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Induction of anti B-cell malignance CTL response by subfamily-shared peptides derived from variable domain of immunoglobulin heavy chain

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Abstract

The variable domain of immunoglobulin heavy chain (Ig HV) is well-characterized tumor associated antigen expressed in B-cell malignancies, which may function as a T-cell target. However, T-cell epitopes derived from shared framework regions (FRs) of each IgHV subfamily capable of inducing cytotoxic T lymphocytes (CTLs) against the B-cell malignancy, have not been identified. Using the specific PCR primers of seven IgHV gene subfamilies, we amplified the IgHV gene rearrangement for 108 cases of B-cell acute lymphoblastic leukemia (B-ALL) patients. The IgHV gene rearrangement fragments of B-ALL patients were directly sequenced then classified into seven different subfamilies. The T-cell epitopes encoded by the IgHV gene in the B-ALL patients were predicted by SYFPEITHI and BIMAS programs and compared with those from 56 representative germline IgHV sequences in the genebank. For the HLA-A*0201 locus, we found 1 or 2 top score shared epitopes from each subfamily and got 12 epitopes altogether. Results showed that ten of them were in the FRs. Using an antigen-specific T-cell expansion system, we generated the peptide-special CTLs in vitro, which were capable of killing B lymphoma cell lines that belonged to the same IgHV subfamily in a peptide-specific and HLA-restricted manner. Furthermore, we proved that the cytotoxicity of CTLs was IgHV subfamily-specific. These data indicate possible immunotherapy approaches for B-cell malignances patients based on IgHV gene subfamilies.

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Abbreviations

Ig:

Immunoglobulin

IgHV:

Variable domain of immunoglobulin heavy chain

CDRs:

Hypervariable complementary determining regions

Id:

Idiotype

FRs:

Framework regions

HLA:

Human-leukocyte-antigen

CTLs:

Cytotoxic T lymphocytes

TCR:

T-cell receptor

B-ALL:

B-cell acute lymphoblastic leukemia

PBMCs:

Peripheral blood mononuclear cells

APCs:

Antigen presenting cells

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Acknowledgements

The thorough reviewing of this manuscript by Dr. Daniel H. Conrad from the Department of Microbiology and Immunology, Virginia Commonwealth University, Medical College of Virginia, and Dr Zeng gang from the Division of Urologic Oncology, Department of Urology, David Geffen School of Medicine at UCLA are greatly appreciated. We thank Dr Dingfang-PU, Yongjin-SHI for their research suggestions and technical assistance. We also thank Jiaxia-YUAN for FCM assay, Dr Weifeng-CHEN for providing the T2 cell line. Dr Mirjam H. M. Heemskerk, (Department of Hematology, Leiden University Medical Center (LUMC), Leiden, the Netherlands) for supplying us with the primer of d TCRBV for RT-PCR. Supported by: National Natural Science Foundation of China (39970313) and grant 2002AA229011 from the ministry of Science and Technology, China.

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Authors and Affiliations

  1. Department of Hematology, Peking University First Hospital, No. 8, Xishiku Street, West District, Beijing, 100034, China

    Guo Xiaoling, Liu Ying, Liu Jing, Li Huifang, Zhu Xia & Zhu Ping

  2. Shanghai Profile Biotech, LTD, Shanghai JiaoTong University, 7th Floor, 245 JiaChuan Rd., Shanghai, 200237, PRC

    Fan Qingqing

  3. School of Pharmacy, Shanghai JiaoTong University, 7th Floor, 245 JiaChuan Rd., Shanghai, 200237, PRC

    Fan Qingqing

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  1. Guo Xiaoling
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  2. Liu Ying
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  3. Liu Jing
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  4. Li Huifang
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  5. Zhu Xia
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  7. Zhu Ping
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Correspondence to Zhu Ping.

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Xiaoling, G., Ying, L., Jing, L. et al. Induction of anti B-cell malignance CTL response by subfamily-shared peptides derived from variable domain of immunoglobulin heavy chain. Cancer Immunol Immunother 54, 1106–1114 (2005). https://doi.org/10.1007/s00262-005-0696-z

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  • DOI: https://doi.org/10.1007/s00262-005-0696-z

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