Abstract 5396: LPS mimotopes: A novel class of TLR4 agonist

Abstract

Abstract Adjuvant driven inflammation is crucial to mounting an antigen specific immune response and is initiated by the activation of toll like receptor (TLR) proteins. Currently, aluminum based adjuvants remain the only FDA approved adjuvants for vaccines. In an effort to develop a new class of adjuvants, TLR agonists, would be natural candidates. LPS, a major structural component of gram negative bacteria cell walls, has been well studied for its property to induce the systemic inflammation observed in septic shock. The objective of the present study was to identify peptide mimics of LPS that could activate TLR-4 and induce an inflammatory condition congenial to an adaptive immune response and in contrast to LPS not induce septic shock. To this end we used phage display peptide library to identify and isolate LPS peptide mimics. The activity of LPS-TLR-4 interaction was assessed by NF-κB translocation analyses in HEK-BLUE™-4 cells, a cell culture model that expresses only TLR-4. NF-κB nuclear translocation and inflammatory cytokine production was assayed by using the murine macrophage cell line RAW264.7. Increasing the NF-κB nuclear translocation is reflected by IκB-degradation within the cytoplasm. As expected, the concentration of cytoplasmic NF-κB was also decreased, which further attests to the shuttling of NF-κB within the nucleus. Similar results pertaining to increased nuclear localization of NF-κB with simultaneous decrease of cytoplasmic IκB-α and NF-κB were observed with HEK-BLUE™-4 cells. Thus, the results observed in this study suggest that the LPS peptide mimics identified act as adjuvants by virtue of their interaction with TLR-4 and thus serve as novel candidates to be considered as a new class of TLR-4 agonist adjuvants. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5396. doi:10.1158/1538-7445.AM2011-5396