Estrategias de modulación de la respuesta inmune frente a la malaria en el modelo murino de "plasmodium yoelll"
Author
Blanco Chapinal, SoledadEntity
UAM. Departamento de Biología MolecularDate
2005-12-16Subjects
Sistema inmunológico - Tesis doctorales; Paludismo - Tesis doctorales; Biología y Biomedicina / BiologíaNote
Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 16-12-2005Abstract
Malaria is one d the most devastating human diseases against which an effective
vaccine is still lacking. In this study we analyzed different strategies that were designed to
modulate the immune response elicited against the CS protein of Plasmodittm ywltt (PyCS), a
murine malaria model.
First, as it has been obsewed that the co-administration of several cytokines enhances
antigen specific ceUular responses, we generated recombinant vaccinia viruses (rWs) that coexpress
the cytokines IL-15 or GM-CSF together with the PyCS antigen or with the luciferase
reporter protein. By using the luciferase expressing rVV we determined that IL15 attenuates
W replication "in vivo". We also determined that the co-expression of either of these cytokines
did not significantly modify the specific cellular immune response against @CS. However,
when the cytokines were co-administered together with the PyCS antigen by DNA vectors
followed by a booster with a rW also expressing PyCS, relevant improvements were observed.
The co-inoculation of GM-CSF results in a significant enhancement of the specific immune
respomes (4-7 times) that correiates with a high degree of protection, higher than 97%. On the
other hand, co-inoculation of IL-15 sustains the specific cellular immune response elicited
against Py€S. This feature is of special interest in the development of a vaccine that ideally
should mduce long-lasting protection.
In an attempt to improve the cellular immune response elicited against PyCS by DNA
vectors we generated a construct with a codon-optimized sequence. The sequence was also
mutated to eliminate two glycosylation sites and the C-teminal membrane-anchoring domain.
Despite these changes, the cellular immune response elicited by this vector was simiiar to that
obtained with the plasmid expressing the original PyG protein.
in another approach, we generated multiepitopic rVV that contain the nucleotide
sequences coding for different epitopes as minigenes ceparated by Interna1 Ribosome Enby Site
(IRES) elemenís from different origins. The expression of the CD8 T cell epitope from PyCS
(PyCD8) by antigen presenting cells (APC) infected with these rW was analyzed by an "in
vitro" ELICPOT assay. Similar levels of epitope presentation were observed irrespective of i) the
context in which it is expressed (inside the CS protein and isolated, immediately after VV
promoter or after an IREC sequence), u) the presence of other epitopes in the rVV and üi) the
origin of the IRES sequence that is preceding it. Furthermore, mice inoeulated with these rW
elicited a specific immune response against ea& of the epitopes that are present in the rW:
PyCD8 (H-2d haplotype), V3 from Env protem of VIH (H-Zd haplotype) and PKD8 from
P.falcipamm CS (H-2k haplotype), and these cellular immune respowes were similar in
magnihide to those induced by r W expressing their respective fuil proteins. This is a novel
approach that could be useful for the development of multivalent vaccines containing epitopes
from antigens of different infectious agenís, and/or antigens present in different stages of the
pathogen Me cycle, that is an important ksue when parasites like Plasntodium are considered as
target of a vaccine.
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