| 1.
論文(リポジトリ) |
論文(リポジトリ)
|
西澤, 幹則 ; 成田, 美和子 ; 岩谷, 俊平 ; 大岩, 恵理 ; 岩渕, 南 ; 内山, 孝由 ; 松山, 麻子 ; 高橋, 益廣
概要:
ウステキヌマブはヒト型抗ヒト interleukin（IL）-12/IL-23p40モノクローナル抗体製剤であり，乾癬の治療に用いられている。しかし，IL-12は抗腫瘍免疫において重要な役割を担うため，ウステキヌマブによる腫瘍発生率の増加が
…
懸念されている。今回の検討では，ウステキヌマブの抗原特異的癌免疫における影響を明らかにすることを目的とした。乾癬患者に対する in vivo の検討では，ウステキヌマブの投与により乾癬症状は改善されたが，腫瘍抗原特異的細胞傷害性 T 細胞（CTL）の frequency は投与開始以降も抑制されることはなかった。また in vitro の検討では，樹状細胞の抗原提示能及び抗原特異的 CTL の誘導に対するウステキヌマブの抑制効果は確認できなかった。これらの結果から，ウステキヌマブは樹状細胞の機能や腫瘍抗原特異的 CTL の誘導を抑制することなく乾癬症状を改善することが可能であり，ウステキヌマブ治療症例における腫瘍発症の増加は見られないという最近の臨床試験の知見を支持するものと考えられた。<br />Ustekinumab （a humanized monoclonal antibody against the common p40 subunit shared by IL-12 andIL-23） blocks the pathways of T helper （Th）-1 and Th-17, which play pivotal roles in cell-mediated immunity and production of pro-inflammatory cytokines. Ustekinumab is currently used for the treatment of moderate to severe psoriasis with remarkable efficiency. However, worries about the development of malignancies in ustekinumab-treated patients could not be completely cleared because of the major role of IL-12 and IL-23 in tumor immunity. In the present study, we tried to elucidate the effects of ustekinumab on antigen-specific tumor immunity. A 56 years-old male volunteer was subcutaneously administered with 20 times of WT1 peptide. WT1 tetramer+ CD8+ T cells appeared after the first peptide administration and the frequency of WT1 tetramer+ T cells elevated to more than 15 in 10^6 CD8+ T cells. He began to be treated with subcutaneous injections of ustekinumab for moderate psoriasis. Psoriasis plaques were almost cleared up at week 12. The frequency of WT1 tetramer+ T cells with cytotoxic ability has not changed for 22 months since the initiation of ustekinumab treatment. The effects of ustekinumab on antigen presenting and CTL inducing abilities of dendritic cells were explored in vitro, resulting in little effects on both immune functions. These in vivo/vitro findings imply that ustekinumab improves psoriasis without suppressing tumor antigen-specific cytotoxic T lymphocytes and support the data of recent clinical trials showing a comparable incidence of malignancies between ustekinumab-treated psoriatic patients and the control.
続きを見る
|
||||
| 2.
論文(リポジトリ) |
論文(リポジトリ)
|
大岩, 恵理 ; 成田, 美和子 ; 岩谷, 俊平 ; 西澤, 幹則 ; 内山, 孝由 ; 高橋, 益廣
概要:
抗原ペプチドが同定されていない腫瘍に対する細胞傷害性T細胞(CTL)を誘導するために，当研究室で樹立した白血病性形質細胞様樹状細胞株(leukemic plasmacytoid dendritic cell line; PMDC05)の直接
…
的な細胞傷害活性を検出することを目的とした。ペニシリン凍結乾燥処理したStreptococcus pyogenesの菌体成分(OK432)及びIFN-γを用いてPMDC05の刺激培養を行った。OK432及びIFN-γで刺激されたPMDC05は，刺激なしに比べてサイトカイン産生が増強し，標的細胞を有意に傷害した。以上のことから，OK432及びIFN-γで刺激されたPMDC05は，腫瘍細胞との共培養によって腫瘍抗原を提示し，腫瘍抗原特異的CTLを誘導するための有力な抗原提示細胞になり得ると考えられた。<br />A leukemic plasmacytoid dendritic cell line, PMDC05, which was previously established in our laboratory, showed the ability of inducing antigen specific cytotoxic T lymphocytes. For tumors that antigenic peptides are not identified, it would be necessary for PMDC05 to have direct cytotoxicity against tumor cells to uptake tumor antigens for presenting them to T cells. Therefore, we aimed to investigate the effects of OK432, penicillin-inactivated and lyophilized preparation of Streptococcus pyogenes which has been clinically used in Japan for more than 30 years, to activate PMDC05 cells. Stimulation of PMDC05 cells with OK432 and IFN-γenhanced the expression of CCR7 and TNF-related apoptosisinducing ligand (TRAIL). Also, we detected a higher cytokine production such as IL-6 and TNF-α compared with unstimulated PMDC05 cells. Furthermore, PMDC05 cells stimulated with OK432 and IFN-γshowed direct cytotoxicity against the tumor cell targets (T2A24 cells) expressing death-inducing receptors (DR4 and DR5). This might have occurred due to binding of TRAIL expressed on PMDC 05 cells with DR4/5 on T2A24 cells. These data suggest that by stimulation with OK432 and IFN-γPMDC05 cells could acquire direct antitumor cytotoxicity, which may be beneficial for PMDC05 cells to uptake tumor cell components for antigen presentation in case of PMDC05 cells are co-cultured with tumor cells. OK432/IFN-γ-stimulated PMDC05 cells, which are loaded with tumor antigen by co-culturing with tumor cells, could be used as potent antigen presenting cells for generating antigen specific cytotoxic T lymphocytes (CTLs) in antitumor cellular immunotherapy.
続きを見る
|
