Service Communautaire d'Information sur la Recherche et le Développement - CORDIS

Dissection of mechanisms of mucosal adjuvanticity of toxin-based immunomodulators

The works performed under this part of the project concerned with mechanisms explaining mucosal adjuvanticity of toxin-based immunomodulators. These studies focused on the bacterial toxins to probe the role of B cells and DC as APC in mucosal immune responses.

The scientific basis of this work was the notion that toxin-based adjuvants affect the functional status of mucosal APC and hence, will determine whether active immunity or tolerance to co-administered antigens will be induced.

For the proposed studies we have used six categories of immunomodulatory molecules:
- The enzymatically active holotoxins,
- The mutated enzymatically inactive holotoxins (e.g. LTK63),
- The partially active mutant holotoxins (e.g. LTR72),
- The B cell targeted enzymatically active CTA1-DD,
- The enzymatically inactive mutants of this fusion protein and finally
- The B-subunits.

The central hypothesis entertained in the project was that the vectors which activate B cells or DC will allow co-administered antigen to prime local and systemic immune responses. Conversely those vectors that bind, but do not activate them fully, will enhance the induction of systemic tolerance that normally occurs after mucosal administration of antigen. Hence we have investigated the ability of adjuvant treated APC to stimulate antigen-specific T cells and have explored the effects in vivo.

We compared the effects of the intact holotoxins and CTA1-DD with those of the enzymatically inactive mutant holotoxins, such as LTK63, or the B-subunits, to understand to what extent one or several distinctive immunomodulatory pathways exist for these mucosal adjuvants. Using the CTA1-DD fusion protein and its inactive mutants we tested the hypothesis that enzymatic activity in general augments APC function and results in active immune responses, whereas enzymatically inactive molecules may suppress/tolerize immune responses.

We have also evaluated the effect of another enzyme, Pertussis toxin S1, which replaced the CTA1 in the fusion protein together with DD, S1-DD. This construct was explored for adjuvant effects and the distinctive and separate enzymatic activity of S1 on Gia was compared with that of CTA1-DD, acting on Gsa.

More information on the MUCIMM project can be found at: http://www.altaweb.it/mucimm/.

Contact

Nils LYCKE, (Head of Laboratory)
Tél.: +46-313424936
Fax: +46-313424621
E-mail