Effects of indoleamine 2,3-dioxygenase inhibitor in non-Hodgkin lymphoma model mice

Nobuhiko Nakamura, Takeshi Hara, Masahito Shimizu, Ryoko Mabuchi, Junji Nagano, Tomohiko Ohno, Takahiro Kochi, Masaya Kubota, Yohei Shirakami, Naoe Goto, Hiroyasu Ito, Kuniaki Saito, Takuji Tanaka, Hisataka Moriwaki, Hisashi Tsurumi

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Indoleamine 2,3-dioxygenase (IDO) catalyzes the rate-limiting step in the metabolism of tryptophan along the kynurenine pathway. In tumors, increased IDO activity inhibits proliferation and induces apoptosis of T cells and natural killer cells. We investigated the therapeutic potential of IDO inhibitor 1-methyl-d-tryptophan (d-1MT) with cyclophosphamide (CY) in a mouse model of lymphoma. To examine the effect of d-1MT, mice were killed on day 28. Serum concentrations of l-kynurenine and l-tryptophan were measured by high-performance liquid chromatography. Regulatory T cells (Tregs) were counted by flow cytometry, and mRNA expressions of IDO1, Foxp3, IFN-γ, and COX-2 were examined by quantitative real-time reverse transcription-polymerase chain reaction. d-1MT+CY combination treatment significantly inhibited tumor growth as compared to either treatment alone. There were no significant differences in the serum l-kynurenine/l-tryptophan ratio or the IDO1 expression level in the tumors among the treatment groups. The expression levels of IFN-γ and COX-2 mRNA in tumor-draining lymph nodes (TDLNs) were found to be significantly up-regulated in the CY and d-1MT+CY groups. The number of Tregs in TDLNs in the d-1MT+CY group was significantly lower than that in CY groups on day 17. These results suggest that d-1MT in combination with CY is an effective treatment for lymphoma in a mouse model.

Original languageEnglish
Pages (from-to)327-334
Number of pages8
JournalInternational Journal of Hematology
Volume102
Issue number3
DOIs
Publication statusPublished - 13-09-2015

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Indoleamine-Pyrrole 2,3,-Dioxygenase
Non-Hodgkin's Lymphoma
Cyclophosphamide
Kynurenine
Tryptophan
Neoplasms
Lymphoma
Lymph Nodes
Messenger RNA
Regulatory T-Lymphocytes
Serum
Natural Killer Cells
Reverse Transcription
Flow Cytometry
High Pressure Liquid Chromatography
Apoptosis
T-Lymphocytes
Polymerase Chain Reaction
Growth

All Science Journal Classification (ASJC) codes

  • Hematology

Cite this

Nakamura, N., Hara, T., Shimizu, M., Mabuchi, R., Nagano, J., Ohno, T., ... Tsurumi, H. (2015). Effects of indoleamine 2,3-dioxygenase inhibitor in non-Hodgkin lymphoma model mice. International Journal of Hematology, 102(3), 327-334. https://doi.org/10.1007/s12185-015-1835-8
Nakamura, Nobuhiko ; Hara, Takeshi ; Shimizu, Masahito ; Mabuchi, Ryoko ; Nagano, Junji ; Ohno, Tomohiko ; Kochi, Takahiro ; Kubota, Masaya ; Shirakami, Yohei ; Goto, Naoe ; Ito, Hiroyasu ; Saito, Kuniaki ; Tanaka, Takuji ; Moriwaki, Hisataka ; Tsurumi, Hisashi. / Effects of indoleamine 2,3-dioxygenase inhibitor in non-Hodgkin lymphoma model mice. In: International Journal of Hematology. 2015 ; Vol. 102, No. 3. pp. 327-334.
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Nakamura, N, Hara, T, Shimizu, M, Mabuchi, R, Nagano, J, Ohno, T, Kochi, T, Kubota, M, Shirakami, Y, Goto, N, Ito, H, Saito, K, Tanaka, T, Moriwaki, H & Tsurumi, H 2015, 'Effects of indoleamine 2,3-dioxygenase inhibitor in non-Hodgkin lymphoma model mice', International Journal of Hematology, vol. 102, no. 3, pp. 327-334. https://doi.org/10.1007/s12185-015-1835-8

Effects of indoleamine 2,3-dioxygenase inhibitor in non-Hodgkin lymphoma model mice. / Nakamura, Nobuhiko; Hara, Takeshi; Shimizu, Masahito; Mabuchi, Ryoko; Nagano, Junji; Ohno, Tomohiko; Kochi, Takahiro; Kubota, Masaya; Shirakami, Yohei; Goto, Naoe; Ito, Hiroyasu; Saito, Kuniaki; Tanaka, Takuji; Moriwaki, Hisataka; Tsurumi, Hisashi.

In: International Journal of Hematology, Vol. 102, No. 3, 13.09.2015, p. 327-334.

Research output: Contribution to journalArticle

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T1 - Effects of indoleamine 2,3-dioxygenase inhibitor in non-Hodgkin lymphoma model mice

AU - Nakamura, Nobuhiko

AU - Hara, Takeshi

AU - Shimizu, Masahito

AU - Mabuchi, Ryoko

AU - Nagano, Junji

AU - Ohno, Tomohiko

AU - Kochi, Takahiro

AU - Kubota, Masaya

AU - Shirakami, Yohei

AU - Goto, Naoe

AU - Ito, Hiroyasu

AU - Saito, Kuniaki

AU - Tanaka, Takuji

AU - Moriwaki, Hisataka

AU - Tsurumi, Hisashi

PY - 2015/9/13

Y1 - 2015/9/13

N2 - Indoleamine 2,3-dioxygenase (IDO) catalyzes the rate-limiting step in the metabolism of tryptophan along the kynurenine pathway. In tumors, increased IDO activity inhibits proliferation and induces apoptosis of T cells and natural killer cells. We investigated the therapeutic potential of IDO inhibitor 1-methyl-d-tryptophan (d-1MT) with cyclophosphamide (CY) in a mouse model of lymphoma. To examine the effect of d-1MT, mice were killed on day 28. Serum concentrations of l-kynurenine and l-tryptophan were measured by high-performance liquid chromatography. Regulatory T cells (Tregs) were counted by flow cytometry, and mRNA expressions of IDO1, Foxp3, IFN-γ, and COX-2 were examined by quantitative real-time reverse transcription-polymerase chain reaction. d-1MT+CY combination treatment significantly inhibited tumor growth as compared to either treatment alone. There were no significant differences in the serum l-kynurenine/l-tryptophan ratio or the IDO1 expression level in the tumors among the treatment groups. The expression levels of IFN-γ and COX-2 mRNA in tumor-draining lymph nodes (TDLNs) were found to be significantly up-regulated in the CY and d-1MT+CY groups. The number of Tregs in TDLNs in the d-1MT+CY group was significantly lower than that in CY groups on day 17. These results suggest that d-1MT in combination with CY is an effective treatment for lymphoma in a mouse model.

AB - Indoleamine 2,3-dioxygenase (IDO) catalyzes the rate-limiting step in the metabolism of tryptophan along the kynurenine pathway. In tumors, increased IDO activity inhibits proliferation and induces apoptosis of T cells and natural killer cells. We investigated the therapeutic potential of IDO inhibitor 1-methyl-d-tryptophan (d-1MT) with cyclophosphamide (CY) in a mouse model of lymphoma. To examine the effect of d-1MT, mice were killed on day 28. Serum concentrations of l-kynurenine and l-tryptophan were measured by high-performance liquid chromatography. Regulatory T cells (Tregs) were counted by flow cytometry, and mRNA expressions of IDO1, Foxp3, IFN-γ, and COX-2 were examined by quantitative real-time reverse transcription-polymerase chain reaction. d-1MT+CY combination treatment significantly inhibited tumor growth as compared to either treatment alone. There were no significant differences in the serum l-kynurenine/l-tryptophan ratio or the IDO1 expression level in the tumors among the treatment groups. The expression levels of IFN-γ and COX-2 mRNA in tumor-draining lymph nodes (TDLNs) were found to be significantly up-regulated in the CY and d-1MT+CY groups. The number of Tregs in TDLNs in the d-1MT+CY group was significantly lower than that in CY groups on day 17. These results suggest that d-1MT in combination with CY is an effective treatment for lymphoma in a mouse model.

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