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Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1), which is a key enzyme in tryptophan metabolism expressed in some subsets of normal and neoplastic cells, participates in tumor-induced tolerance. However, the mechanisms involved are not clearly understood. A hypothesis suggests that IDO1 may be involved in proliferation and conversion of regulatory T cells (Tregs). In this study, we evaluated the levels of IDO1 and forkhead box P3 (FoxP3) in non-Hodgkin lymphoma (NHL) tissues and performed ex vivo experiments to investigate the role of IDO1 on T-cell tolerance in NHL. The results showed that expressions of IDO1 mRNA and protein were coincidentally higher in NHL tissues than in reactive hyperplasia of lymph node tissues. Up-regulation of IDO1 was correlated with later clinical phases, larger tumors and higher serum lactate dehydrogenase (LDH), and indicated a worse prognosis. FoxP3 mRNA and protein levels were markedly increased alongside elevated IDO1 levels. Co-culture of murine CD4 + CD25− T cells with A20 cells could initiate the conversion of CD4 + CD25+ T cells, which showed a suppressive function in the mixed lymphocyte reaction. Moreover, the potent inhibitor of IDO1, 1-methyl-l-tryptophan, attenuated the conversion of CD4 + CD25− T cells into CD4 + CD25+ FoxP3 + T cells. The results suggested that up-regulation of IDO1 in NHL tissues could induce local immune tolerance by favoring development and infiltration of FoxP3 + Tregs through the conversion of CD4 + CD25− T cells into CD4 + CD25+ FoxP3 + T cells in the tumor microenvironment. This could be a novel mechanism of NHL escape from immune control.
Potential conflict of interest:
Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
This study was partly supported by the National Natural Science Foundation (No. 81270598), Natural Science Foundation of Shandong Province (No. Y2007C053, No. 2009ZRB14176 and No. ZR2012HZ003), Technology Development Projects of Shandong Province (No. 2007GG10 and No. 2010GSF10250), Program of Shandong Medical Leading Talent and Taishan Scholar Foundation of Shandong Province.