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Induction of cytotoxic T lymphocytes specific for minor histocompatility antigen through transferringThell receptor gene

通过转移Thell受体基因诱导对次要组织相容性抗原具有特异性的细胞毒性T淋巴细胞

基本信息

批准号：
18591049
负责人：
TAKAMI Akiyoshi
金额：
$ 2.53万
依托单位：
Kanazawa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591049/
关键词：
minor histocompatibility antigen leukemia stem cell transplantation

项目摘要

In hematopoietic SCT from HLA-matched donors, allogeneic immune reactions such as GVHD and GVL effect are induced by disparities in minor histocompatibility antigens (mHas) between donor and recipient. CD62L has been reported to act as an mHa based on analysis of the outcome of allogeneic SCT. To identify peptides derived from CD62L that may be involved in GVL effect, we prepared all possible 18 different 9-mer peptides derived from CD62L that include codon 213 in one of the 9 positions, and tested for cytotoxic T-cell precursors specific to any of these peptides in patients after CD62L-disparate SCT. PBMC obtained from 5 patients with I-ILA-A*2402 who developed GVHD following transplantation were incubated with autologous monocyte-derived DCs or HLA-A*2402-transfected T2 cells which were pulsed with the 9-mer peptides, or incubated with the peptides only, and 1FN-gamma secretion from PBMC after 16 hours incubation was examined. Two to 4 different recipient-type peptides for each patient induced higher IFN-gamma secretion than the others. By stimulating PBMC with the peptide-pulsed T2-A24 cells, T-cell lines specific for 4 peptides were obtained. The cultured T cells efficiently lysed peptide-pulsed T2-A24 cells as well as HLA-A*2402-positive lymphoblastic cell line cells that were disparate with CD62L. Addition of mAbs against HLA-class I blocked this cytotoxicity. WIC stabilization assay demonstrated that the 4 peptides bound to the cell surface and HLA complex stabilized. These results suggest these peptides may serve as mHas capable of inducing GVL effect, and CTLs recognizing CD62L-derived polymorphic peptides may have therapeutic value in treating relapsed leukemia after SCT.

在来自HLA匹配供体的造血SCT中，供者和受者之间的次要组织相容性抗原（mHas）的差异诱导同种异体免疫反应，例如GVHD和GVL效应。根据对同种异体SCT结果的分析，已报告CD 62 L可作为mHa。为了鉴定可能参与GVL效应的源自CD 62 L的肽，我们制备了源自CD 62 L的所有可能的18种不同的9聚体肽，其在9个位置之一包括密码子213，并在CD 62 L-不同SCT后的患者中测试对任何这些肽特异的细胞毒性T细胞前体。将从移植后发生GVHD的5名I-ILA-A*2402患者获得的PBMC与用9-mer肽脉冲的自体单核细胞衍生的DC或HLA-A*2402转染的T2细胞一起孵育，或仅与肽一起孵育，并检查孵育16小时后PBMC的IFN-γ分泌。每名患者的2至4种不同的免疫型肽诱导比其他患者更高的IFN-γ分泌。通过用肽脉冲的T2-A24细胞刺激PBMC，获得对4种肽特异的T细胞系。培养的T细胞有效地裂解肽脉冲的T2-A24细胞以及与CD 62 L不同的HLA-A*2402阳性淋巴母细胞系细胞。添加抗HLA-I类的mAb阻断了这种细胞毒性。WIC稳定化试验表明，4种肽与细胞表面结合，HLA复合物稳定。这些结果表明这些肽可能作为能够诱导GVL效应的mHas，识别CD 62 L衍生多态性肽的CTL可能在治疗SCT后复发的白血病中具有治疗价值。