2001 Fiscal Year Annual Research Report

インターロイキン15を用いた癌免疫療法の開発

Research Project

Project/Area Number	13218058
Research Institution	Nagoya University
Principal Investigator	吉開泰信名古屋大学, 大学院・医学研究科, 教授 (90158402)
Keywords	IL-15 / メラノーマ / トランスジェニックマウス / 遺伝子治療 / CD8キラーT細胞
Research Abstract	IL-15のメモリーCD^<8+>T細胞の活性化と維持に働く作用に注目して、IL-15の腫瘍免疫療法への応用開発を行う。本年度は分泌型IL-15cDNAマウスにMHCクラスI陰性メラノーマ(B16L)細胞にMHCクラスI H-2Kb遺伝子を導入したMHCクラスI陽性メラノーマ(B16Kb)を5x104を皮下に接種して、腫瘍増殖曲線を調べたところ、腫瘍増殖抑制が認められた。接種10日目の脾臓細胞をさらにマイトマイシン処理B16Kbと5日間in vitro培養して、このメラノーマに対する細胞傷害活性を調べたところ、強い細胞傷害活性が認められた。この細胞傷害活性は脾臓細胞からCD8T細胞を除くと有意に低下したが、完全には抑制されなかった。抗MHCクラスI抗体の添加やcold inhibition testでこの細胞傷害活性は抑制されたが、完全ではなかった。腫瘍接種IL-15Tgマウスに抗CD8抗体を400μgx4回投与で抗腫瘍抑制効果が阻害された。また腫瘍接種IL-15Tgマウスに抗asialoGM1抗体を400μgx4回投与でも抗腫瘍抑制効果が阻害された。一方、抗CD4抗体を400μgx4回投与では抗腫瘍抑制効果は影響されなかった。以上のことから、IL-15の過剰発現はMHCクラスI陽性メラノーマに対してCD8キラーT細胞とNK細胞の活性化によって抗腫瘍効果を示すがことが明かとなった。IL15cDNAをpCR3.1に組み込んだpCR3.1:IL-15プラスミドを作成し、gene gunを用いて4mgのIL-15プラスミドをマウスに毎週投与したところ、脾臓でのCD8T細胞数が有意に増加した。MHCクラスI陽性メラノーマを接種したマウスに同様にIL-15プラスミドを投与したところ、有意に腫瘍の大きさが抑制された。

Research Products

(12 results)

All Other

All Publications (12 results)

[Publications] Ishimitsu, R.: "Overexpression of Interleukin-15 in vivo enhances Tcl response which inhibits allergic inflammation in a murine model of asthma"J.Immunol.. 166. 1991-2001 (2001)
[Publications] Nishimura, H.: "Mice lacking IL-2/IL-15 receptor β chain are susceptilbe but mice lacking IL-2 are resistant to infection with avirulent Salmonella choleraesuis"Infect.Immun.. 69. 1226-1229 (2001)
[Publications] Yajima, T.: "Memory phenotype CD8+T cells increased in IL-15 transgenic mice are involved in early protection against a primary infection with Listeria monocytogenes"Eur.J.Immunol.. 31. 757-766 (2001)
[Publications] Musikacharoen, T.: "NF-κB and STAT5 play important roles in the regulation of mouse Toll-like receptor 2 gene expression"J.Immunol.. 166. 4516-4524 (2001)
[Publications] Umemura, M.: "Impaired IL-15 production in murine AIDS mice might uderlie susceptibility to mycobacterial infection"J.Leuko.Biol.. 69. 138-148 (2001)
[Publications] Umemura, M.: "Overexpression of IL-15 in vivo induces a predominant Tcl response in mice inoculated with Mycobacterium bovis Bacille Calmette-Guerin infection"J.Immunol.. 167. 946-956 (2001)
[Publications] Yoshikai Y: "The role of prostaglandins and leukotoriens in acute inflammation caused by bacterial infection"Curr.Opin.Infect.Disease. 14. 257-264 (2001)
[Publications] Masuda, A.: "Interleukin-15 prevents mouse mast cells from apoptosis through STAT6-mediated Bcl-xL Expression"J.Biol.Chem.. 276. 26107-26113 (2001)
[Publications] Matsuguchi, T.: "A novel MAP kinase phosphatase is an important negative regulator of LPS-mediated JNK activation in mouse macrophage cell lines"Mol.Cell.Biol.. 20. 6999-7009 (2001)
[Publications] Yajima, T.: "Overexpression of IL-15 in vivo Increases antigen-driven memory CD8^+T cells following a microbe exposure"J.Immunol.. 168. 1198-1203 (2002)
[Publications] Shimizu, H.: "Toll-like receptor 2 contributes to liver injury induced by Salmonella infection through Fas ligand expression on NKT cells in mice"Gastroenterology. (in press). (2002)
[Publications] Yajima, T.: "Overexpression of interleukin-15 in vivo enhances anti-tumor activity against MHC class I-negative and positive B16 melanoma throught augmented NK activity or Ag-specific cytotoxic T cell responses"Int.J.Cancer. (in press). (2002)

2001 Fiscal Year Annual Research Report

インターロイキン15を用いた癌免疫療法の開発

Principal Investigator

吉開 泰信 名古屋大学, 大学院・医学研究科, 教授 (90158402)

Research Products

[Publications] Ishimitsu, R.: "Overexpression of Interleukin-15 in vivo enhances Tcl response which inhibits allergic inflammation in a murine model of asthma"J.Immunol.. 166. 1991-2001 (2001)

[Publications] Nishimura, H.: "Mice lacking IL-2/IL-15 receptor β chain are susceptilbe but mice lacking IL-2 are resistant to infection with avirulent Salmonella choleraesuis"Infect.Immun.. 69. 1226-1229 (2001)

[Publications] Yajima, T.: "Memory phenotype CD8+T cells increased in IL-15 transgenic mice are involved in early protection against a primary infection with Listeria monocytogenes"Eur.J.Immunol.. 31. 757-766 (2001)

[Publications] Musikacharoen, T.: "NF-κB and STAT5 play important roles in the regulation of mouse Toll-like receptor 2 gene expression"J.Immunol.. 166. 4516-4524 (2001)

[Publications] Umemura, M.: "Impaired IL-15 production in murine AIDS mice might uderlie susceptibility to mycobacterial infection"J.Leuko.Biol.. 69. 138-148 (2001)

[Publications] Umemura, M.: "Overexpression of IL-15 in vivo induces a predominant Tcl response in mice inoculated with Mycobacterium bovis Bacille Calmette-Guerin infection"J.Immunol.. 167. 946-956 (2001)

[Publications] Yoshikai Y: "The role of prostaglandins and leukotoriens in acute inflammation caused by bacterial infection"Curr.Opin.Infect.Disease. 14. 257-264 (2001)

[Publications] Masuda, A.: "Interleukin-15 prevents mouse mast cells from apoptosis through STAT6-mediated Bcl-xL Expression"J.Biol.Chem.. 276. 26107-26113 (2001)

[Publications] Matsuguchi, T.: "A novel MAP kinase phosphatase is an important negative regulator of LPS-mediated JNK activation in mouse macrophage cell lines"Mol.Cell.Biol.. 20. 6999-7009 (2001)

[Publications] Yajima, T.: "Overexpression of IL-15 in vivo Increases antigen-driven memory CD8^+T cells following a microbe exposure"J.Immunol.. 168. 1198-1203 (2002)

[Publications] Shimizu, H.: "Toll-like receptor 2 contributes to liver injury induced by Salmonella infection through Fas ligand expression on NKT cells in mice"Gastroenterology. (in press). (2002)

[Publications] Yajima, T.: "Overexpression of interleukin-15 in vivo enhances anti-tumor activity against MHC class I-negative and positive B16 melanoma throught augmented NK activity or Ag-specific cytotoxic T cell responses"Int.J.Cancer. (in press). (2002)

吉開泰信名古屋大学, 大学院・医学研究科, 教授 (90158402)