| Project/Area Number |
14570996
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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 | KEIO UNIVERSITY |
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Principal Investigator |
SUMIMOTO Hidetoshi Keio University, School of Medicine, Instructor, 医学部, 助手 (00306838)
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| Co-Investigator(Kenkyū-buntansha) |
IKEDA Yasuo Keio University, School of Medicine, Professor, 医学部, 教授 (00110883)
FUJITA Tomonobu Keio University, School of Medicine, Instructor, 医学部, 助手 (20199334)
KAWAKAMI Yutaka Keio University, School of Medicine, Professor, 医学部, 教授 (50161287)
OKAMOTO Shinichiro Keio University, School of Medicine, Associate Professor, 医学部, 助教授 (50160718)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2003: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 2002: ¥1,100,000 (Direct Cost: ¥1,100,000)
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| Keywords | minor histocompatibility antigen / hematopoietic stem cell transplantation / single nucleotide polymorphism / Graft versus leukemia effect / Graft versus host disease / 抗原特異的T細胞 / 白血病 / 同種造血肝細胞移植 / GVL / GVHD / SNP / HLA / マイナー組織適合抗原 / T細胞 |
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| Research Abstract |
We investigated new minor histocompatibility antigens (mHas) that are preferentially expressed in hematopoietic cells using two strategies.
In the first method, we tried to induce allo reactive T lymphocytes from 38 patients who had received HLA-matched allogeneic hematopoietic stem cell transplantation (allo-HSCT). Twelve T lymphocyte lines specific for the recipient antigens were generated by in vitro stimulation of donor-derived peripheral blood mononuclear cells (PBMC). One of thee T cells, Tycell-A, generated from a patient with Non-Hodgikin Lymphoma was predominantly CD4 positive, and recognized an allogeneic antigen expressed in 11 of 13 HLA-DPB1^*0501-positive EBV-transformed B cell lines (EBV-LCL) or HLA-DPB1 ^*0501-positive phytohaemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PHA blasts), however, the T cell didn't recognize any HLA-DPB1 ^*0501-positive fibroblasts or HLA-DPB1 *0501-ne ative EBV LCL and PHA blasts. This T cell line also recognized 4 of 5 HL
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A-DPB1 ^*0501-positive leukemia and lymphoma cells. These results suggest that T cell-A recognizes a novel minor histocompatibility antigen (mHa) that is referentially expressed in hematopoietic cells. Another T cell line, T cell-B, was obtained from a patient with chronic myelogenous leukemia (CML). It also consists of CD4 positive cells, and recognized mismatched HLA-DQB1 ^*0303. T cell-B did not recognize IFN-γ stimulated recipient's skin fibroblasts. It was revealed that expression of HLA-DQ in non-hematopoietic cells, such as skin fibroblasts, hepatocytes, HUVEC, was merely upregulated by IFN-γ stimulation, however, MHC class II was constitutively expressed in hematopoietic cells and most leukemia and lymphoma cells. Therefore T cells that recognize mismatch HLA-DQ might play an important role only in graft-versus leukemia (GVL) effect but not in graft-versus host disease (GVHD).
In the second method we chose some candidates of mHa from molecules with codin SNPs (single nucleotide of polymorphisms). We designed 8 peptides that involve SNP lesion of proteinase3 and try to induce peptide-specific-T cells. Unfortunately we failed to induce reactive T cells. Mismatch of SNP did not related to the relapse rate according to the analysis of 35 pairs of recipient and donor. Less
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