Alloreactive NK-cells activity to leukemia with HLA-LOH after HLA haplomismatch stem cell transplantation

HLA 单倍体匹配干细胞移植后，NK 细胞对 HLA-LOH 的白血病有同种异体反应活性

• 批准号: 23591536
• 负责人: TAKAHASHI Yoshiyuki
• 金额: $ 2.91万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2013
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23591536/
• 关键词: 白血病; NK細胞; GVL効果; KIR; 造血幹細胞移植; HLA

We investigated HLA expression on leukemic blasts derived from patients at diagnosis and relapse after hematopoietic stem cell transplantation (HSCT) using flow cytometry with locus-specific antibodies. HLA expression analysis was useful for analysis of donor chimerism and minimal residual diseases. We found that leukemic blasts with HLA-LOH at relapse were efficiently killed by donor NK cells. This was partially explained because ULBP2 on the leukemic blasts with HLA-LOH was highly expressed. We could monitor single KIR positive NK cells that are not inhibited by patient's HLA. Increased single KIR positive NK cells were related to higher NK cell alloreactivity. Finally, GMP grade NK cell expansion method was established using FDA approved gene modified K562 cells. These findings could establish the rationale of allogeneic NK cell therapy using KIR mismatched donor NK cells.

我们利用流式细胞术检测了造血干细胞移植（HSCT）后诊断和复发患者白血病母细胞中HLA的表达。HLA表达分析有助于分析供体嵌合和微小残留疾病。我们发现复发时带有HLA-LOH的白血病原细胞被供体NK细胞有效地杀死。这部分解释了ULBP2在HLA-LOH白血病细胞上的高表达。我们可以监测单个不受患者HLA抑制的KIR阳性NK细胞。单个KIR阳性NK细胞增加与NK细胞同种异体反应性升高有关。最后，利用FDA批准的基因修饰K562细胞建立GMP级NK细胞扩增方法。这些发现可以为使用KIR错配的供体NK细胞进行同种异体NK细胞治疗奠定基础。

项目成果

Pediatric AplasticAnemia-Immunosupressive Therapy

小儿再生障碍性贫血-免疫抑制治疗

• 发表时间: 2011
• 作者: Takahashi S;Futatsugi-Yumikura S;Yoshimoto T;Yonehara S;Nakanishi K.;Takahashi Y.
• 通讯作者: Takahashi Y.

CD20-negative Epstein-Barr virus-associated post-transplant lymphoproliferative disease refractory to rituximab in a patient with severe aplastic anemia

严重再生障碍性贫血患者对利妥昔单抗耐药的 CD20 阴性 Epstein-Barr 病毒相关移植后淋巴增殖性疾病

• DOI: 10.1007/s12185-011-0870-3
• 发表时间: 2011
• 期刊: Int J Hematol
• 影响因子: 2.1
• 作者: Mur amatsu H;Takahashi Y;Shimoyama Y;Doisaki S;Nishio N;Ito Y;Hama A;Shimada A;Yagasaki H;Ito M and Kojima S.
• 通讯作者: Ito M and Kojima S.

先天性角化不全症

先天性角化不良

• 发表时间: 2011
• 期刊: 新しい診断と治療のABC７２／血液８ 再生不良性貧血
• 作者: 高橋義行;西尾信博;小島勢二
• 通讯作者: 小島勢二

Unmanipulated HLA Haploidentical Bone Marrow Transplantation Combined With PBSC With The Options Of Donor Virus Specific CTLs and Mesenchymal Stem Cells Infusion

未操作的 HLA 单倍相合骨髓移植结合 PBSC，可选择供体病毒特异性 CTL 和间充质干细胞输注

• 发表时间: 2013
• 作者: Takahashi Y;Kawashima N;Narita A;Sakaguchi H;Muramatsu H;Hama A;Kojima S.
• 通讯作者: Kojima S.

小児ハイリスク神経芽腫に対する抗ヒトGD2抗体(ch14.18)療法.日本臨床72巻増刊号2.最新がん薬物療法学―がん薬物療法の最新知見―

抗人 GD2 抗体（ch14.18）治疗儿童高危神经母细胞瘤。日本临床第 72 卷特刊 2。最新癌症药物治疗 - 癌症药物治疗的最新发现 -

• 发表时间: 2014
• 作者: 高橋義行