We previously demonstrated that interferon γ (IFN-γ) derived from donor T cells co-opts the indoleamine 2,3-dioxygenase 1 (IDO1) → aryl hydrocarbon receptor (AHR) axis to suppress idiopathic pneumonia syndrome (IPS). Here we report that the dysregulated expression of AP-1 family genes in Ahr−/− lung epithelial cells exacerbated IPS in allogeneic bone marrow transplantation settings. AHR repressed transcription of Jund by preventing STAT1 from binding to its promoter. As a consequence, decreased interleukin-6 impaired the differentiation of CD4+ T cells toward Th17 cells. IFN-γ– and IDO1-independent induction of Ahr expression indicated that the AHR agonist might be a better therapeutic target for IPS than the IDO1 activator. We developed a novel synthetic AHR agonist (referred to here as PB502) that potently inhibits Jund expression. PB502 was highly effective at inducing AHR activation and ameliorating IPS. Notably, PB502 was by far superior to the endogenous AHR ligand, L-kynurenine, in promoting the differentiation of both mouse and human FoxP3+ regulatory CD4+ T cells. Our results suggest that the IDO1-AHR axis in lung epithelial cells is associated with IPS repression. A specific AHR agonist may exhibit therapeutic activity against inflammatory and autoimmune diseases by promoting regulatory T-cell differentiation.
A human monoclonal antibody can be a good method for tumor diagnosis and treatment. This study is aimed at the generation of human antibody fragments against urokinase plasminogen activator (uPA) known to be related to tumor metastasis using the naive human antibody phage display library. Three clones--A2, A8, and E4--were selected from 1 x 10(10) sized human naïve antibody phage library using BIAcore rescue and screen. Clone A8 was finally selected by flow cytometry against Hep3 and HT1080, uPA overexpressing tumor cell lines. A8 clone consisted of 324 bp lambda and 402 bp heavy chains. The affinity (K(D)) of purified A8 antibody fragments was 1.44 x 10(-8) M(-1). The antibody fragment was reacted with HT1080 in a dose-dependent manner but not reacted with LS513 normal fibroblast. In this study, uPA specific human monoclonal antibody fragment A8 was made with BIAcore selection. Selected A8 was bound specifically to uPA expressed on the tumor cell surface. Further study for the application of A8 antibody clones will be needed.
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