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IMPCSF Informe resumido

Project ID: QLK2-CT-2001-01374
Financiado con arreglo a: FP5-LIFE QUALITY
País: Switzerland

High-throughput culture systems for the evaluation of vaccine-induced innate immune responses

Novel vaccines and modern delivery systems designed specifically to target dendritic cells (DC) holds promise for improving the immunogenicity of vaccines and modulating the immune response towards the desired direction. Such systems have been established and can be based on synthetic micro- and nanoparticles, virus like particles, virosomes, virus replicating particles or non-particulate system using proteins or nucleic acids linked to a targeting ligand promoting their uptake. The latter of course can also be combined with particulate vaccines. The characterization of the in vitro interactions of such elements with DC permits a "high throughput" screening of delivery systems and vaccine/vaccine components to identify the most potent with respect to their potential to stimulate both innate (DC activation and maturation) as well as adaptive immune responses (Th and Tc responses).

In particular the following has be achieved:
1. A rationalised approach to identify immunogenic viral proteins was established. Due to the access to large volumes of porcine blood, monocyte-derived dendritic cells (MoDC) can be easily generated in vitro in large quantities and used as APC for monitoring T-cell responses and identification of immunogenic proteins or peptides. Although the simple use of blood leukocytes, which already contain APC's can also be used, the employment of MoDC as APC can have an advantage or even be required for certain situations. For example, the ratios of APC can be kept constant and if required high enough to enable efficient T-cell stimulation. Furthermore, MoDC permit controlled antigen delivery, for example when viral vectors, mRNA transfection, micro- or nanoparticle-mediated delivery are used.

In particular the mRNA transfection approach has several major advantages and applications:
(i) It is suitable for MHC class I-restricted CTL epitopes;
(ii) the production of mRNA molecules is easy and quick compared to recombinant proteins,
(iii) in contrast to peptides the approach is not dependent on MHC haplotype,
(iv) MoDCs and fibrocytes can be efficiently transfected with mRNA molecules, whereas gene expression after plasmid DNA transfection is not detectable,
(v) the system is more controllable compared to viral vectors which express many genes with potential to interfere with the experimental system
(vi) mRNA-transfected APCs potentially display the complete spectrum of epitopes relevant to a particular protein, rather than those present on the synthesised peptides. This has the advantage of uncovering previously unknown epitopes, but is particularly valuable in not suffering from restrictions imposed by MHC haplotype.

2. A culture systems for screening of potential immunostimulants suitable as vaccine adjuvants were established.
Using cultures of enriched natural interferon producing cells (NIPC) we have identified vaccines able to induce high levels of IFN-a. These could promise important to improve vaccines in particular for emergency scenarios caused by epidemic outbreaks of virus infections.

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Artur SUMMERFIELD, (Head of Laboratory)
Tel.: +41-318489377
Fax: +41-318489222
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