Identification of minor histocompatibility antigens as targets for allogeneic adoptive immunotherapy against hematological malignancies.

鉴定次要组织相容性抗原作为针对血液恶性肿瘤的同种异体过继免疫疗法的靶标。

基本信息

批准号：
17591025
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：
2005
资助国家：
日本
起止时间：
2005 至 2006
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 identified 4 mHAgs including 3 novel mHAgs and an HA-1 mHAg presented by HLA-A2 subtype other than the original HLA-A^*0201.(1)We found HLA-A^*3101 and-A^*3303-restricted mHAg epitopes whose expression was controlled by an SNP in Cathepsin H (CTSH) gene. CTSH protein was expressed relatively ubiquitously, but its expression was highest in monomyelocytic cells. Nevertheless, CTL clones specific for CTSH did not lyse any non-hematopoietic cells, although the reason remained unclear.(2)A mHAg gene recognized by HLA-B44-restricted CTL was localized to 18q23 by linkage analysis. Expression cloning revealed that the mHAg was encoded by a splice variant of HMSD gene. The variant was produced by alternative splicing due to an SNP in the intron 2 SD site leading to exclusion of exon 2, which is a novel mechanism in mHAg generation. The HMSD was found to be highly expressed in myeloid and plasma cell malignancies, suggesting the HMSD encoded mHAg(s) should serve as a good target for immunotherapy against AML and myeloma.(3)By using a 29-mer peptide spanning HA-1^H epitope in the middle, we isolated HLA-A^*0206-restricted CTL from posttransplant peripheral blood samples of a patient receiving HA-1 mismatched transplant. The epitope was found to be identical to that presented by HLA-A^*0201 molecule, indicating HA-1^H mHAg can also be presentable by HLA-A^*0206, which was totally unexpected from the known binding motif of HLA-A^*0206 molecule.(4)We have started recruiting patients eligible for mHAg-based immunotherapy. The target mHAgs used in this clinical study so far are ACC-1, ACC-2 and HA-1, which are expected to cover more than 30% of Japanese patients receiving allogeneic transplantation.

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较小组织相容性抗原（MHAG）可用于复发性白血病/淋巴瘤的免疫疗法，同种异体造血细胞后（HCT）。我们已经确定了4个MHAG，包括3个新型MHAG和HLA-A2亚型提出的HA-1 MHAG，而不是原始的Hla-A^*0201。（1）我们发现HLA-A^*3101和-A^*3303 rag^*3303限制的Mhag epiatepes的表达受到Cathpsepsepsin hhp in Cathepsin hh的表达（Cte）。 CTSH蛋白表达相对普遍存在，但在单肌细胞细胞中的表达最高。尽管如此，尽管不清楚的原因仍然不清楚，但针对CTSH的CTL克隆并未裂解任何非造成杂物的细胞。（2）通过链接分析，由HLA-B44限制的CTL识别的MHAG基因被定位为18Q23。表达克隆表明，MHAG是由HMSD基因的剪接变体编码的。该变体是由于内含子2 SD位点中的SNP而导致的替代剪接产生的，导致外显子2的排除，这是MHAG生成中的一种新型机制。 The HMSD was found to be highly expressed in myeloid and plasma cell malignancies, suggesting the HMSD encoded mHAg(s) should serve as a good target for immunotherapy against AML and myeloma.(3)By using a 29-mer peptide spanning HA-1^H epitope in the middle, we isolated HLA-A^*0206-restricted CTL from posttransplant peripheral blood samples of接受HA-1不匹配移植的患者。发现表位与HLA-A^*0201分子所提出的表位相同，表明Ha-1^H Mhag也可以由HLA-A^*0206出现，这是HLA-A^*0206 Molecule的已知结合图案完全出乎意料的。到目前为止，这项临床研究中使用的目标MHAG是ACC-1，ACC-2和HA-1，预计将覆盖30％以上接受同种异体移植的日本患者。