Grant: CIHR Fellowship

Endotoxin from microbes has been implicated in the pathogenesis of severe life-threatening infections and septic shock through the activation of innate receptors (Toll-like receptors, TLR). Lipopolysaccharide (LPS) is well known to activate the innate immune system through TLR4, and inhibitors of TLR are in clinical trial for treatment of sepsis. In contrast, stimulants of the TLR are being used to activate specific immune responses to improve vaccines. A new synthetic TLR4 agonist gluco-pyranosylphospho-lipid A (GLA) is been developed as a potential adjuvant. Therefore in one situation TLR4 activation is detrimental while in the other TLR4 stimulation is desired. Clearly large knowledge gaps exist in our understanding of TLR4 mediated inflammation and immunity and these gaps need resolution as we attempt to manipulate the human immune system. Dendritic cells (DC) are highly specialized immune cells that express multiple Toll-receptors including TLR4, and act as a bridge between the innate and adaptive systems. Depending on the initial inflammatory stimuli DC directly influence the type of T cell response, which can either positively or negatively impact the host. Monocytes and monocyte subsets are also important immune cells that are activated through TLR4. They are intimately related to DC, but many unresolved issues remain concerning the relationship and contribution of each of these cells to inflammation and immunity. We are interested in determining how molecules that stimulate the innate inflammatory immune response through TLR4 (LPS, and GLA) alter the function of DC subsets, monocytes and monocyte subsets in mice and humans. We will determine the effects of both GLA and LPS on these cells in mice and use this information to provide scientific direction to aid a phase I randomized human trial evaluating the immunogenicity and safety of the TLR4 agonist GLA. Key concepts of human immunology will be gained for both vaccine science and host defence.