T cell proliferation is blocked by indoleamine 2,3-dioxygenase

Frumento, Guido; Rotondo, Rita; Tonetti, Michela; Ferrara, Giovanni Battista

doi:10.1016/s0041-1345(00)02078-9

Cited by 39 publications

(28 citation statements)

References 5 publications

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“…Activation of IDO thus causes tryptophan depletion, resulting in reduced lymphocyte proliferation [28]. In contrast to previous findings in human MSCs stimulated by IFN-γ [29], we did not detect significant IDO activity in MSC-suppressed mixed lymphocyte reactions, even in the presence of IFN-γ (not shown). Thus, the mechanism of MSC-mediated suppression remains controversial.…”

Section: Discussioncontrasting

confidence: 99%

Mesenchymal stem cells protect NOD mice from diabetes by inducing regulatory T cells

et al. 2009

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Aims/hypothesis Displaying immunomodulatory capacities, mesenchymal stem cells (MSCs) are considered as beneficial agents for autoimmune diseases. The aim of this study was to examine the ability of MSCs to prevent autoimmune diabetes in the NOD mouse model. Methods Prevention of spontaneous insulitis or of diabetes was evaluated after a single i.v. injection of MSCs in 4-week-old female NOD mice, or following the coinjection of MSCs and diabetogenic T cells in irradiated male NOD recipients, respectively. The frequency of CD4 + FOXP3 + cells and Foxp3 mRNA levels in the spleen of male NOD recipients were also quantified. In vivo cell homing was assessed by monitoring 5,6-carboxyfluorescein diacetate succinimidyl ester (CFSE)-labelled T cells or MSCs. In vitro, cell proliferation and cytokine production were assessed by adding graded doses of irradiated MSCs to insulin B9-23 peptide-specific T cell lines in the presence of irradiated splenocytes pulsed with the peptide. Results MSCs reduced the capacity of diabetogenic T cells to infiltrate pancreatic islets and to transfer diabetes. This protective effect was not associated with the modification of diabetogenic T cell homing, but correlated with a preferential migration of MSCs to pancreatic lymph nodes. While injection of diabetogenic T cells resulted in a decrease in levels of FOXP3 + regulatory T cells, this decrease was inhibited by MSC co-transfer. Moreover, MSCs were able to suppress both allogeneic and insulin-specific proliferative responses in vitro. This suppressive effect was associated with the induction of IL10-secreting FOXP3 + T cells. Conclusions/interpretation MSCs prevent autoimmune beta cell destruction and subsequent diabetes by inducing regulatory T cells. MSCs may thus offer a novel cell-based approach for the prevention of autoimmune diabetes and for islet cell transplantation.

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Section: Discussioncontrasting

confidence: 99%

Mesenchymal stem cells protect NOD mice from diabetes by inducing regulatory T cells

et al. 2009

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“…Lee and colleagues (14) found that IDO-positive cells were frequently host immune cells but not metastatic tumor cells. Munn and colleagues (15) reported that the IDO-positive cells in TDLNs seemed the host dendritic cells, and the IDO-positive dendritic cells proved to efficiently suppress the proliferation and the function of the activated T cells (17,18). Using the spontaneous tumorigenic mouse model, we also observed that IDO was expressed in TDLNs and spleen but never tumor tissues in MT/ret 304/B6 mice immunized with or without the Ret/ CpG vaccine.…”

Section: Discussionsupporting

confidence: 50%

“…The IDO pathway has been cited as one important reason for immunologic tolerance to tumors (13)(14)(15)(16)(17)(18). In most tumor-bearing hosts, a tolerant microenvironment is constructed through expression of IDO in tumors and host immune cells or only in immune cells to reject the host immune system.…”

Section: Discussionmentioning

confidence: 99%

“…Regulatory T cells can induce a high level of functional IDO in mouse dendritic cells (16). By depleting tryptophan and producing activated metabolites, IDO inhibits the proliferation and activation of antigen-specific T lymphocytes and conducts tolerance (17,18). Moreover, IDO expression in the antigenpresenting cells can be up-regulated by the cancer treatments themselves, such as chemotherapeutic drugs, tumor vaccines, and immunostimulants, including IFN-g, IFN-a, CpG oligodeoxynucleotides, 4-1BB ligation (19)(20)(21)(22)(23), etc.…”

Section: Introductionmentioning

confidence: 99%

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Prevention of Spontaneous Tumor Development in aretTransgenic Mouse Model by Ret Peptide Vaccination with Indoleamine 2,3-Dioxygenase Inhibitor 1-Methyl Tryptophan

Zeng

Cai

et al. 2009

Cancer Research

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The present study investigated an immunotherapeutic strategy for rearranged during transfection proto-oncogene (ret)-associated carcinomas in a transgenic MT/ret 304/B6 mouse model in which spontaneous tumors develop due to overexpression of the ret gene. A Ret peptide vaccine comprising an extracellular fragment of Ret protein and Th1-polarized immunoregulator CpG oligonucleotide (1826) induced strong and specific cellular and humoral immune responses in wildtype C57BL/6 mice, showing that the Ret peptide has a strong immunogenic potential as part of an antitumor vaccine. In MT/ret 304/B6 mice, however, the vaccine was only modestly effective as an inducer of the humoral immune response, and it failed to elicit a T-cell response. An immunohistochemical analysis revealed marked indoleamine 2,3-dioxygenase expression after immunization with Ret peptide vaccine in the lymph nodes and spleens of MT/ret 304/B6 mice. The systemic administration of the potent inhibitor of indoleamine 2,3-dioxygenase 1-methyl tryptophan (1MT) along with Ret vaccine produced a significant increase in tumor-specific cytotoxic activity. A delay in spontaneous tumor development was also observed in the MT/ret 304/B6 mice to which the Ret vaccine and 1MT were administered. These results indicate that an improved Ret vaccine composed of Ret peptide plus CpG oligonucleotide plus 1MT is a potential therapeutic strategy for treatment of ret-associated carcinomas.

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“…Expression of the tryptophan-catabolizing enzyme indoleamine 2,3 dioxygenase (IDO) in human and murine cells inhibits Agspecific T cell proliferation in vitro and suppresses T cell responses to fetal alloantigens during murine pregnancy (7)(8)(9)(10). Correlations between IDO expression and immunoregulatory outcomes have been confirmed in several experimental systems (11)(12)(13)(14)(15). Recently, Grohmann et al (16) reported that the synthetic immunomodulatory reagent CTLA4-Ig induces IDO expression in CD11c ϩ DCs from murine spleen.…”

Section: Inor Subsets Of Murine Cd11cmentioning

confidence: 99%

Cutting Edge: Induced Indoleamine 2,3 Dioxygenase Expression in Dendritic Cell Subsets Suppresses T Cell Clonal Expansion

Mellor¹,

Baban²,

Chandler³

et al. 2003

The Journal of Immunology

428

324

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In mice, immunoregulatory APCs express the dendritic cell (DC) marker CD11c, and one or more distinctive markers (CD8α, B220, DX5). In this study, we show that expression of the tryptophan-degrading enzyme indoleamine 2,3 dioxygenase (IDO) is selectively induced in specific splenic DC subsets when mice were exposed to the synthetic immunomodulatory reagent CTLA4-Ig. CTLA4-Ig did not induce IDO expression in macrophages or lymphoid cells. Induction of IDO completely blocked clonal expansion of T cells from TCR transgenic mice following adoptive transfer, whereas CTLA4-Ig treatment did not block T cell clonal expansion in IDO-deficient recipients. Thus, IDO expression is an inducible feature of specific subsets of DCs, and provides a potential mechanistic explanation for their T cell regulatory properties.

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T cell proliferation is blocked by indoleamine 2,3-dioxygenase

Cited by 39 publications

References 5 publications

Mesenchymal stem cells protect NOD mice from diabetes by inducing regulatory T cells

Mesenchymal stem cells protect NOD mice from diabetes by inducing regulatory T cells

Prevention of Spontaneous Tumor Development in aretTransgenic Mouse Model by Ret Peptide Vaccination with Indoleamine 2,3-Dioxygenase Inhibitor 1-Methyl Tryptophan

Cutting Edge: Induced Indoleamine 2,3 Dioxygenase Expression in Dendritic Cell Subsets Suppresses T Cell Clonal Expansion

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