A reduction of recipient regulatory T cells by cyclophosphamide contributes to an anti-tumor effect of nonmyeloablative allogeneic stem cell transplantation in mice

Authors

  • Ario Takeuchi,

    1. Division of Host Defense, Research Center for Prevention of Infectious Disease, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Kyushu, Japan
    2. Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Kyushu, Japan
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  • Masatoshi Eto,

    Corresponding author
    1. Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
    • Department of Urology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
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    • Tel.: +81-96-373-5240, Fax: +81-96-373-5242

  • Hisakata Yamada,

    1. Division of Host Defense, Research Center for Prevention of Infectious Disease, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Kyushu, Japan
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  • Katsunori Tatsugami,

    1. Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Kyushu, Japan
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  • Seiji Naito,

    1. Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Kyushu, Japan
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  • Yasunobu Yoshikai

    1. Division of Host Defense, Research Center for Prevention of Infectious Disease, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Kyushu, Japan
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Abstract

We have recently established a unique model system of nonmyeloablative allogeneic stem cell transplantation (SCT) for treatment of murine solid tumors, based on cyclophosphamide-induced tolerance. An injection of allogeneic donor spleen cells and bone marrow cells (BMC) followed by cyclophosphamide treatment induced a stable mixed chimerism with long lasting tolerance to the allografts. A donor lymphocyte infusion (DLI) in the cyclophosphamide-induced tolerant mice exerted strong anti-tumor effects on an MBT-2 murine bladder tumor, MBT-2 via their graft versus tumor (GVT) activity. In the present study, we determined whether a cyclophosphamide-induced reduction of naturally occurring regulatory T cells (Tregs) was associated with the anti-tumor activity in our nonmyeloablative SCT system. The number of recipient CD4+ CD25+ Foxp3+ Tregs significantly decreased 3 days after an intraperitoneal injection of cyclophosphamide in C3H/HeN mice that had been injected with spleen cells and BMC of donor AKR/J mice, compared with the number of CD4+ CD25+ Foxp3- T cells. An adoptive transfer of CD4+ CD25+ T cells from naïve C3H/He x AKR/J F1 mice into recipient mice 1 day after DLI significantly suppressed the expansion and IFN-γ production of host-reactive donor CD4+T cells and hampered the MBT-2 anti-tumor activity when compared with the transfer of CD4+ CD25- T cells. These results indicated that cyclophosphamide-induced reduction of recipient Tregs is associated with retardation of tumor progression via the expansion of host-reactive donor T cells and IFN-γ production after DLI in our nonmyeloablative SCT system.

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