Interstitial pneumonitis in bone marrow transplant recipients is associated with local production of TH2-type cytokines and lack of T cell-mediated cytotoxicity

Background. Interstitial pneumonitis, especially associated with cytomegalovirus (CMV) infection, is a serious complication after bone marrow transplantation (BMT), with a high fatality rate despite adequate antiviral treatment. The aim of this study was to elucidate the local immunopathogenesis of interstitial pneumonitis caused by CMV or other agents in BMT recipients. Methods. Cryopreserved lung tissue obtained from 12 patients with interstitial pneumonitis following BMT was analyzed for cytokine production at the single-cell level using a cytokine-specific monoclonal antibody and immunohistochemical technique. Cytokine production in individual cells was analyzed using monoclonal antibodies to 23 different human cytokines: interleukin (IL)-1 to IL-13, tumor necrosis factor (TNF)-alpha, TNF-beta, interferon-gamma (IFN gamma), granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and transforming growth factor (TGF)-beta 1 to 3. Results. Marrow transplant patients with interstitial pneumonia had increased numbers of infiltrating alveolar macrophages, CD3(+), CD4(+) T cells, and CD40(+) B cells and significantly increased numbers of IL-4-, IL-10-, IL-1-, TGF-beta 1-, TGF-beta 2-, and TGF-beta 3-producing cells than controls, IL-2-, IFN-gamma-, and TNF-beta-producing cells were undetectable in most patients with CMV pneumonitis (n=7), Neither perforin-positive CD8(+) T lymphocytes nor up-regulation of the apoptotic pathway was detected in lung tissue from patients with interstitial pneumonia, In contrast, extensive local production of IgA, IgG, and IgM was demonstrated in all patients, Intracellular and extensive extracellular deposition of CD68, the L-1 antigen synthesized in CD14(+) macrophages, was found. Conclusions. The cytokine profile suggested that Th1-type cytokine production was absent, whereas production of Th2-type cytokines was significantly upregulated, Interstitial pneumonitis in BMT recipients with fatal outcome (11/12 patients) was associated with dysregulation in the local cytokine network notable for a predominant Th2 immune response with minimal or absent T cell-mediated cytotoxicity.