Granulocyte-macrophage colony-stimulating factor (GM-CSF) was first described as a growth factor that induces the differentiation and proliferation of myeloid progenitors in the bone marrow. GM-CSF also has an important cytokine effect in chronic inflammatory diseases by stimulating the activation and migration of myeloid cells to inflammation sites, promoting survival of target cells and stimulating the renewal of effector granulocytes and macrophages. Because of these pro-cellular effects, an imbalance in GM-CSF production/signaling may lead to harmful inflammatory conditions. In this context, GM-CSF has a pathogenic role in autoimmune diseases that are dependent on cellular immune responses such as multiple sclerosis (MS) and rheumatoid arthritis (RA). Conversely, a protective role has also been described in other autoimmune diseases where humoral responses are detrimental such as myasthenia gravis (MG), Hashimoto's thyroiditis (HT), inflammatory bowel disease (IBD), and systemic lupus erythematosus (SLE). In this review, we aimed for a comprehensive analysis of literature data on the multiple roles of GM-CSF in autoimmue diseases and possible therapeutic strategies that target GM-CSF production.

The central role of T cells in the induction of immunological tolerance against i.v. Ags has been well documented. However, the role of dendritic cells (DCs), the most potent APCs, in this process is not clear. In the present study, we addressed this issue by examining the involvement of two different DC subsets, CD11c⁺CD11b⁺ and CD11c⁺CD8⁺ DCs, in the induction of i.v. tolerance. We found that mice injected i.v. with an autoantigen peptide of myelin oligodendrocyte glycoprotein (MOG) developed less severe experimental autoimmune encephalomyelitis (EAE) following immunization with MOG peptide but presented with more CD11c⁺CD11b⁺ DCs in the CNS and spleen. Upon coculturing with T cells or LPS, these DCs exhibited immunoregulatory characteristics, including increased production of IL-10 and TGF-β but reduced IL-12 and NO; they were also capable of inhibiting the proliferation of MOG-specific T cells and enhancing the generation of Th2 cells and CD4⁺CD25⁺Foxp3⁺ regulatory T cells. Furthermore, these DCs significantly suppressed ongoing EAE upon adoptive transfer. These results indicate that CD11c⁺CD11b⁺ DCs, which are abundant in the CNS of tolerized animals, play a crucial role in i.v. tolerance and EAE and may be a candidate cell population for immunotherapy of autoimmune diseases.

Multiple sclerosis is a CD4⁺ T cell-mediated autoimmune disease affecting the CNS. Multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), have been thought to be Th1-mediated diseases. However, recent studies provide strong evidence that the major pathogenic T cell subsets in EAE are Th17 cells. IL-9, a hematopoietic growth factor, is considered to be a mediator of Th17 cells, but the precise mechanisms of its action are largely unknown. The present study was designed to investigate the role of IL-9 in autoimmune demyelination. IL-9 blockade with anti–IL-9 mAb inhibited the development of EAE, reduced the serum levels of IL-17, the CNS mRNA expression of IL-17, IL-6, IFN-γ, and TNF-α, and the myelin oligodendrocyte glycoprotein (MOG)-induced IL-17, IFN-γ secretion of lymphocytes. Furthermore, anti–IL-9 mAb in culture suppressed IL-17 production of MOG-reactive T cells and their potency in adoptive transfer EAE. These findings indicate that the protective effect of IL-9 blockade in EAE was likely mediated via inhibition of the development of MOG peptide-specific T cells, which in turn led to reduced infiltration of T cells into the CNS. Thus, anti–IL-9 mAb treatment may provide an effective therapeutic strategy against autoimmune diseases.

Extracellular vesicles from oligodendrocytes restore antigen-specific immune tolerance in mice models of multiple sclerosis.