The Role of IL-10 in Regulation of Allergic Inflammation

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

Persistent eosinophilic inflammation is a principal characteristic of asthma, with important physiologic consequences. The intensity of the allergic inflammatory response does not differentiate allergic subjects, with and without asthma. Inflammation in asthma, however, is prolonged. Therefore, signals that switch-off inflammation may be crucial in promoting resolution of allergic inflammation. One putative switch-off factor is the cytokine interleukin-10 [IL-10], which induces eosinophil apoptosis, and suppresses TNF-" production. We have shown that lung expression of IL-10 in allergic asthmatics is virtually absent, in contrast to allergic non- asthmatics, in whom IL-10 levels are increased compared to healthy volunteers. We propose the following Central Hypothesis: IL-10 is a critically important to the resolution of allergic inflammation. A genetically-engineered IL-10 deficient "knockout" (IL-10i) mouse strain offers the opportunity to perform critical mechanistic tests of the role of IL-10 in the allergic inflammatory process. Accordingly, the Specific Aims are to establish: 1) the pattern and timing of development and resolution of inflammation and physiologic changes following allergen sensitization and challenge, and the degree and characteristics of allergic sensitization; 2) the mechanisms which underlie the observations of Aim 1; 3) the specificity of IL-10 in mediating the anti-inflammatory response after allergen challenge, and 4) the role of TNF-" in enabling the inflammatory response to allergen challenge. These cytokines have direct and demonstrable relevance to human asthma. IL-10i mice and control strain animals will undergo allergen sensitization and challenge; allergen specific IgE, differentiation of Th1-Th2 lymphocytes, allergen-driven inflammation, and airway hyperresponsiveness will be key outcome variables. In addition, functional knock-out animals will be produced by administration of neutralizing IL-10 antibody, and will undergo similar studies. This information will provide direct evidence of the role of IL-10 in regulating allergic inflammation, and will help to ascertain the relationships between inflammation and airway hyperresponsiveness.