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Combination Adjuvants to Activate Human Dendritic Cell Subsets and B Cells
Clinical Trial ( IRB ) #: 16-164J-3
Title: Combination Adjuvants to Activate Human Dendritic Cell Subsets and B Cells
Principal Investigator: Dr. George Kuchel
Description: Vaccination is the most effective method for preventing infectious diseases. Many current vaccines are "inactivated" or "subunit" vaccines composed of purified or recombinant pathogen components to which an adjuvant is often added to increase the magnitude of antibody responses. However, subunit vaccines formulated with current FDA-approved adjuvants do not sufficiently boost immunity in some populations, particularly immunocompromised and elderly subjects. Numerous adjuvants have been discovered in recent years and show enhanced immunogenicity as single agents; however, little is known about the activity of their combination, their safety, their efficacy and their mechanisms of action. Responses to vaccination and adjuvants involve dendritic cells (DCs), which capture and present vaccine antigens thereby facilitating the differentiation of follicular helper T cells (Tfh) and B cells and subsequent humoral immunity Therefore, we will examine the molecular mechanisms and functional outputs of human DC subsets exposed to combination adjuvants ex vivo and in vivo (humanized mouse models). The focus on human DCs is essential given the substantial differences in innate immune receptor distribution and function between the mouse and the human. Healthy human subjects will be recruited to provide blood, waste skin or blood and waste skin from planned plastic surgical procedures along with skin specimens acquired from the UConn Health Research Biorepository to provide the human dendritic cells required for this research. Our goal is to select a combination adjuvant using functional assays, followed by in-depth investigation of molecular pathways accounting for enhanced immunogenicity. Our Specific Aims are built towards this goal. Specific Aims Aim 1: We will screen adjuvant combinations by assessing the capacity of adjuvant-activated human DC subsets to skew the differentiation of naive CD4+T cells into Tfh cells that secrete IL-21 and induce B cells to produce IgG and IgA antibodies. Aim 2: Promising combinations will be further studied in DCs using validated, sensitive and high-throughput transcriptomic epigenomic, proteomic and metabolomic methods, and by functional knockdown in vitro, to determine the underlying molecular pathways of adjuvant efficacy. Aim 3: We will then validate the identified molecular pathways through functional knockdown studies in vivo using humanized mice carrying a functionally reconstituted human immune system, which will also enable the examination of possible side effects This research program will leverage cutting-edge epigenetic (ATAC-seq), transcriptional, gene editing (CRISPR/Cas9) and metabolomic technologies; innovative humanized mouse models; a powerful computational and bioinformatics infrastructure at The Jackson Laboratory. Our deliverable is a combination adjuvant for enhanced humoral immunity and molecular pathways that are essential for its efficacy.
  Infectious Disease/Immune System (HIV/AIDS, Hepatitis)
Eligibility Criteria: Check with study contact
How to Contact: Lisa Kenyon-Pesce. Telephone: (860) 679-2305. Email: Kenyon-Pesce@uchc.edu