Immunotherapy


  HEADProf. MARCHAL Gilles / gmarchal@pasteur.fr
  MEMBERSDr ABOLHASSANI Mohammad / Dr KLUGE Christoph / LAGRANDERIE Micheline


  Annual Report

The absence of infectious diseases during early infancy correlates with increased incidence of allergic and autoimmune diseases. An epidemiological report demonstrated a protective effect of BCG against the development of atopy in infants. Extensive freeze-drying to was used to prepare killed BCG. This gentle physical method removes water so that there is less 0.5% water remaining in the bacterial corpses. The material named EFD has no toxicity and induces only a marginal DTH reactivity against mycobacterial antigens. Treating OVA-sensitized mice subcutaneously with EFD reduces establish asthma, eosinophilia, IL-5 production, mucosal metaplasia, in a murine model of experimental asthma.

Crucial role of plasmacytoid DCs and Tregs in the control of experimental asthma by EFD

Plasmacytoid dendritic cells (pDCs), are potentially involved in the differentiation of naïve T lymphocytes into regulatory cells (Tregs). We detected high numbers of pDCs producing IL-10 in the draining lymph nodes of mice injected with EFD, whereas live- or HK- BCG injections failed to induce this cell subset. In vitro, the pDCs isolated from draining lymph nodes after EFD injection induced the differentiation of naïve CD4+ T lymphocytes into Tregs (FOXP3-expressing CD4+CD25+ cells). If we adoptively transferred DCs, purified four days after EFD treatment, to OVA-sensitized mice, the recipient mice were protected. Moreover, transient depletion of pDCs just before EFD treatment, decreased the Tregs number and the mice were not protected.

If we depleted Tregs, in vivo the beneficial effects of EFD treatment were abolished. At the opposite, Tregs transferred i.v. before challenge controlled asthma symptoms. These transfer experiments allowed to demonstrate the absence of specificity for the response.

In correlation we observed important difference, after s.c. injection of PBS, live-BCG, HK-BCG or EFD, in the expression of the transcription factors recognized to monitor Th1 and Th2 cell subsets.

The described mechanisms may also be active in other diseases in which autoimmunity is involved.

Other autoimmune diseases: Crohn’s disease

Crohn’s disease is a chronic relapsing inflammatory reaction that may affect any part of the gastrointestinal tract. It appears to result from an inappropriate immune response to normal gut flora. A “perfect” experimental model for this disease does not exist. Inflammatory bowel disease (IBD) induced in mice by ingestion of dextran sulphate is one model. EFD was able to prevent IBD in mice and it also diminished the severity of symptoms in a curative model.

Perspectives:

The effects of EFD treatment on other experimental inflammatory diseases like rheumatoid arthritis, experimental allergic encephalitis (a model for multiple sclerosis)… will be assayed. Differences between inflammatory models may give indications on the mechanisms of EFD activity.

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  Publications

Publications 2006 of the unit on Pasteur's references database




Activity Reports 2006 - Institut Pasteur
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