Abstract
Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been known as a hematopoietic growth factor and immune modulator. Recent studies revealed that GM-CSF also had pro-inflammatory functions and contributed to the pathogenicity of Th17 cells in the development of Th17-mediated autoimmune diseases. GM-CSF inhibition in some animal models of autoimmune diseases showed significant beneficial effects. Therefore, several agents targeting GM-CSF are being developed and are expected to be a useful strategy for the treatment of autoimmune diseases. Particularly, in clinical trials for rheumatoid arthritis (RA) patients, GM-CSF inhibition showed rapid and significant efficacy with no serious side effects. This article summarizes recent findings of GM-CSF and information of clinical trials targeting GM-CSF in autoimmune diseases.
Highlights
Granulocyte-macrophage colony-stimulating factor (GMCSF) was originally defined by its ability in vivo to generate colonies of both granulocytes and macrophages from bone marrow precursors [1]
GM-CSFdeficient mice have relatively normal myelopoiesis with abnormal lung histology that is indistinguishable from human pulmonary alveolar proteinosis (PAP) [5], indicating a redundant role of Granulocyte-macrophage colony-stimulating factor (GM-CSF) in myeloid cell development and its differentiation and critical roles in the maturation and surfactant catabolism of alveolar macrophages [6]
In addition to these cells, recent studies reported the existence of an IL-2- or IL-7-activated STAT5dependent novel subset of GM-CSF-producing Th cells (Th-GM) which express low or undetectable T-bet, GATA-3, or RORγt [55, 56] and that Th-GM cells were able to induce more severe EAE than Th17 or Th1 cells [55]
Summary
Granulocyte-macrophage colony-stimulating factor (GMCSF) was originally defined by its ability in vivo to generate colonies of both granulocytes and macrophages from bone marrow precursors [1]. Recent findings on Th17 plasticity and heterogeneity indicate that it is necessary to re-examine previous studies in this field In addition to these cells, recent studies reported the existence of an IL-2- or IL-7-activated STAT5dependent novel subset of GM-CSF-producing Th cells (Th-GM) which express low or undetectable T-bet, GATA-3, or RORγt [55, 56] and that Th-GM cells were able to induce more severe EAE than Th17 or Th1 cells [55]. GM-CSF-producing CD4 T cells induce the polarization of neurotoxic M1-like phenotype of microglia and promote the production of pro-inflammatory cytokines such as IL-1β, IL-6, and TNFα, which contribute to myelin sheath damage [72, 73]. A phase 2a randomized, double-blind, placebocontrolled, ascending-dose study in subjects with moderate to severe active RA (EARTH study) reported significant efficacy with no serious adverse
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