Identification of minor histocompatibility antigens restricted by HLA alleles common in Japanese

日本人常见的 HLA 等位基因限制的次要组织相容性抗原的鉴定

基本信息

批准号：
15591035
负责人：
AKATSUKA Yoshiki
金额：
$ 2.18万
依托单位：
Aichi Cancer Center Research Institute
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

Cytotoxic T lymphocytes(CTL) specific for minor histocompatibility antigens(mHAgs) whose tissue expression is limited to hematopoietic cells are useful for immunotherapy of relapsed leukemia/lymphoma following allogeneic hematopoietic cell transplantation(HCT). We have collected peripheral blood samples 26 patients receiving HCT and generated CTL restricted by HLA alleles commonly seen in Japanese population. First we examined the impact of BCL2A1/A24 disparity on clinical outcome using 320 HLA-A24-positive patients receiving HLA-identical HCT.donor pairs. The results indicate the disparity is unlikely to augment GVHD, suggesting this mHAg may be used for immunotherapy against hematological malignancies after HCT. We next attempted to identify a gene encoding HLA-A^*3303 restricted, male specific mHAg using a CTL clone that preferentially lysed hematopoietic cells. Using a panel of Y chromosome deletion mutant LCLs, the gene was narrowed down to Yq11.221. Further studies using RT-PCR, … More minigene expression and CTL recognition, demonstrated that the mHAg was indeed located in the 5'UTR of TMSB4Y gene. Third, identification of mHAg gene(s) encoding HLA-A^*3303 and -A^*3101-restricted mHAgs was conducted. Linkage analysis demonstrated that two CTL clones specific for these mHAgs recognized a similar epitope(s) from a single region, 15q25. A single polymorphic gene, Cathepsin H, was identified by the aid of expression cloning. This gene has three non-synonymous SNPs and the first one controlled the specificity of these CTL clones. HLA-A^*3303-rectricted CTL recognized 10-mer epitope ending Arg while HLA-A^*3101 -rectricted CTL recognized 9-mer epitope ending the same Arg. Substitution of Arg with Gly which is encoded by Ag-negative allele totally abrogated the binding of the peptide. Cathespsin H is not specifically expressed in hematopoietic cells, but its function is tightly correlated with metastasis of cancer cells. Thus we are currently questioning wheather these epitope is useful for immunotherapy against solid tumors. Less

针对较小的组织相容性抗原（MHAGS）的细胞毒性T淋巴细胞（CTL），其组织表达仅限于造血细胞的细胞毒性抗原（MHAG）可用于继电联合性白血病/淋巴瘤的免疫疗法。我们已经收集了外周血样本26例接受HCT的患者，并产生了受日本人群中常见的HLA等位基因限制的CTL。首先，我们使用320名HLA-A24阳性患者接受了HLA-相同的HCT.DONOR对。结果表明，差异不太可能增加GVHD，这表明该MHAG可用于免疫疗法，以抵抗HCT后血液学恶性肿瘤。接下来，我们尝试使用使用CTL克隆（优选衬有衬里的造血细胞）来识别编码HLA-A^*3303的基因。使用Y染色体缺失突变体LCLS的面板，将基因缩小到YQ11.221。使用RT-PCR的进一步研究，…更多的小型表达和CTL识别表明，MHAG确实位于TMSB4Y基因的5'UTR中。第三，进行了编码HLA-A^*3303和-a^*3101限制MHAG的MHAG基因的鉴定。链接分析表明，两个针对这些MHAG的CTL克隆识别出单个区域的相似表位，第15季度。通过表达克隆的帮助，鉴定出单个多态基因组织蛋白酶H。该基因具有三个非同义SNP，第一个基因控制了这些CTL克隆的特异性。 Hla-a^*3303 rectractry的CTL识别出10-MER的发作，而HLA-A^*3101-Rectrationd CTL识别出9-mer表位，结束了同样的ARG。用Ag阴性等位基因编码的Gly替换Arg完全消除了肽的结合。 Cathespsin H在造血细胞中并未明确表达，但其功能与癌细胞的转移密切相关。我们目前正在质疑为什么这些发作可用于针对实体瘤的免疫疗法。较少的