RESUMO
The translation machinery of a eukaryotic cell produces errors in decoding mRNA that may give rise to alternative reading frame (Arf) polypeptides. We predicted these putative aberrant translation products from the cDNA of three tumor-associated antigens (Ag): a transmembrane glycoprotein of the class I receptor tyrosine kinase erbB family HER-2, telomerase reverse transcriptase (TERT) and prostatic acid phosphatase (PAP). Immunization of mice with Arf peptide-pulsed antigen presenting cells (APC) generated potent in vivo immune protection against tumors expressing respective tumor-associated Ag. CD8+ T cells from mice immunized with HER-2 derived protective Arf peptides specifically recognized HER-2 transfected tumor cells. The strategy described here has potential for designing highly efficient novel vaccines for Ag-specific immunotherapy of human malignancies.
Assuntos
Antígenos/uso terapêutico , Imunoterapia , Neoplasias/terapia , Fragmentos de Peptídeos/uso terapêutico , Animais , Antígenos/genética , Antígenos/imunologia , Proteínas de Ligação a DNA , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/imunologia , Proteínas Associadas a Pancreatite , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/imunologia , Proteínas/genética , Proteínas/imunologia , Proteínas/uso terapêutico , Fases de Leitura , Receptor ErbB-2/genética , Receptor ErbB-2/imunologia , Receptor ErbB-2/uso terapêutico , Telomerase/genética , Telomerase/imunologia , Telomerase/uso terapêutico , Células Tumorais CultivadasRESUMO
From the recombinant human leukocyte antigen (HLA)-DR1/H2-E(k) major histocompatibility complex (MHC) class II-transgenic mice, we have generated two CD4(+) T-cell hybridomas specific for peptides which were derived from human prostatic acid phosphatase (PAP) complexed to the human class II molecule HLA-DR1. Both hybridomas strongly react to PAP-pulsed antigen-presenting cells (APC) from transgenic mice. Interestingly, these hybridomas also responded to PAP antigen presented by HLA-DR1-positive human APC. The species-mismatched T-cell stimulation occurs despite the biologic discordance in participating accessory molecules, which are required for the optimal T-cell-APC interaction. Our results demonstrate various degrees of functional interaction between coreceptors, costimulatory molecules, and integrins, which are expressed on the surface of T-cell hybridomas and heterologous APC.
Assuntos
Apresentação de Antígeno , Células Apresentadoras de Antígenos/imunologia , Antígenos Heterófilos/imunologia , Linfócitos T CD4-Positivos/imunologia , Antígenos H-2/imunologia , Antígeno HLA-DR1/imunologia , Hibridomas/imunologia , Fosfatase Ácida , Animais , Linfócitos T CD4-Positivos/metabolismo , Linhagem Celular/imunologia , Epitopos de Linfócito T/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Antígenos H-2/genética , Antígeno HLA-DR1/genética , Humanos , Interleucina-2/metabolismo , Camundongos , Camundongos Transgênicos , Proteínas Tirosina Fosfatases/imunologia , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes/imunologia , Especificidade da EspécieRESUMO
Certain types of malignant tumors overexpress HER-2, a transmembrane glycoprotein of the class I receptor tyrosine kinase erbB family. To develop an effective HER-2 vaccine for the selective immunotherapy of these malignancies, we have genetically engineered fusion proteins containing portions of extra- and intracellular HER-2 domains. Activated dendritic cells (DC) cocultured with these novel antigens (Ag) could induce potent responses of Ag-specific T-cell lines in vitro and a protection against HER-2-expressing tumor in vivo. The protective capabilities of HER-2-derived fusion proteins correlated with the efficiency of their presentation to Ag-specific T-cell hybridomas. The most effective Ag contained GM-CSF, the presence of which facilitated their internalization by antigen-presenting cells (APC) in a receptor-mediated manner.