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Published ahead of print on May 29, 2008, doi:10.1164/rccm.200711-1648OC

Am. J. Respir. Crit. Care Med., Volume 178, Number 4, August 2008, 379-388

A more recent version of this article appeared on August 15, 2008
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Submitted on November 7, 2007
Accepted on May 29, 2008

Interferon {gamma} Regulates Idiopathic Pneumonia Syndrome, A Th17+CD4+ T-cell-mediated GvH Disease

Nora Mauermann1, Julia Burian1, Christophe von Garnier1, Stefan Dirnhofer2, Davide Germano1, Christine Schuett3, Michael Tamm4, Roland Bingisser5, Urs Eriksson1, and Lukas Hunziker1*

1 Experimental Critical Care Medicine, Departments of Research and Internal Medicine, University Hospital, Basel, Switzerland, 2 Department of Pathology, University Hospital, Basel, Switzerland, 3 Institut for Immunology and Transfusionsmedicine, Ernst-Moritz-Arndt-University, Greifswald, Germany, 4 Department of Respiratory Medicine, University Hospital, Basel, Switzerland, 5 Emergency Department, University Hospital, Basel, Switzerland

* To whom correspondence should be addressed. E-mail: lhunziker{at}uhbs.ch.

Rationale: Pulmonary complications of hematopoietic stem cell transplantation include infections and graft-versus-host diseases, such as idiopathic pneumonia syndrome (IPS). Conflicting data exist regarding the role of the interferon-gamma-producing Th1 CD4+ T-cell subset and IL-17A in IPS. Objectives: To determine the role of interferon-gamma (IFN-{gamma}) and IL-17A in the establishment of pulmonary graft-versus-host disease. Methods: A semi-allogeneic model based on C57BL/6 x BALB/c as recipients with transplantation of BALB/c RAG2-/- bone marrow and transfer of different genetic knockout T cells (T-bet-/-, IFN-{gamma}-/-, IFN-{gamma}R-/-) on a BALB/c background. Lung tissue was examined for parenchymal changes and infiltrating cells by histology and FACS analysis. Main results: After transfer of semi-allogeneic bone marrow together with donor CD4+ T cells lacking IFN-{gamma} or T-bet-a T-box transcription factor controlling Th1 commitment- we found severe inflammation in the lungs, but no enhancement in other organs. In contrast, wild-type donor CD4+ T cells mediated minimal inflammation only, and donor CD8++ T cells were not required for IPS development. Mechanistically, the absence of IFN-{gamma} or IFN-{gamma} signaling in pulmonary parenchymal cells promoted expansion of IL-17A producing CD4+ T cells and local IL-17A release. In vivo depletion of IL-17A reduced disease severity. Conclusions: One mechanism of IFN-{gamma} protection against IPS is negative regulation of the expansion of pathogenic IL-17A-producing CD4+ T cells through interaction with the IFN-{gamma} receptor on the pulmonary parenchymal cell population.
Key words: idiopathic pneumonia syndrome, graft versus host disease, CD4 T cells, IL-17, antigen presenting cells




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