T time…Is it time for Otilimab/ mavrilimumab?

T

Otilimab and mavrilimumab are human antibodies that block Granulocyte-macrophage colony stimulating factor (GM-CSF) of the GM-CSF receptor respectively. The may block macrophage function but could also block a new T cell type implicated in MS, which secretes GM-CSF

J. Rasouli et al. A distinct GM-CSF+ T helper cell subset requires T-bet to adopt a TH1 phenotype and promote neuroinflammation.Science Immunology 2020: 5: eaba9953. DOI: 10.1126/sciimmunol.aba9953.

The Authors say

“Production of GM-CSF by T helper cells not only guides adaptive immune responses but also can contribute to the pathogenesis of autoimmune disease. Rasouli et al. used single-cell RNA sequencing, mass cytometry, and GM-CSF fate mapper mice to identify a distinct subset of T helper cells in humans and mice that specialize in sustained GM-CSF production but lack key phenotypic features of other T helper lineages. In a mouse model of experimental autoimmune encephalomyelitis, these cells were poised to up-regulate IFN-γ within the central nervous system and promote development of encephalitis, processes that required the transcription factor T-bet. These results provide insight into the identity of GM-CSF–producing CD4 T cells and their function during autoimmune neuroinflammation”.

“Elevation of granulocyte-macrophage colony-stimulating factor (GM-CSF)–producing T helper (TH) cells has been associated with several autoimmune diseases, suggesting a potential role in the pathogenesis of autoimmunity. Using single-cell RNA sequencing and high-dimensional single-cell mass cytometry, we identified eight populations of antigen-experienced  T cells in blood of healthy individuals including a population of GM-CSF–producing cells, known as THGM, that lacked expression of signature transcription factors and cytokines of established TH lineages (TH1, TH2, TH17). We show that THGM cells are present in the periphery and central nervous system in experimental autoimmune encephalomyelitis. In addition to GM-CSF, human and mouse THGM cells also expressed IL-2, tumor necrosis factor (TNF), IL-3, and CCL20. THGM cells constitute a distinct population of TH cells with lineage characteristics that are poised to adopt a TH1 phenotype and promote neuroinflammation”.

We know about these cells

IL-17 and GM-CSF Expression Are Antagonistically Regulated by Human T Helper Cells.Rebecca Noster et al. Science Translational Medicine  2014: 6:241ra80

Although T helper 17 (TH17) cells have been acknowledged as crucial mediators of autoimmune tissue damage, the effector cytokines responsible for their pathogenicity still remain poorly defined, particularly in humans. In mouse models of autoimmunity, the pathogenicity of TH17 cells has recently been associated with their production of granulocyte-macrophage colony-stimulating factor (GM-CSF). We analyzed the regulation of GM-CSF expression by human TH cell subsets. Surprisingly, the induction of GM-CSF expression by human TH cells is constrained by the interleukin-23 (IL-23)/ROR-γt/TH17 cell axis but promoted by the IL-12/T-bet/TH1 cell axis. IL-2–mediated signal transducer and activator of transcription 5 (STAT5) signaling induced GM-CSF expression in naïve and memory TH cells, whereas STAT3 signaling blocked it. The opposite effect was observed for IL-17 expression. Ex vivo, GM-CSF+ TH cells that coexpress interferon-γ and T-bet could be distinguished by differential chemokine receptor expression from a previously uncharacterized subset of GM-CSF–only–producing TH cells that did not express TH1, TH2, and TH17 signature cytokines or master transcription factors. Our findings demonstrate distinct and counterregulatory pathways for the generation of IL-17– and GM-CSF–producing cells and also suggest a pathogenic role for GM-CSF+ T cells in the inflamed brain of multiple sclerosis (MS) patients. This provides not only a scientific rationale for depleting T cell–derived GM-CSF in MS patients but also multiple new molecular checkpoints for therapeutic GM-CSF suppression, which, unlike in mice, do not associate with the TH17 but instead with the TH1 axis.

GM-CSF has been blocked in MS, in

Constantinescu CS, Asher A, Fryze W, Kozubski W, Wagner F, Aram J, Tanasescu R, Korolkiewicz RP, Dirnberger-Hertweck M, Steidl S, Libretto SE, Sprenger T, Radue EW. Randomized phase 1b trial of MOR103, a human antibody to GM-CSF, in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2015;2(4):e117. 

Was it good enough after all that was 5 years ago,

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MouseDoctor

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