Abstract | PURPOSE: Cytotoxic T lymphocytes (CTL)- and T-helper cell-specific, and major histocompatibility complex (MHC) class-I and class-II peptides, respectively, of the HER-2/ neu protein, induce immune responses in patients. A major challenge in developing cancer peptide vaccines is breaking tolerance to tumor-associated antigens which are functionally self- proteins. An adequate CD4+ T-helper response is required for effective and lasting responses. METHODS: Stimulating anti- cancer CD4+ T cell responses by MHC class-II epitope peptides has been limited by their weak potency, at least compared with tight-binding MHC class-I epitope peptides. Previously, a potent T-cell response to a MHC class-II epitope was engineered by coupling the N-terminus of the pigeon cytochrome C [PGCC(95-104)] MHC class-II epitope to the C-terminus of an immunoregulatory segment of the Ii protein (hIi77-81, the Ii-Key peptide) through a polymethylene spacer. RESULTS: In vitro presentation of the MHC class-II epitope to a T hybridoma was enhanced greatly (>250 times). Now, an Ii-Key/HER-2/neu (777-789) MHC class-II epitope hybrid peptide stimulated lymphocytes from both a healthy donor and a patient with metastatic breast carcinoma. The in vitro primary stimulation with the hybrid peptide strongly activated IFN-gamma release, whereas the epitope-only peptide was weakly active. In fact, the hybrid stimulated IFN-gamma release as well as the wild-type peptide when augmented with IL-12; however, the hybrid was comparable to free peptide in stimulating IL-4 release. This pattern is consistent with preferential activation along a non-tolerogenic Th1 pathway. CONCLUSION:
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Authors | Michael E Gillogly, Nikoletta L Kallinteris, Minzhen Xu, Joseph V Gulfo, Robert E Humphreys, James L Murray |
Journal | Cancer immunology, immunotherapy : CII
(Cancer Immunol Immunother)
Vol. 53
Issue 6
Pg. 490-6
(Jun 2004)
ISSN: 0340-7004 [Print] Germany |
PMID | 14740174
(Publication Type: Journal Article)
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Chemical References |
- Antigens, Differentiation, B-Lymphocyte
- Antigens, Neoplasm
- Cancer Vaccines
- Epitopes
- Histocompatibility Antigens Class II
- Recombinant Fusion Proteins
- Vaccines, Subunit
- invariant chain
- Interleukin-12
- Interleukin-4
- Interferon-gamma
- Receptor, ErbB-2
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Topics |
- Antigens, Differentiation, B-Lymphocyte
(immunology)
- Antigens, Neoplasm
(immunology)
- Breast Neoplasms
(immunology, pathology, secondary)
- Cancer Vaccines
(immunology)
- Cell Division
(immunology)
- Epitopes
(immunology)
- Female
- Histocompatibility Antigens Class II
(immunology)
- Humans
- Immunization
- Interferon-gamma
(metabolism)
- Interleukin-12
(pharmacology)
- Interleukin-4
(metabolism)
- Lymph Nodes
(immunology, metabolism, pathology)
- Lymphocyte Activation
(drug effects)
- Male
- Receptor, ErbB-2
(immunology)
- Recombinant Fusion Proteins
(immunology)
- Vaccines, Subunit
(immunology)
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