Induction of anti B-cell malignance CTL response by subfamily-shared peptides derived from variable domain of immunoglobulin heavy chain.
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.
Xiaoling
Guo
G
Department of Hematology, Peking University First Hospital, No. 8, Xishiku Street, West District, Beijing 100034, China.
Ying
Liu
L
Jing
Liu
L
Huifang
Li
L
Xia
Zhu
Z
Qingqing
Fan
F
Ping
Zhu
Z
D002051:Burkitt Lymphoma / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D018984:Epitopes, T-Lymphocyte; D015321:Gene Rearrangement; D019674:Genes, T-Cell Receptor beta; D015234:HLA-A Antigens / Q000378:metabolism; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D010446:Peptide Fragments / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D010446:Peptide Fragments