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Rachel Spiering

Thursday 7 March 2013

Dendritic cells and immuno-modulation in autoimmune arthritis

Promotor: Prof.dr W. van Eden
Defence: 7 March 2013

Summary
Stable tolerogenic dendritic cells (DCs) have a great potential as treatment in autoimmune diseases. In addition, the anti-inflammatory effects of stress proteins have been reported extensively and in several experimental autoimmune models administration of stress proteins proved beneficial. The aim of this thesis was to study the promising immuno-regulatory role of stress proteins on DCs or produced by DCs. Furthermore, since DCs are naturally tolerogenic in a steady state condition, we explored whether targeting of these steady state DCs in vivo with a disease inducing antigen could protect mice from experimental arthritis.

In chapter 2 we studied whether targeting of immature steady state DEC-205+ DCs with an immunodominant peptide of proteoglycan (PG) fused to an antibody directed against DEC-205 could inhibit or reduce symptoms of proteoglycan induced arthritis (PGIA), a chronic B and T cell mediated mouse model for rheumatoid arthritis (RA). We found that PGIA severity was significantly reduced after DEC-205-PG administration. This suppression of disease was at least partly mediated by the induction of antigen-specific T cell anergy/deletion and antigen-specific regulatory T cell induction.

In chapter 3 we tried to refute the idea that heat shock proteins (HSPs) are danger/damage associated molecular patterns (DAMPs), a name HSPs have obtained due to their production under stressful conditions, such as tissue damage or inflammation. In addition, the regulatory role of HSPs on the immune system is described.

Chapter 4 describes the regulatory role of exogenously given mouse or mycobacterial HSP70 on the DC. The phenotype and function of HSP70 treated DCs was studied by means of examining DC phenotype, HSP70-DC activated T cell phenotype, and the possible immunoregulatory role of HSP70-DCs on PGIA. We concluded that HSP70 treated DCs were tolerogenic and able to diminish PGIA symptoms when injected in a prophylactic manner.

In chapter 5 we examined the effect of carvacrol, a plant compound earlier discovered as HSP70 co-inducer, in combination with heat stress, on the phenotype and function of DCs. The phenotype was analyzed by microarrays and function was determined by way of studying the role of carvacrol-heat stress treated DCs in the PGIA model. Carvacrol-heat stress treated DCs produced large amounts of the stress proteins HSP70 and metallothionein 1 (MT1) and after prophylactic injection mice had less severe arthritis symptoms as compared to controls.

In chapter 6 we studied the role of MT1 produced by tolerogenic DCs in the induction of a regulatory phenotype in T cells. DC membrane-bound MT1 was able to induce elevated expression levels of FoxP3 on T cells. Herewith, we have found a new marker and mechanism for functional tolerogenic DCs.

The research described in this thesis shows that stress proteins can be used as tolerogenic DC inducers and that tolerogenic DCs can function mechanistically via the secretion of stress induced proteins like MT1 and possibly HSP70. We showed that HSP70 treated DCs and DCs secreting stress proteins like MT1 and HSP70 are suppressive in the PGIA model when pulsed with PG and injected in the preclinical phase. Furthermore, targeting of immature DCs in the steady state situation with very low amounts of PG suppressed clinical symptoms of arthritis in the PGIA model via induction of PG specific T cell deletion/anergy and possibly the induction of PG-specificTregs. In conclusion, DCs have a high potential in the treatment of autoimmune diseases like RA, but several points, like costs and safety, need to be considered closely before applying this therapy into a human setting.