COMBINATORIAL ADMINISTRATION OF SYNTHETIC TLR4 AGONIST INI-2002 AND NOVEL MINCLE AGONIST UM-1098 DELIVERED VIA A-SNPS RESULTS IN SYNERGISTIC IL-1β PRODUCTION IN HUMAN PRIMARY CELLS AND ENHANCES TH1 AND TH17 RESPONSES IN VIVO

Author

Grace D. Jones, University of Montana, MissoulaFollow
Asia Marie Stephanie Riel, University of Montana - Missoula
Alexander Riffey, University of Montana, Missoula
Cassandra Buhl, University of Montana, Missoula

Year of Award

2022

Document Type

Thesis

Degree Type

Master of Science (MS)

Degree Name

Cellular, Molecular and Microbial Biology

Other Degree Name/Area of Focus

Immunology

Department or School/College

Division of Biological Sciences

Committee Chair

Jay T. Evans

Commitee Members

Andrij Holian, Erica Woodahl, Mike Minnick, Scott Wetzel

Keywords

Vaccine, Tuberculosis, Adjuvant, Toll-like Receptor 4, Macrophage Inducible C-Type Lectin Receptor, M72

Subject Categories

Immunoprophylaxis and Therapy

Abstract

Tuberculosis (TB) kills more people each year than any infectious disease worldwide with recent exception of SARS-CoV-2. Though the Bacille Calmette Guerin (BCG) vaccine confers protection against severe extrapulmonary forms of TB, there is no licensed vaccine for the prevention of pulmonary tuberculosis. The strongest correlate of protection against pulmonary tuberculosis is Th1/Th17 biased cell mediated immunity. Several candidates for TB vaccine adjuvants have shown Th1/Th17 polarizing capacity in clinical trials including Mincle agonist trehalose dibehenate (TDB) and TLR4 agonist monophosphoryl lipid A (MPL). Furthermore, combinatorial administration of MPL and TDB formulated in dimethyldioctadecylammonium (DDA) liposomes has been previously reported to produce synergistic Th1/Th17 immunity. Though this novel combination offered proof of concept for TLR4 and Mincle combination vaccines, use of shorter chain length agonists would afford increased stability and decreased toxicity while maintaining or improving efficacy. Coating of Mincle ligands to silica nanoparticles (SNPs) provides an additional opportunity to form multiple ligand-receptor interactions for increased signaling as previously characterized in Dectin-1. Herein, we characterize several molar ratios of synthetic MPL mimetic INI-2002 and novel TDB derivative UM-1098 delivered via A-SNPs, reporting synergistic IL-1β production in human peripheral blood mononuclear cells and an increased percentage of CD4+ T cells producing Th1/17 cytokines including TNF- α, IL-17, and IFN-γ following combination vaccination against recombinant TB antigen M72.

Recommended Citation

Jones, Grace D.; Riel, Asia Marie Stephanie; Riffey, Alexander; and Buhl, Cassandra, "COMBINATORIAL ADMINISTRATION OF SYNTHETIC TLR4 AGONIST INI-2002 AND NOVEL MINCLE AGONIST UM-1098 DELIVERED VIA A-SNPS RESULTS IN SYNERGISTIC IL-1β PRODUCTION IN HUMAN PRIMARY CELLS AND ENHANCES TH1 AND TH17 RESPONSES IN VIVO" (2022). Graduate Student Theses, Dissertations, & Professional Papers. 11994.
https://scholarworks.umt.edu/etd/11994