PGI2 inhibition of pulmonary innate allergic immune responses

Veterans Health Administration, Decatur PA

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Abstract

DESCRIPTION (provided by applicant): Allergic airway inflammation is a hallmark of asthma, one of the most common chronic diseases in the United States. While the contribution of the adaptive immune response, particularly the CD4+ Th2 cell, to the development of allergen-induced airway inflammation has been well described, the contribution of the innate immune response to the allergic phenotype is not clearly defined. The Group 2 innate lymphoid cell (ILC2) is a recently described lineage negative (Lin-) cell type that is present in humans and mice. ILC2s are far more potent producers of IL-5 and IL-13 on a per cell basis than CD4+ Th2 cells, and therefore may be critical to both the genesis and amplification of allergic inflammatory responses. So far, there are no known inhibitors of ILC2 cytokine secretion that are approved by the FDA for use in human diseases; however, our in vivo and in vitro preliminary data strongly suggests that prostaglandin (PG) I2 negatively regulates ILC2 function. Using a model of airway challenge with an extract of Alternaria alternata, a fungal aeroallergen that has been associated with severe asthma excaerbations, we found that mice deficient in the PGI2 receptor IP had a significant increase in lung IL-13 protein expression 6 hours after challenge, a time at which innate, and not adaptive, immunity predominates. Our in vitro preliminary data reveals that the PGI2 analog cicaprost significantly inhibited IL-5 and IL-13 protein expression from ILC2 purified from mouse bone marrow. The long term objective of this application is to define the role of PGI2 in ILC2 function in an allergen challenge model in mice and also in human ILC2 cells purified from peripheral blood. In aim 1, we hypothesize that endogenous PGI2 signaling inhibits lung ILC2 cytokine expression and cell number in vivo. Investigating the role of endogenous PGI2 is critical to understanding the effect of cyclooxygenase-inhibiting drugs, one of the most widely used classes of over-the-counter medications in the world, on the innate allergic immune response as these agents inhibit PGI2 production. In aim 2, we hypothesize that airway administration of an exogenous PGI2 analog inhibits lung ILC2 function and proliferation. Investigating the role of exogenous PGI2 is important to understand the potential effects of inhaled PGI2 or its analogs on the innate allergic immune response as such agents are FDA approved and currently used therapeutically for pulmonary hypertension, and therefore could be used to treat allergic respiratory diseases such as asthma. In aim 3, we will determine the effect of PGI2 on human ILC2 cytokine expression and proliferation. The proposed studies are paradigm shifting in that they may identify the first inhibitor of ILC2 and will advance the field by determining the molecular mechanism by which PGI2 regulates ILC2 function.