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Establecimiento de un modelo experimental para el estudio de la leishmaniosis. Estrategias de inmunización con las histonas de Leishmania frente a la leishmaniosis cutánea y visceral

AuthorsCarrión, Javier
AdvisorAlonso, Carlos
Issue Date2007
PublisherUniversidad Autónoma de Madrid
AbstractLeishmaniases refer to a wide range of vector-borne diseases caused by intracellular protozoa parasites of the genus Leishmania. These zoonotic diseases are a major public health problem in many countries. Several experimental animal models of leishmaniosis have been developed over the years. However, the level of protection provided by vaccines against visceral leishmaniosis (VL) is low, probably due to the lack of appropriate models to study both the disease and the protective immunity. We have analysed the immunohistological features occurring in BALB/c mice after intravenous administration of 103, 105 and 106 parasites of Leishmania infantum. We found, that in mice, the development of some quantifiable immunohistological features was dependent on the inoculum size: level of anti- Leishmania antibodies, up-regulation of spleen arginase activity, balance between IFN-γ and IL-10, lymphoid follicle depletion in the splenic white pulp and the development of hepatic granulomas. Our results suggested that a challenge of mice with 105 parasites should prove useful for the study of the level of protection induced by vaccines against VL. The mechanisms underlying the protective effects induced by dendritic cells (DC)- based vaccines against leishmaniosis in mice are not yet completely understood. In the present study, we investigated the potential of DC loaded with a mixture of the L. infantum histones in the absence (HIS-pulsed DC) or presence of CpG motifs (HISCpG-pulsed DC) against cutaneous (CL) and visceral leishmaniosis (VL). Our data showed that a single intravenous administration of HIS-pulsed DC or HISCpG-pulsed DC confers control to L. major infection in BALB/c mice. All HIS-pulsed DC vaccinated mice were able to control the primary infection but remained susceptible to a second challenge. Interestingly, HISCpG-pulsed DC vaccinated mice were able to control the L. major reinfection. The antileishmanial immunological mechanisms of protection were dependent on the ability to induce a Th1 response, a restriction of Th2 and a low frequency of Foxp3+ regulatory T-cells at the site of infection. These results document that a vaccine based on a HISCpG-pulsed DC formulation may prove to be a new and further tool to add to those designed to protect against L. major infection. Also, we found that the use of HIS- or HISCpG-pulsed DC partially restricts the splenic and hepatic parasite burdens in the 50 % of mice upon challenge with L. infantum parasites. We cloned the nucleosomal histones of L. infantum into the mammalian expression vector pcDNA3 in order to generate the following clones pcDNA3-H2AH3JC, pcDNA3- H2BH4JC, pcDNA3-H2AH4JC and pcDNA3-H2BH3JC. The clones were expressed well in mammalian cells. Finally, we studied the immune response induced by double DNA plasmids against murine CL or VL. A delayed footpad swelling and a restriction in the parasite growth in the DLN were observed in the inoculated mice after 6 weeks of infection with L. major parasites. We think that the high accumulation of splenic Treg cells may explain the attenuation of the Th2 response, but also of the Th1 response. However, similar genetic immunization in mice did not result in control of L. infantum challenge. Finally, we discuss various strategies to prevent or treat leishmaniosis for the optimization of the use of DC and of the histones of Leishmania for vaccine development
DescriptionTesis doctoral inédita de la Universidad Autónoma de Madrid. Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura : 22-06-2007
Appears in Collections:(CBM) Tesis
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