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dc.contributor.advisorWhitney, Elizabethen_US
dc.contributor.advisorLevy, Oferen_US
dc.contributor.authorShaheen, Tanziaen_US
dc.date.accessioned2018-09-17T13:34:06Z
dc.date.available2018-09-17T13:34:06Z
dc.date.issued2018
dc.identifier.urihttps://hdl.handle.net/2144/31282
dc.description.abstractBACKGROUND: The human immune system is comprised of various cells that function to fight infection while also avoiding harmful inflammatory and autoimmune responses. The immune system consists of the innate and adaptive immune responses. While the adaptive immune response is involved in the late phase of infection and plays a role in generating classic T and B-cell based immunological memory, the innate immune response is the first line of defense and plays a role in early recognition of foreign substances and induction of an inflammatory response. Although the innate immune response is a natural and inborn response, it varies with age. Human newborns in particular are immunologically distinct due to their polarized T helper type 2 (Th2) cell response and increased anti-inflammatory cytokine production. While these adaptations protect the fetus from rejection by the mother, they lead to increased susceptibility of newborns to infection. While immunization is the most promising strategy to combat this increased susceptibility of newborns, the responses of newborns to different vaccines are impaired as a result of their functionally distinct immune system. For this reason, there have been efforts to develop and incorporate adjuvants into vaccines in order to enhance the immune response of newborns and young infants, who suffer the greatest burden of infectious diseases. OBJECTIVE: The objective of this thesis is to determine which compound(s) in a small molecule library (compound 037 family) that had been identified based on a high throughput TNF-α screen of human primary mononuclear cells activates immune cells and has the potential to act as effective vaccine adjuvants. METHODS: Human cord blood was collected from 7 healthy term newborns after Cesarean section and peripheral blood was collected from the arms of 15 healthy adult volunteers between the ages of 18 and 60. The blood was processed and the compounds of the small molecule library were tested via whole blood assays and enzyme-linked immunosorbent assays (ELISAs) to measure production of pro-inflammatory cytokines, specifically tumor necrosis factor (TNF) and interleukin-1β (IL-1β). The responses of the compounds were further characterized by measuring additional cytokines and chemokines via a 41-plex cytokine multiplex assay. RESULTS: It was determined that at the top two concentrations that were tested (3.7 μM and 11.0 μM), certain compounds of the 037 family induced TNF and IL-1β production comparable to that produced by R848, an already established adjuvant. The compounds with the most activity depended on which cytokine was being produced as well as the age group (newborn vs. adult). Results of the 41-plex cytokine multiplex showed that while there is no clear indication of which group of cytokines are produced after stimulation with these compounds, there was increased production of certain chemokines, especially in adults. CONCLUSIONS: The difference in activity of the compounds in the 037 family suggests that the functional groups might play a role in enhancing activity of certain compounds. The increased production of chemokines after stimulation with these compounds suggests that the compounds might activate pathways different from TLR7/8 but still results in an inflammatory response. More work needs to be done in order to identify the receptors and pathways that these compounds activate.en_US
dc.language.isoen_US
dc.subjectImmunologyen_US
dc.titleScreening lead small molecules for cytokine induction in a human whole blood assay informs candidate adjuvant selectionen_US
dc.typeThesis/Dissertationen_US
dc.date.updated2018-07-24T22:23:42Z
etd.degree.nameMaster of Scienceen_US
etd.degree.levelmastersen_US
etd.degree.disciplineMedical Sciencesen_US
etd.degree.grantorBoston Universityen_US


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