13 research outputs found
Chimeric carrier proteins for targeted delivery of tumor antigens to professional antigen presenting cells
Tumor-specific T lymphocytes can be regarded as a highly effective mechanism for tumor rejection. A substantial number of T-cell defined tumor antigens including mutated oncoproteins and differentiation antigens have been identified. However, while most spontaneous tumors appear to be antigenic, few are immunogenic. Activation of tumor-specific cytotoxic T cells (CTL) requires presentation of tumor antigens by professional antigen presenting cells (APCs) via MHC I molecules. Due to their crucial role in T-cell activation, APCs are being exploited for active cancer immunotherapy. Present experimental strategies include the incubation of dendritic cells with synthetic, tumor specific peptides to achieve uptake of tumor antigens and presentation in the context of MHC molecules. Alternatively, gene therapeutic approaches are aimed at the endogenous expression of tumor antigens in APCs upon transfer of suitable vector constructs. Our strategy for the presentation of tumor antigens by APCs is based on the intracellular delivery of tumor antigens as part of a fusion protein specifically targeted to APC cell surface receptors. We have constructed prototype molecules that contain a soluble fragment of CTLA-4 for cell binding via interaction with B7 molecules, genetically fused to a protein fragment derived from the tumor-associated antigen ErbB2. To improve uptake and direct the antigenic determinant preferentially to the MHC class I pathway, in one of these protein vaccines also the translocation domain of the bacterial Pseudomonas exotoxin A has been included. In the parental toxin this protein domain facilitates escape from the endosomal compartment to the cytosol upon receptor mediated endocytosis. Here we have investigated the in vitro cell binding activity of such reagents and their antitumoral activity in immunocompetent murine model systems. Specific binding to B7 molecules and uptake of bacterially expressed protein vaccines could be demonstrated. Ex vivo restimulation with an ErbB2-derived peptide of splenocytes from Balb/c mice injected with the fusion proteins resulted in enhanced IFN-gamma production by T cells. Protective and therapeutic effects of ErbB2 protein vaccines were also investigated. Vaccinated animals were protected against subsequent challenge with syngeneic ErbB2 expressing tumor cells. Likewise, s.c. injection of ErbB2 protein vaccines in the vicinity of established tumors resulted in tumor rejection and long lasting protection indicating that immunological memory was induced. Our results suggest that chimeric proteins combining a tumor antigen and specific recognition of APCs in a single molecule are suitable for targeted delivery of antigens to professional APCs and might become valuable tools for cancer immunotherapy
Promotionsordnung der Mathematisch-Naturwissenschaftlichen Fachbereiche der Johann Wolfgang Goethe-Universität Frankfurt am Main vom 26. Mai 1993 (ABL.1/94, S. 21), zuletzt geändert am 16. Juni 2009 (Uni-Report 22. September 2009) : genehmigt durch Beschluss des Präsidiums der Johann Wolfgang Goethe-Universität Frankfurt am Main am 17. August 2010 ; hier: Änderung
Studien- und Prüfungsordnung für die Lehramtsstudiengänge an der Johann Wolfgang Goethe-Universität, Frankfurt am Main und der Hochschule für Musik und Darstellende Kunst, Frankfurt am Main (SPoL) vom 21.12.2005 : erster Beschluss zur Änderung und Ergänzung der Studien- und Prüfungsordnung für die Lehramtsstudiengänge an der Johann Wolfgang Goethe-Universität, Frankfurt am Main und der Hochschule für Musik und Darstellende Kunst, Frankfurt am Main (SPoL) vom 21.12.2005 ; genehmigt durch das Präsidium der Johann Wolfgang Goethe-Universität am 01.03.2011
Strategisches Handeln im Arbeitsprozeß : mit einer empirischen Studie zum Komplexitätsmanagement von Fach- und Führungskräften im Tätigkeitsfeld Absatzwirtschaft/Marketing
Targeted Delivery of the ErbB2/HER2 Tumor Antigen to Professional APCs Results in Effective Antitumor Immunity
Phenotype and function of monocyte derived dendritic cells in chronic hepatitis B virus infection
The Evolving Neural and Genetic Architecture of Vertebrate Olfaction
Evolution sculpts the olfactory nervous system in response to the unique sensory challenges facing each species. In vertebrates, dramatic and diverse adaptations to the chemical environment are possible because of the hierarchical structure of the olfactory receptor (OR) gene superfamily: rapid growth or pruning across the OR gene tree accompany major changes in habitat and lifestyle; independent selection on OR subfamilies can permit local adaptation or conserved chemical communication; and genetic variation in single OR genes among thousands can alter odor percepts and behaviors driven by precise chemical cues. However, this genetic flexibility contrasts with the relatively fixed neural architecture of the vertebrate olfactory system, whose slower rate of divergence mandates that new olfactory receptors integrate into segregated and functionally-distinct neural pathways. This organization allows evolution to couple critical chemical signals with selectively advantageous responses, but also constrains relationships between olfactory receptors and behavior. The coevolution of the OR repertoire and the structure of the olfactory system therefore reveals general principles of how the brain solves specific sensory problems and how it adapts to new ones