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Amphiphilic polyanhydride-based recombinant MUC4?-nanovaccine activates dendritic cells.

ABSTRACT: Mucin 4 (MUC4) is a high molecular weight glycoprotein that is differentially overexpressed in pancreatic cancer (PC), functionally contributes to disease progression, and correlates with poor survival. Further, due to its aberrant glycosylation and extensive splicing, MUC4 is a potential target for cancer immunotherapy. Our previous studies have demonstrated the utility of amphiphilic polyanhydride nanoparticles as a useful platform for the development of protein-based prophylactic and therapeutic vaccines. In the present study, we encapsulated purified recombinant human MUC4-beta (MUC4?) protein in polyanhydride (20:80 CPTEG:CPH) nanoparticles (MUC4?-nanovaccine) and evaluated its ability to activate dendritic cells and induce adaptive immunity. Immature dendritic cells when pulsed with MUC4?-nanovaccine exhibited significant increase in the surface expressions of MHC I and MHC II and costimulatory molecules (CD80 and CD86), as well as, secretion of pro-inflammatory cytokines (IFN-?, IL-6, and IL-12) as compared to cells exposed to MUC4? alone or MUC4? mixed with blank nanoparticles (MUC4?+NP). Following immunization, as compared to the other formulations, MUC4?-nanovaccine elicited higher IgG2b to IgG1 ratio of anti-MUC4?-antibodies suggesting a predominantly Th1-like class switching. Thus, our findings demonstrate MUC4?-nanovaccine as a novel platform for PC immunotherapy.

SUBMITTER: Banerjee K

PROVIDER: S-EPMC6584211 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Amphiphilic polyanhydride-based recombinant MUC4β-nanovaccine activates dendritic cells.

Banerjee Kasturi K Gautam Shailendra K SK Kshirsagar Prakash P Ross Kathleen A KA Spagnol Gaelle G Sorgen Paul P Wannemuehler Michael J MJ Narasimhan Balaji B Solheim Joyce C JC Kumar Sushil S Batra Surinder K SK Jain Maneesh M

Genes & cancer 20190501 3-4

Mucin 4 (MUC4) is a high molecular weight glycoprotein that is differentially overexpressed in pancreatic cancer (PC), functionally contributes to disease progression, and correlates with poor survival. Further, due to its aberrant glycosylation and extensive splicing, MUC4 is a potential target for cancer immunotherapy. Our previous studies have demonstrated the utility of amphiphilic polyanhydride nanoparticles as a useful platform for the development of protein-based prophylactic and therapeu ...[more]

PMID: 31258832

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Project description:Purpose:Salmonellosis is a severe economic threat in poultry and a public health concern. Currently available vaccines are ineffective, and thus, developing effective oral Salmonella vaccine is warranted. Especially, a potent oral vaccine such as the mucoadhesive polyanhydride nanoparticle (PNP) protects the vaccine cargo and delivers to intestinal immune sites to elicit robust mucosal immunity and mitigate Salmonella colonization and shedding. Materials and methods:We designed a Salmonella subunit vaccine using PNP containing immunogenic Salmonella outer membrane proteins (OMPs) and flagellar (F) protein-entrapped and surface F-protein-coated PNPs (OMPs-F-PNPs) using a solvent displacement method. Using high-throughput techniques, we characterized the OMPs-F-PNPs physicochemical properties and analyzed its efficacy in layer birds vaccinated orally. Results:The candidate vaccine was resistant in acidic microenvironment and had ideal physicochemical properties for oral delivery in terms of particle size, charge, morphology, biocompatibility, and pH stability. In vitro, in vivo, and ex vivo studies showed that F-protein surface-anchored nanoparticles were better targeted to chicken immune cells in peripheral blood and splenocytes and intestinal Peyer's patch sites. In layer chickens inoculated orally with OMPs-F-PNPs, substantially higher OMPs-specific IgG response and secretion of Th1 cytokine IFN-? in the serum, enhanced CD8+/CD4+ cell ratio in spleen, and increased OMPs-specific lymphocyte proliferation were observed. OMPs-F-PNPs vaccination also upregulated the expression of toll-like receptor (TLR)-2 and -4, TGF-?, and IL-4 cytokines' genes in chicken cecal tonsils (lymphoid tissues). Importantly, OMPs-F-PNPs vaccine cleared Salmonella cecal colonization in 33% of vaccinated birds. Conclusion:This pilot in vivo study demonstrated the targeted delivery of OMPs-F-PNPs to ileum mucosal immune sites of chickens and induced specific immune response to mitigate Salmonella colonization in intestines.

Dataset Information

Amphiphilic polyanhydride-based recombinant MUC4?-nanovaccine activates dendritic cells.

Publications

Amphiphilic polyanhydride-based recombinant MUC4β-nanovaccine activates dendritic cells.

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