated induction of more effective mucosal antibody-mediated protection in the lung. The research work proposed in the second specific aim will examine the ability of pre-existing iBALT structures to enhance the establishment of the viral-specific memory B cell populations (resting memory B cells and long-lived plasma B cells). This work will make use of a chimeric mouse model in order to isolate iBALT-derived responses from those of conventional secondary lymphatic tissues. The results of this work determine if the accelerated primary responses that we see in PCN-treated mice are reflected by an accelerated establishment of memory B cell populations in tissues that harbor these cells and whether or not iBALT, in the absence of conventional secondary lymphatic tissues is capable of generating these memory B cell populations. Results from the proposed experiments will be used to design studies on iBALT-dependent mechanisms that enhance antibody-mediated immunity at the mucosal surface of the lung. . The research work in this proposal will provide groundwork evidence for a means to accelerate primary antibody-mediated responses at the level of the mucosal epithelia of the lung. Accelerating the onset of the primary antibody-mediated responses effectively reduces the time of unabated pathogen proliferation and thereby reduces pathogen burdens and the extent of tissue damage to the individual. This immune enhancement strategy takes advantage of the asymptomatic induction of a naturally occurring, transient lymphatic tissue in the lung known as inducible bronchio-alveolar lymphatic tissue (iBALT). These iBALT structures are integrated within the submucosal tissues of the lung when they are induced. The significance of this work is seen in its immuno-therapeutic application to enhance resistance to infection by antigenic variants of circulating viral pathogens for which acquired memory immunity would have negligible effect, for infection by viral pathogens for which we do not yet possess a vaccine construct and for the rapid maturation of vaccine-induced immunity in the event that infection by a viral pathogen is imminent.
. The research work in this proposal will provide groundwork evidence for a means to accelerate primary antibody-mediated responses at the level of the mucosal epithelia of the lung. Accelerating the onset of the primary antibody-mediated responses effectively reduces the time of unabated pathogen proliferation and thereby reduces pathogen burdens and the extent of tissue damage to the individual. This immune enhancement strategy takes advantage of the asymptomatic induction of a naturally occurring, transient lymphatic tissue in the lung known as inducible bronchio-alveolar lymphatic tissue (iBALT). These iBALT structures are integrated within the submucosal tissues of the lung when they are induced. The significance of this work is seen in its immuno-therapeutic application to enhance resistance to infection by antigenic variants of circulating viral pathogens for which acquired memory immunity would have negligible effect, for infection by viral pathogens for which we do not yet possess a vaccine construct and for the rapid maturation of vaccine-induced immunity in the event that infection by a viral pathogen is imminent.
| Richert, Laura E; Rynda-Apple, Agnieszka; Harmsen, Ann L et al. (2014) CD11c? cells primed with unrelated antigens facilitate an accelerated immune response to influenza virus in mice. Eur J Immunol 44:397-408 |
| Richert, Laura E; Harmsen, Ann L; Rynda-Apple, Agnieszka et al. (2013) Inducible bronchus-associated lymphoid tissue (iBALT) synergizes with local lymph nodes during antiviral CD4+ T cell responses. Lymphat Res Biol 11:196-202 |
| Richert, Laura E; Servid, Amy E; Harmsen, Ann L et al. (2012) A virus-like particle vaccine platform elicits heightened and hastened local lung mucosal antibody production after a single dose. Vaccine 30:3653-65 |
| Wiley, James A; Richert, Laura E; Swain, Steve D et al. (2009) Inducible bronchus-associated lymphoid tissue elicited by a protein cage nanoparticle enhances protection in mice against diverse respiratory viruses. PLoS One 4:e7142 |
