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

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

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.