Cross-talk Between GM-CSF and LPS/TLR4 in the Generation of MDSC-like Cells

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DESCRIPTION (provided by applicant): Although often thought of as a disease of childhood, allergic asthma is a chronic inflammatory condition of the lower airways that is frequently diagnosed later in life. Allergic asthma is promoted by repeated interactions between allergen(s) and the immune system and the nature of asthmatic disease combined with the deterioration of immune function in the elderly, results in increased diagnoses with age. Furthermore, symptoms are often worse in the aging population, resulting in fewer treatment options and poor response to current therapeutic interventions. Recent results from our laboratory suggest a connection between environmental exposure to endotoxin and the establishment of tolerance to allergens via the formation of myeloid-derived suppressor cells (MDSCs) in the lung following inhalation of bacterial endotoxin (lipopolysaccharide-LPS). This finding is a potential mechanism underlying the hygiene hypothesis, which was postulated in 1989, stating that exposure to pathogen-associated products, like endotoxin, may be protective against future allergic responses. This link between encounter with endotoxin and suppressor cell formation has huge implications for our understanding of pulmonary function. Importantly, we have been able to use these suppressor cells (MDSCs) therapeutically in a model of allergic inflammation. Because MDSCs can be generated in vitro by the combination of GM-CSF and LPS, there is great potential for therapeutic intervention on a patient-by-patient basis warranting further investigation of the generation and function of these cells. PUBLIC HEALTH RELEVANCE: The hygiene hypothesis, first postulated in 1989, suggests that exposure to bacterial-derived products like endotoxin very early in life, may contribute to tolerance to inhaled allergens. Recent work in our laboratory has found a potential mechanism underlying the hygiene hypothesis. A suppressive myeloid cell population has been observed in increased frequency in the lung after encounter with bacterial endotoxin. These myeloid cells are able to suppress allergic inflammation in a therapeutic manner warranting further investigation into the formation and function of this cell population.