Tesis doctoral de Francesc Rudilla Salvador
?Development of new methods of vaccination based on the anaphylatoxin c5a,the extra a protein of fibronectin and synthetic peptides inhibitors of regulatory t cells.¿ pathogens and cancer remain the leading causes of death worldwide. The development of vaccines to prevent diseases for which there is no vaccination remains a priority. In most cases, the development of such vaccines requires strategies capable of specifically stimulating the cd8+ cytotoxic t lymphocytes (ctls). ctls are activated by the presentation to t cell receptor (tcr) of small peptides associated with mhc class i molecules that are presented by mature dendritic cells. This presentation requires that ag-presenting cell has undergone a maturation process that is activated by signals from exogenous pathogens or endogenous signals, which transforms dendritic cells in apc able to activate t cells. For this reason, laboratories are trying to incorporate to vaccine formulations different molecules to activate the maturation of dendritic cells. This work focuses on the development of vectors or methods to transport antigens to dcs, which in turn transmit appropriate signals to the dc to induce activation. Among the surface receptors that can activate dcs this maturation is the tlr family «toll like receptors.» In previous work we demonstrated that the extra domain of fibronectin (eda) is capable of activating maturation of dendritic cells through tlr4 and promote the capture of antigen by the dc and induce their maturation for the proper activation of lymphocytes t. On the other hand, in this study, we investigated the potential of immuno anaphylatoxins (proteins derived from the cascade of complement activation) as adjuvants in vaccination. We found that the anaphylatoxin c5a, together with an antigen capable of activating in vivo response against the antigen specific t. We constructed several fusion proteins combining the eda with an antigen protein and the anaphylatoxin c5a, and found that the combination of eda-ag-c5a is the most effective formulation in the activation of a response to the antigen. on the other hand, it is known that the immune system has mechanisms of immunosuppression that control the activation of the immune response. Among them, it is known that the subpopulation of regulatory t cells (treg)(cd4 + cd25 + foxp3 +) play a crucial role. their action is important in preventing autoimmune diseases but may have negative effects on the activation of an antiviral or antitumor response. Therefore, we have worked on the development of molecules capable of inhibiting the action of these treg cells. Previous work from aour department showed that mice knock out for ae2a,b anion exchanger ae2 develop an autoimmune disease associated with a reduction of treg numbers we have identified peptides able to inhibit the anion exchanger ae2 and found that those peptides have an inhibitory effect on treg activity. The combination of both strategies (eda-fusion proteins, c5a ag) along with peptide inhibitors of treg is a very promising tool in the design of new prophylactic and therapeutic alternatives against viral infections or against cancer.
Datos académicos de la tesis doctoral «Desarrollo de nuevos métodos de vacunación basados en la anafilotoxina c5a y la proteína extra a de la fibronectina y péptidos sintéticos inhibidores de las células t reguladoras«
- Título de la tesis: Desarrollo de nuevos métodos de vacunación basados en la anafilotoxina c5a y la proteína extra a de la fibronectina y péptidos sintéticos inhibidores de las células t reguladoras
- Autor: Francesc Rudilla Salvador
- Universidad: Navarra
- Fecha de lectura de la tesis: 04/07/2011
Dirección y tribunal
- Director de la tesis
- Juan José Lasarte Sagastibelza
- Tribunal
- Presidente del tribunal: Jesús m. Prieto valtueña
- mercé Martí ripoll (vocal)
- ramon Merino perez (vocal)
- africa Gonzalez fernandez (vocal)