Tesis doctoral de María Del Carmen Durántez Delgado
The development of immunization strategies to induce strong and multiepitopic t cell responses against tumor antigens is needed for anti-tumor immunotherapy. In the present work, on the one hand, we have designed a minigene construct encoding four hla-a2-restricted epitopes belonging to tumor antigens cea (cea-691 and cea-571), mage2 (mage2-157), and mage3 (mage3-112), as well as the universal padre epitope recognized by t helper lymphocytes, with the aim of inducing multiepitopic responses against several common tumor antigens. We have used different antigen formats (short peptides encompassing individual epitopes, dna plasmids and adenoviral constructs expressing the minigene) in single or combined immunization schedules to optimize the activation of immune responses against these epitopes. Combination of peptide priming followed by a boost with the plasmid and the recombinant adenovirus expressing the minigene induced strong, multi-specific and long lasting anti-tumor immune responses, overcoming the immunodominance imposed by the main t cell epitope. These results suggest that heterologous immunization strategies combining peptides and dna or recombinant adenoviruses can be useful to broaden the specificity and enhance the efficacy of subunit vaccines. On the other hand, we analyzed whether the covalent linkage of a t cell epitope to phenol-soluble modulin peptides (psm) derived from stapylococcus epidermidis, which stimulate macrophages to produce proinflammatory cytokines via activation of toll like receptor 2 (tlr2) signaling pathway would facilitate its capture by tlr2-expressing dendritic cells and favour the in vivo induction of antigen specific immune responses. We demonstrated that synthetic modulins alpha (alpha-mod) or gamma (gamma-mod) induced maturation of bone marrow derived dendritic cells (bmdc). Synthetic peptides containing alpha-mod or gamma-mod and the cytotoxic t-cell epitope siinfekl from ovalbumin (ova) were able to bind to the surface of bmdc and to various subpopulations of splenocytes. These peptides, injected in vivo to mice in combination with different tlr ligands, induced strong and persistent ctl responses which were able to protect mice against the growth of ova-expressing tumors. Surprisingly, this immunomodulatory property of modulin-derived peptides was found to be tlr2 independent and at least partially dependent upon the epidermal growth factor (egf) receptor signaling pathway. Our results suggest that alpha or gamma modulin peptides may serve as a suitable antigen carrier for the development of anti-viral or anti-tumoral vaccines.
Datos académicos de la tesis doctoral «Inducción de respuestas inmunitarias mediante la combinación de diferentes formatos de antígeno. desarrollo de un método de vacunación basado en las modulinas producidas por staphylococcus epidermidis«
- Título de la tesis: Inducción de respuestas inmunitarias mediante la combinación de diferentes formatos de antígeno. desarrollo de un método de vacunación basado en las modulinas producidas por staphylococcus epidermidis
- Autor: María Del Carmen Durántez Delgado
- Universidad: Navarra
- Fecha de lectura de la tesis: 27/02/2009
Dirección y tribunal
- Director de la tesis
- Juan José Lasarte Sagastibelza
- Tribunal
- Presidente del tribunal: Francisco Borras cuesta
- Luis Alberto Anel bernal (vocal)
- margarita Del val latorre (vocal)
- ramon Merino perez (vocal)