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Re-directing B cell responses to carbohydrate antigens

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Bacterial carbohydrates (CHO) present numerous opportunities for vaccine development, but the immune response to them can be dominated by T-independent B cell activation with short-lived responses, limited antibody (Ab) class switch, and poor B cell memory. New vaccines are needed for emerging infectious diseases and this includes Clostridium difficile which abundantly expresses a candidate vaccine antigen (Ag) known as the PSII poly-hexasaccharide. Although conjugation of such CHO Ags to carrier proteins has been effective in some instances by stimulating T cell help for CHOspecific B cells, producing glyco-conjugates can be technically demanding and expensive. If an alternative means can be found to induce T cell help without conjugation, then more candidate CHO Ags could be inexpensively screened, and may even function as vaccines without conjugation. Key findings: We observed that immunization of mice with NP-hapten-conjugated Ficoll mixed with the CD1dbinding ligand known as ?-galactosylceramide (?-GC) led to CD1d- and NKT cell-dependent changes in the anti-NP-Ficoll Ab response. The classical IgM/IgG3 profile was altered such that IgG1 was also produced. The ?-GC ligand induces differentiation and/or expansion of the NKT follicular helper (NKTfh) cell subset which may influence B cell responses. It is not known whether NKTfh cells influence Ab responses against C. difficile CHO Ag. Hypothesis: NKTfh cells stimulate B cell memory and production of high affinity IgG1 against the C. difficile PSII Ag. Suitability for R21 funding: An R21 grant will allow us to test our novel exploratory idea and build a suitable foundation for an RO1-funded study. Before embarking on such a project, it will be necessary to determine if ?- GC induces CHO-specific IgG1 production and B cell memory (Specific Aim 1). We will then need to determine if NKTfh cells are responsible for the effects observed (Specific Aim 2). Integral to both specific aims is determining how well observations using model Ags translate to ?real world? pathogen-derived Ags. The project described herein will achieve these goals and position our laboratory to undertake a longer-term molecular examination of how NKT cells (or the NKTfh sub-set) influence anti-CHO Ab responses Potential Impact and Relevance to Public Health: The impact of our work could be profound because it could lead to more rapid and inexpensive screening of vaccine candidate CHO Ags. The work could also lead to a complementary approach to glyco-conjugate vaccines in the clinic, whereby CHO/ CD1d ligand mixtures could be used to inexpensively vaccinate individuals in resource-scarce environments. The proof of principle experiments with C. difficile PSII Ag could be used as a model for several pathogen-derived CHO Ags.
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