Myeloid regulatory cells in allergic airway inflammation

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DESCRIPTION (provided by applicant): Hypothesis: Myeloid derived regulatory cells (MDRC), recruited to the lung during allergic airway inflammatory responses such as asthma, help to control the level of tissue inflammation by regulating the bioavailability of reactive free radicals, including nitric oxide (NO) and superoxide (02-). Specific Aims: (1) To test the hypothesis that myeloid subpopulations recruited to the lung of sensitized mice following antigen challenge generate and regulate the critical balance of reactive free radicals during allergic airway inflammation (2) Determine whether MDRC attenuate the asthmatic inflammatory response by mechanisms using reactive free radical species in a mouse model. Experimental Approach: C57BL/6, INOS-/- or B6 (Cg)-Ncf1m1 J/J mice will be sensitized intraperitoneally and challenged with the intranasal antigen, ovalbumin (OVA). Bronchoalveolar lavage (BAL) fluid and lung tissue will be examined for (1) dynamics of recruitment of MDRC (2) function of MDRC including phagocytic ability, and generation of cytokines and free radical species by MDRC. In addition, we will investigate (3) whether MDRC mediate suppression of T cell proliferation in vitro via iNOS, Arginase or NADPH oxidase pathways (4) whether MDRC mediate suppression of T cell proliferation following adoptive transfer in vivo and the role of NO and 02- in this effect, and (5) whether the adoptively transferred MDRC modulate airway hyper-responsiveness in a model of airway inflammation. Rationale: During allergic airway inflammatory responses, innate cells are recruited to the lung prior to adaptive immune cells. We present preliminary data to show (1) that two subsets of MDRC which generate O2- and NO are recruited to the lungs, and (2) MDRC suppress T cell proliferation via mechanisms that depend on free radicals, suggesting the potential for these cells to attenuate inflammation in vivo. Relevance to Public Health and the NHLBI Mission: The proposed studies will test directly the potential of MDRC to suppress asthma disease severity, potentially identifying novel targets for anti-asthmatic therapy.