title: A reduction of recipient regulatory T cells by cyclophosphamide contributes to an anti-tumor effect of nonmyeloablative allogeneic stem cell transplantation in mice.
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.
authors.affiliation: Division of Host Defense, Research Center for Prevention of Infectious Disease, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Kyushu, Japan.
authors.forename: Ario
authors.initials: A
authors.lastname: Takeuchi
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Eto
authors.forename: Hisakata
authors.initials: H
authors.lastname: Yamada
authors.forename: Katsunori
authors.initials: K
authors.lastname: Tatsugami
authors.forename: Seiji
authors.initials: S
authors.lastname: Naito
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Yoshikai
mesh_terms: D000818:Animals; D003520:Cyclophosphamide / Q000494:pharmacology*; D005260:Female; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008806:Mice, Inbred AKR; D008809:Mice, Inbred C3H; D019653:Myeloablative Agonists / Q000494:pharmacology; D033581:Stem Cell Transplantation / Q000379:methods*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology*; D001749:Urinary Bladder Neoplasms / Q000276:immunology* / Q000601:surgery / Q000628:therapy*
chemical_list: D007166:Immunosuppressive Agents; D019653:Myeloablative Agonists; D003520:Cyclophosphamide