PMID- 11698283
OWN - NLM
STAT- MEDLINE
DCOM- 20011221
LR  - 20210216
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 98
IP  - 10
DP  - 2001 Nov 15
TI  - Induction of cytotoxic T-cell responses against immunoglobulin V region-derived 
      peptides modified at human leukocyte antigen-A2 binding residues.
PG  - 2999-3005
AB  - Cytotoxic T-lymphocyte (CTL) responses can be generated against peptides derived 
      from the immunoglobulin (Ig) V region in some but not all patients. The main 
      reason for this appears to be the low peptide-binding affinity of Ig-derived 
      peptides to major histocompatibility complex (MHC) class I molecules and their 
      resulting low immunogenicity. This might be improved by conservative amino acid 
      modifications at the MHC-binding residues of the peptides (heteroclitic 
      peptides). In this study, it was found that in 18 Ig-derived peptides, that 
      heteroclitic peptides from the Ig gene with improved binding to human leukocyte 
      antigen (HLA)-A*0201 can be used to improve CTL responses. Amino acid 
      substitution substantially increased predicted binding affinity, and there was a 
      strong correlation between predicted and actual binding to HLA-A*0201. CTLs 
      generated against the heteroclitic peptide had not only enhanced cytotoxicity 
      against the heteroclitic peptide but also increased killing of antigen-presenting 
      cells pulsed with the native peptide. Surprisingly, no difference was observed in 
      the frequency of T cells detected by MHC class I peptide tetramers after 
      stimulation with the heteroclitic peptide compared with the native peptide. CTLs 
      generated against heteroclitic peptides could kill patients' tumor cells, showing 
      that Ig-derived peptides can be presented by the tumor cell and that the failure 
      to mount an immune response (among other reasons) likely results from the low 
      immunogenicity of the native Ig-derived peptide. These results suggest that 
      heteroclitic Ig-derived peptides can enhance immunogenicity, thereby eliciting 
      immune responses, and that they might be useful tools for enhancing immunotherapy 
      approaches to treating B-cell malignant diseases.
FAU - Harig, S
AU  - Harig S
AD  - Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, 
      USA.
FAU - Witzens, M
AU  - Witzens M
FAU - Krackhardt, A M
AU  - Krackhardt AM
FAU - Trojan, A
AU  - Trojan A
FAU - Barrett, P
AU  - Barrett P
FAU - Broderick, R
AU  - Broderick R
FAU - Zauls, A J
AU  - Zauls AJ
FAU - Gribben, J G
AU  - Gribben JG
LA  - eng
GR  - CA78378/CA/NCI NIH HHS/United States
GR  - CA81534/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (HLA-A2 Antigen)
RN  - 0 (Immunoglobulin Idiotypes)
RN  - 0 (Immunoglobulin Variable Region)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Peptide Fragments)
SB  - IM
MH  - Amino Acid Sequence
MH  - Amino Acid Substitution
MH  - Antigen Presentation
MH  - Binding Sites
MH  - Cytotoxicity, Immunologic
MH  - HLA-A2 Antigen/immunology/*metabolism
MH  - Humans
MH  - Immunoglobulin Idiotypes/chemistry/*immunology
MH  - Immunoglobulin Variable Region/chemistry/*immunology/metabolism
MH  - Leukemia, B-Cell/*immunology
MH  - Lymphoma, B-Cell/*immunology
MH  - Neoplasm Proteins/chemistry/*immunology
MH  - Peptide Fragments/chemistry/*immunology/metabolism
MH  - T-Lymphocytes, Cytotoxic/*immunology
EDAT- 2001/11/08 10:00
MHDA- 2002/01/05 10:01
CRDT- 2001/11/08 10:00
PHST- 2001/11/08 10:00 [pubmed]
PHST- 2002/01/05 10:01 [medline]
PHST- 2001/11/08 10:00 [entrez]
AID - S0006-4971(20)56833-X [pii]
AID - 10.1182/blood.v98.10.2999 [doi]
PST - ppublish
SO  - Blood. 2001 Nov 15;98(10):2999-3005. doi: 10.1182/blood.v98.10.2999.