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Blood, 15 November 2001, Vol. 98, No. 10, pp. 2999-3005
IMMUNOBIOLOGY
Induction of cytotoxic T-cell responses against
immunoglobulin V region-derived peptides modified at
human leukocyte antigen-A2 binding residues
Sabine Harig,
Mathias Witzens,
Angela M. Krackhardt,
Andreas Trojan,
Patrick Barrett,
Ryan Broderick,
A. Jason Zauls, and
John G. Gribben
From the Department of Adult Oncology, Dana-Farber
Cancer Institute; and the Department of Medicine, Brigham and Women's
Hospital and Harvard Medical School, Boston, MA.
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.
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