Synthetic peptide analogs derived from bcr/abl fusion proteins and the induction of heteroclitic human T-cell responses Journal Article

  

Authors:	Pinilla-Ibarz, J.; Korontsvit, T.; Zakhaleva, V.; Roberts, W.; Scheinberg, D. A.
Article Title:	Synthetic peptide analogs derived from bcr/abl fusion proteins and the induction of heteroclitic human T-cell responses
Abstract:	Background and Objectives. Chronic myelogenous leukemia (CML) presents a unique opportunity to develop therapeutic strategies using vaccination against a truly tumor-specific antigen that is also the oncogenic protein required for neoplasia. We have shown in phase I and II trials that a tumor-specific, bcr-abl-derived peptide vaccine can be safely administered to patients with chronic phase CML and can elicit a reliable specific CD4 immune response. However, variable CD8 responses and no HLA A0201-restricted responses were found. One strategy to circumvent this poor immunogenicity is to design synthetic immunogenic analog peptides that cross-react with the native peptides (a heteroclitic response). The aim of this study was to design such peptides. Design and Methods. By using computer prediction analysis. We designed a number of synthetic peptides derived from the junctional sequences of CML (p210/b3a2 or p210/b2a2) in which single and double amino acid substitutions were introduced at key HLA A0201 binding positions. The binding of these peptides was tested by a thermostabilization assay using a T2 cell line. Results. We found three peptides that predicted good binding to HLA A0201 molecules and stabilized MHC class I A0201 molecules on the surface of T2 cell lines. These peptides were screened for eliciting HLA restricted, peptide-specific cytotoxic T lymphocyte responses using CD3+ T cells from several A0201 donors and CML patients. The CD8+ cytotoxic T lymphocytes lines were assessed by either interferon-γ ELISPOT or a chromium release assay using pulsed, HLA-matched leukemic cell lines. The analog peptides generated larger immune responses (increased CD8 T-cell precursor frequency) than did the native peptides. Importantly, CD8+ T cells stimulated with the new synthetic peptides cross-reacted with the native bcr-abl peptides. Interpretations and Conclusions. In conclusion, analog CML fusion peptides with increased immunogenicity and heteroclitic properties can be synthesized and may be useful in vaccination strategies. ©2005 Ferrata Storti Foundation.
Keywords:	human cell; cd8 antigen; t lymphocyte; t-lymphocytes; amino acid substitution; cell line; protein binding; cell line, tumor; chronic myeloid leukemia; gene transfer; donor; immune response; amino acid sequence; immunotherapy; gamma interferon; protein synthesis; screening; immunogenicity; peptide fragments; vaccination; cytotoxic t lymphocyte; bcr abl protein; enzyme linked immunospot assay; hla-a antigens; fusion proteins, bcr-abl; combinatorial chemistry techniques; major histocompatibility antigen class 1; hla system; patient; molecule; t cell receptor; computer aided design; minor histocompatibility antigen; chromium
Journal Title:	Haematologica
Volume:	90
Issue:	10
ISSN:	0390-6078
Publisher:	Ferrata Storti Foundation
Date Published:	2005-10-01
Start Page:	1324
End Page:	1332
Language:	English
PUBMED:	16219568
PROVIDER:	scopus
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-27144520232&partnerID=40&md5=a8a1e632829373c7d1b5d8b7a6dbd731
Notes:	--- - "Cited By (since 1996): 24" - "Export Date: 24 October 2012" - "CODEN: HAEMA" - "Source: Scopus"

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