2003 Fiscal Year Final Research Report Summary
Immunotherapy of hematological melignancies based on activation of innate immunity and costimulation through OX40/OX40L
| Project/Area Number |
14207041
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
UCHIYAMA Takashi Kyoto University, Graduate School of Medicine, Professor, 医学研究科, 教授 (80151900)
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| Co-Investigator(Kenkyū-buntansha) |
HORI Toshiyuki Kyoto University, Graduate School of Medicine, Lecturer, 医学研究科, 講師 (70243102)
KADOWAKI Norimitsu Kyoto University, Graduate School of Medicine, Assistant Professor, 医学研究科, 助手 (60324620)
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| Project Period (FY) |
2002 – 2003
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| Keywords | innate immunity / ONO-4007 / OX40 / OX40 ligand / fumor vaccine / anti-fumor immunity |
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| Research Abstract |
In the present study, we attempted to develop novel immune therapeutic modalities against hematological melignancies based on activation of innate immunity and costimulation through OX40/OX40L..
A LPS-derived compound, ONO-4007, was enclosed in liposomes and injected to C57/B6 mice that had been preinoculated with EL4, a mouse T cell lymphoma cell line. The tumor was infiltrated with neutrophils after 24 h and showed necrotic change after 72 h. However, we could not detect significant difference between liposome-enclosed and non-enclosed ONO-4007.
Fresh leukemic cells from 5 AML patients were cultured with SCF, Flt3-L, GM-CSF, and TNF-α to differentiate into dendritic cell (DC)-like cells. At the same time, a part of cultured leukemic cells were retrovirally transduced with OX40L or mock control. We showed that OX40L-transduced leukemia-DC had the highest capacity to induce proliferation and IFN-g production of allogeneic CD-4+ T cells.
C57BL/6 mice were inoculated with 1×10^5 cells of parental EL4, OX40L-transfected EL4 (EL4-OX40L), or mock control vector-transfected EL4 (EL4-mock). While both parental EL4 and EL4-mock grew rapidly, EL4-OX40L was rejected or grew slower than parental EL4 or EL4-mock. In vitro CTL assay demonstrated that spleen cells of mice that had rejected EL4-OX40L had significant cytotoxic activity against parental EL4.
In conclusion, activation of innate immunity was demonstrated to be efficacious to eradicate tumors, and the gene transfer of OX40L into lymphoma cells is an eligible and efficient modality to induce anti-lymphoma immunity.
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