Plasmacytoid Dendritic Cells and Immunotherapy in Multiple Sclerosis

Felipe von Glehn; Leonilda M Santos; Konstantin E Balashov


Immunotherapy. 2012;4(10):1053-1061. 

In This Article

pDCs as Potential Therapeutic Targets in MS

The effect of immunomodulatory therapy on pDC phenotype and function has been reported.[85–91,92] Treatment with glatiramer acetate seems to restore the impaired maturation and altered regulatory function of pDCs in MS.[85] Activated pDCs had decreased ability to produce IFN-α, IL-6, TNF-α and the chemokines CCL3, CCL4 and CCL5 in IFN-β-treated patients compared with untreated patients.[91,92] This effect may potentially lead to decreased migration of activated pDCs to the CNS and, afterwards, attraction of CCR5+Th1 lymphocytes, which would diminish formation of new demyelinating lesions.[38,92]

TLR9 is abundantly expressed in pDCs and appears to be important in the pathogenesis of EAE. Activation of APCs through TLR9 can overcome tolerance and precipitate EAE,[93–95] while TLR9 knockout mice have decreased susceptibility to EAE.[94] By contrast, TLR3 stimulation suppresses EAE by activation of the MyD88-independent pathway.[96] TLR9 gene and protein expression in pDCs of patients with MS was comparable with healthy donors. However, it was identified that IFN-β inhibited TLR9 processing necessary for TLR9-mediated activation of pDCs when compared with untreated MS patients.[90] In the present authors' recent study, pDC gene expression was analyzed by oligo microarrays before and after IFN-β treatment in patients with relapsing form of MS. The expression of 283 genes was found to be affected by treatment.[93]

Inhibitory oligodeoxyribonucleotides (INH-ODN), also called TLR9 antagonists, are able to block downstream signaling events in TLR9-expressing cells.[97,98] Some of these INH-ODNs can also target TLR7 signaling pathways. INH-ODNs are in the early stages of testing in vitro and in vivo. They are able to inhibit activation of human pDCs and B cells in vitro, block reactive arthritis and delay development of lupus nephritis in mice.[97,98] TLR antagonists could also offer a way to lower steroid dosage and thus reduce side effects in lupus patients.[99] INH-ODNs may be an optimal specific tool to prevent activation of TLR9-expressing pDCs by DNA viruses such as EBV, which have been implicated in MS pathogenesis.[100,101] The use of TLR9 antagonists may well have a major effect on MS.

Another potential therapeutic option would be to control pDC recruitment to the CNS through chemokine receptor antagonists, for example, antibodies against CCR7, CXCR4, CXCR5 or ChemR23. One may hypothesize that the reduction of activated pDCs in the CSF, leptomeninges and demyelinating lesions of patients with MS would attenuate the proinflammatory microenvironment. On the other hand, mature pDCs, pDCs stimulated via surface molecules BDCA-2 and ILT-7,[36] and alternatively activated pDCs[102,103] promote tolerance. Increased expression of IDO in activated pDCs promotes generation of FoxP3+ Tregs in vitro.[104,105]