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Interleukin-17–mediated Immunopathogenesis in Experimental Hypersensitivity Pneumonitis

¹ Department of Pathology, University of Michigan Medical School; ² Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan

Correspondence and requests for reprints should be addressed to Cory M. Hogaboam, Ph.D., Immunology Program, Department of Pathology, University of Michigan Medical School, Room 4057, BSRB 109 Zina Pitcher Place, Ann Arbor, MI, 48109-0602. E-mail: Hogaboam{at}med.umich.edu

Rationale: T cells play a critical role in the development of Saccharopolyspora rectivirgula-induced hypersensitivity pneumonitis (HP) but little is known about the role of IL-17A in this disease.

Objectives: We examined the role of IL-17A in a murine model of S. rectivirgula antigen (SR-Ag)-induced HP.

Methods: Experimental HP was induced by oropharyngeal instillation of SR-Ag in wild-type and IL-17 gene-deficient mice.

Measurements and Main Results: SR-Ag–induced murine HP was characterized by increased transcript levels of IFN- and IL-12p35 compared with saline-treated control mice. Furthermore, mice with HP showed increased IL-17 in lung homogenates, bronchoalveolar lavage fluid, and ex-vivo lung cultures compared with control mice. Flow cytometric analysis of SR-Ag–challenged lungs revealed increased Th17 and CD11c⁺ cells. The role of IL-17 in SR-induced HP was examined in IL-17 deficient (IL17^–/–) and in wild-type (IL-17^+/+) mice immunodepleted of IL-17. Histological examination of IL17^–/– mice challenged with SR-Ag revealed reduced inflammatory cell infiltration, decreased CD11c⁺ cells, and reduced levels of inflammatory mediators such as IL-12p70, CCL3, and CXCL9 compared with similarly treated IL17^+/+ mice. Anti–IL-17 antibody treatment of IL-17^+/+ mice with HP resulted in reduced inflammation and a lower percentage of CD11c⁺ cells compared with IgG-treated IL-17^+/+ mice with HP.

Conclusions: SR-Ag–induced IL-17 plays a pivotal role in the immunopathology of HP and targeting IL-17 is an attractive therapeutic option for this disease.

Key Words: Th17 • CD11c⁺ cells • IL-17 knock-out mice • immunoneutralization of IL-17

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Th1 cells play a pivotal role in the development of mouse models of hypersensitivity pneumonitis. Recent microarray analysis of biopsies from patients with hypersensitivity pneumonitis shows up-regulation of Th17-associated genes. What This Study Adds to the Field Genetic deletion and immunoneutralization of IL-17 protects against the development of mouse hypersensitivity pneumonitis.

 

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