ABSTRACT
The lung is a prototypic organ that was evolved to reduce immunopathology during the immune response to potentially hazardous endogenous and exogenous antigens. In this study, we show that donor CD4+ T cells transiently induced expression of indoleamine 2,3-dioxygenase (IDO) in lung parenchyma in an IFN-γ-dependent manner early after allogeneic hematopoietic stem cell transplantation (HSCT). Abrogation of host IDO expression by deletion of the IDO gene or the IFN-γ gene in donor T cells or by FK506 treatment resulted in acute lethal pulmonary inflammation known as idiopathic pneumonia syndrome (IPS). Interestingly, IL-6 strongly induced IDO expression in an IFN-γ-independent manner when deacetylation of STAT3 was inhibited. Accordingly, a histone deacetylase inhibitor (HDACi) could reduce IPS in the state where IFN-γ expression was suppressed by FK506. Finally, l-kynurenine produced by lung epithelial cells and alveolar macrophages during IPS progression suppresses the inflammatory activities of lung epithelial cells and CD4+ T cells through the aryl hydrocarbon receptor pathway. Taken together, our results reveal that IDO is a critical regulator of acute pulmonary inflammation and that regulation of IDO expression by HDACi may be a therapeutic approach for IPS after HSCT.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/metabolism , Hematopoietic Stem Cell Transplantation , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Pneumonia/metabolism , Receptors, Aryl Hydrocarbon/metabolism , Animals , Basic Helix-Loop-Helix Transcription Factors/immunology , Female , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation/mortality , Histone Deacetylase Inhibitors/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics , Interferon-gamma/genetics , Interferon-gamma/metabolism , Interferon-gamma/pharmacology , Kynurenine/metabolism , Lung/immunology , Lung/metabolism , Lung/pathology , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Mutant Strains , Pneumonia/drug therapy , Receptors, Aryl Hydrocarbon/immunology , Receptors, Interferon/genetics , Receptors, Interferon/metabolism , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , T-Lymphocytes, Regulatory/immunology , Tacrolimus/pharmacology , Interferon gamma ReceptorABSTRACT
Our previous study demonstrated that G-CSF treatment increased the expression of TLR2 in donor grafts; this contributed to rapid engraftment after allogeneic hematopoietic stem cell transplantation (HSCT) in mice. In the current study, we investigated the effects of upregulated TLR2 expression in G-CSF-mobilized donor grafts on acute graft-versus-host disease (GVHD). We found that TLR2 was highly expressed on myeloid cell populations but not T and B cells from the spleens of G-CSF-treated donor mice. After transplantation, the mortality and disease severity in recipients were not significantly different between G-CSF-treated TLR2-/- and wt donor grafts. Although endogenous TLR2 ligand was detected in the serum of both recipients, T cells from TLR2-/- and wt donors have the same ability regarding alloreactivity. Moreover, the blockade of TLR2 signaling in recipients by administering anti-TLR2 blocking antibody after BMT did not lead to a significant difference in acute GVHD compared with control IgG treatment. However, the hematopoietic ability of G-CSF-mobilized lin−c-kit+ HSCs from TLR2-/- donor grafts was lower than that from wt donor grafts. Our results demonstrate that upregulated TLR2 expression in G-CSF-mobilized donor grafts has no effect on acute GVHD, suggesting that TLR2 is a valuable target for increasing HSCT efficiency in order to enhance engraftment without exacerbating acute GVHD.
