Interferon-alpha as an anti-inflammatory modulator

The anti-inflammatory properties of interferon-alpha (IFNa) and IFNa-producing cells will be employed to inhibit arthritis. Systemic activation of IFNa inhibits development of joint inflammation but it is unknown how this is mediated by the immune system.

Interferon-producing cells as tolerance-promotors

The plasmacytoid dendritic cell is an antigen-presenting cell and the major producer of IFNaThese dendritic cells can be employed to prevent pathologic immune responses against self and foreign (e.g. transplanted) antigens (Ochando, 2006). This state is called immunological tolerance and is characterized by absence of pathogenic T- and B-cell responses. This can be due to quiescent cells or activation of T-cells that inhibits pathogenic cells. The mechanism of how plasmacytoid DC achieves this state of tolerance and the importance of their IFNa production for this effect is not known.
To study the ability of pDC to promote immune tolerance we use a model of joint inflammation called antigen-induced arthritis. In this model we have shown (unpublished data) that interferon-alpha can protect against development of arthritis.

One property of IFNa is to induce expression of immunoglobulin-like transcript (ILT) 3 and ILT4 on DC, which in turn enables DC to induce regulatory T-cells that inhibits inflammation (Manavalan, 2003). The plasmacytoid DC have two properties that suggest their involvement in IFNa-mediated protection against mBSA-induced arthritis. First, among all cells, they have the highest capacity to produce IFNa. Second, presentation of antigen by plasmacytoid DC to T helper cells may contribute to antigen-specific immune suppression (Ochando, 2006). I will therefore test the hypothesis that the protective effect of IFNa signalling in mBSA-induced arthritis is dependent on plasmacytoid DC.

Regulatory T-cells as mediators of the anti-inflammatory effecty of IFN 

Our data clearly shows that inability to signal through IFNa severely aggravates, whereas activation of IFNa dampens experimental antigen-induced arthritis (Ying et. al).

It has earlier been shown that IFNa is an important cytokine in the generation of regulatory T-cells with a suppressive capacity on other T-cells (Levings, 2001; Baban, 2009). I will therefore determine if the protective effect of IFNa signalling on antigen-induced arthritis can be mediated by regulatory T-cells.

References

• Ying, F., Chalise, J. P., Narendra, S. C. and Magnusson, M., Type I IFN protects against antigen-induced arthritis. Eur J Immunol 2011. 41: 1687-1695.
• Baban B, Chandler PR, Sharma MD et al. IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J Immunol 2009, 183(4):2475-2483
• Levings MK, Sangregorio R, Galbiati F, Squadrone S, de Waal Malefyt R, Roncarolo MG. IFN-alpha and IL-10 induce the differentiation of human type 1 T regulatory cells. J Immunol 2001, 166(9):5530-5539
• Manavalan JS, Rossi PC, Vlad G et al. High expression of ILT3 and ILT4 is a general feature of tolerogenic dendritic cells. Transpl Immunol 2003, 11(3-4):245-258
• Ochando JC, Homma C, Yang Y et al. Alloantigen-presenting plasmacytoid dendritic cells mediate tolerance to vascularized grafts. Nat Immunol 2006, 7(6):652-662