2006 Fiscal Year Final Research Report Summary
Identification of minor histocompatibility antigens as targets for allogeneic adoptive immunotherapy against hematological malignancies.
| Project/Area Number |
17591025
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Aichi Cancer Center Research Institute |
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Principal Investigator |
AKATSUKA Yoshiki Aichi Cancer Center Research Institute, Division of Immunology, Section Head, 腫瘍免疫学部, 室長 (70333391)
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| Project Period (FY) |
2005 – 2006
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| Keywords | minor histocompatibility antigen / cytotoxic T lymphocyte / adoptive immunotherapy / hematological malignancies) |
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| Research Abstract |
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.
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