Chloroquine Treatment Enhances Regulatory T Cells and Reduces the Severity of Experimental Autoimmune Encephalomyelitis

Abstract

BackgroundThe modulation of inflammatory processes is a necessary step, mostly orchestrated by regulatory T (Treg) cells and suppressive Dendritic Cells (DCs), to prevent the development of deleterious responses and autoimmune diseases. Therapies that focused on adoptive transfer of Treg cells or their expansion in vivo achieved great success in controlling inflammation in several experimental models. Chloroquine (CQ), an anti-malarial drug, was shown to reduce inflammation, although the mechanisms are still obscure. In this context, we aimed to access whether chloroquine treatment alters the frequency of Treg cells and DCs in normal mice. In addition, the effects of the prophylactic and therapeutic treatment with CQ on Experimental Autoimmune Encephalomyelitis (EAE), an experimental model for human Multiple Sclerosis, was investigated as well.Methodology/Principal FindingsEAE was induced in C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein (MOG35–55) peptide. C57BL/6 mice were intraperitoneally treated with chloroquine. Results show that the CQ treatment provoked an increase in Treg cells frequency as well as a decrease in DCs. We next evaluated whether prophylactic CQ administration is capable of reducing the clinical and histopathological signs of EAE. Our results demonstrated that CQ-treated mice developed mild EAE compared to controls that was associated with lower infiltration of inflammatory cells in the central nervous system CNS) and increased frequency of Treg cells. Also, proliferation of MOG35–55-reactive T cells was significantly inhibited by chloroquine treatment. Similar results were observed when chloroquine was administrated after disease onset.ConclusionWe show for the first time that CQ treatment promotes the expansion of Treg cells, corroborating previous reports indicating that chloroquine has immunomodulatory properties. Our results also show that CQ treatment suppress the inflammation in the CNS of EAE-inflicted mice, both in prophylactic and therapeutic approaches. We hypothesized that the increased number of regulatory T cells induced by the CQ treatment is involved in the reduction of the clinical signs of EAE.

Chloroquine Autophagic Inhibition Rebalances Th17/Treg-Mediated Immunity and Ameliorates Systemic Lupus Erythematosus

“…Clearly, CQ does prevent lysosomedependent degradation of Foxp3, preserving Treg-cell functionality [36]. This phenomenon was similarly described in an earlier report of reduced severity of experimental autoimmune encephalomyelitis, achieved through CQ-induced enhancement of Treg functionality [37]. However, the means by which such differential autophagic regulation occurs will require further research.…”

Deficiency of Autophagy in Dendritic Cells Protects against Experimental Autoimmune Encephalomyelitis

“…As autoimmunity results from uncontrolled activation of adaptive immune system and CD4 T cells are the central component of adaptive immunity, autophagy might modulate autoimmune diseases through antigen presentation and activation of CD4 T cells. CQ treatment could also affect other cell types, including regulatory T cells, which might also affect in vivo development of EAE (30). CQ treatment could not completely abolish the disease.…”

Nitric oxide plays a key role in the suppressive activity of tolerogenic dendritic cells

“…EAE was induced as previously described. 9 The adoptive transfer was performed 10 days after MOG 35-55 immunization. Corroborating our previous report, 1 CQ-DCs WT were able to significantly reduce the clinical signs of EAE compared with the control group (PBSDCs WT ) (Figure 1e).…”