| Abstract |
One of the main unresolved issues in autoimmune diseases is the restoration of immune
homeostasis and self-tolerance. Although the variety of therapeutic targets is enormous,
a large number of patients with autoimmune syndromes fail to either respond to current
therapy or to achieve long-lasting remission after its cessation. Thus, despite our
increasing knowledge of the cellular and molecular processes involved in the
development of autoimmune diseases, the most effective targets for immunotherapy
remain unknown. The goal therefore, would be to develop novel therapeutic protocols
that could cure and not only palliate autoimmunity by resolving inflammation and
establishing lasting tolerance. To achieve this goal it is important to decipher the
mechanisms involved in the initiation and perpetuation of autoimmune diseases and in
particular to understand how the different cell subsets and molecules participate in such
processes.
In this Thesis, we focused on a dendritic cell subset, the plasmacytoid dendritic cells
(pDCs), that have been shown to have an instrumental role in the regulation of
autoimmune diseases. pDCs represent a unique DC subset, capable of inducing immunity
or tolerance. However, the contribution of these cells in the priming of an autoimmune
response remains elusive.
Our aims were (a) to investigate the role of pDCs during the priming of the autoimmune
response and (b) to explore the mechanism involved in the pDC-mediated regulation of
the autoimmune response.
In this study, we demonstrate that pDCs depletion during (MOG)-induced EAE resulted in
less severe disease compared to control mice. pDC-depleted/MOG-immunized mice, had
reduced cellularity in the draining lymph nodes (dLNs) which associated with decreased
frequency of IAb-MOG+CD4+ T cells than in control mice. DLNs MOG-specific T cells, from
pDC-depleted/MOG-immunized mice showed impaired proliferation and decreased IFN-
γ secretion in recall assays in vitro. Impaired T cell priming in pDC-depleted mice, was
not attributed to defective recruitment of conventional DCs in the dLNs or impaired
development of CD4+ T regulatory cells. Of interest, pDC-depleted mice had a markedly
increase in the frequency and absolute numbers of an immature population of myeloid
cells (myeloid-derived suppressor cells -MDSCs) in the dLNs, spleen and bone marrow,
implying that expansion of MDSCs after pDC depletion may account for the amelioration
of the autoimmune pathology.
To further explore the roles of MDSCs in the resolution of autoimmune inflammation
and reestablishment of self tolerance, we did a series of experiment.
We found that granulocytic MDSCs (G-MDSCs), were abundantly accumulated within the
peripheral lymphoid compartments and target organ of mice with EAE, prior to disease
remission. In vivo transfer of G-MDSCs ameliorated EAE, significantly decreased
demyelination and delayed disease onset, through inhibition of encephalitogenic Th1
and Th17 immune responses. Exposure of G-MDSCs to the autoimmune milieu led to upregulation
of the programmed death 1 ligand (PD-L1) that was required for the G-MDSCmediated
suppressive function both in vitro and in vivo. Importantly, MDSCs were
enriched in the periphery of subjects with active multiple sclerosis (MS) and suppressed
the activation and proliferation of autologous CD4+ T cells ex vivo. Collectively, this study
reveals a crucial role of MDSCs in the regulation of EAE and MS.
Overall, our data provide novel insights into the regulatory pathways of MS as
well as the mechanisms that limit inflammation during autoimmune diseases. Further
understanding on the immunosuppressive mechanisms of MDSCs, may open new
avenues for the development of more specific cell-based therapies in patients with
autoimmune inflammatory diseases.
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