G-CSF Therapy of Ongoing Experimental Allergic Encephalomyelitis Via Chemokine- and Cytokine-Based Immune Deviation

Abstract

Converging evidence that G-CSF, the hemopoietic growth factor of the myeloid lineage, also exerts anti-inflammatory and pro-Th2 effects, prompted us to evaluate its direct therapeutic potential in autoimmune diseases. Here we report a novel activity of G-CSF in experimental allergic encephalomyelitis, a murine model for multiple sclerosis, driven by Th1-oriented autoaggressive cells. A short 7-day treatment with G-CSF, initiated at the onset of clinical signs, provided durable protection from experimental autoimmune encephalomyelitis. G-CSF-treated mice displayed limited demyelination, reduced recruitment of T cells to the CNS, and very discrete autoimmune inflammation, as well as barely detectable CNS mRNA levels of cytokines and chemokines. In the periphery, G-CSF treatment triggered an imbalance in the production by macrophages as well as autoreactive splenocytes of macrophage inflammatory protein-1α and monocyte chemoattractant protein-1, the prototypical pro-Th1 and pro-Th2 CC chemokines, respectively. This chemokine imbalance was associated with an immune deviation of the autoreactive response, with reduced IFN-γ and increased IL-4 and TGF-β1 levels. Moreover, G-CSF limited the production of TNF-α, a cytokine also associated with early CNS infiltration and neurological deficit. These findings support the potential application of G-CSF in the treatment of human autoimmune diseases such as multiple sclerosis, taking advantage of the wide clinical favorable experience with this molecule.

Effect of hematopoietic growth factors on severity of experimental autoimmune encephalomyelitis

“…They reported that G-CSF treatment before immunization with MPB or during peak of disease (from days 10 or 20 post immunization) significantly reduced disease severity. 40 Although peripheral lymphocyte Th1/Th2 cytokine skewing did not explain G-CSF disease exacerbation, the severity of inflammatory infiltration within the CNS did correlate with both G-CSF and Flt-3L and SCF-mediated disease exacerbation. Specifically, moderate to extensive infiltration of spinal cords by T lymphocytes and macrophages was observed in all the G-CSF-, SCF-and Flt-3L-treated groups.…”

“…Two clinical reports have also documented disease flare when using G-CSF in patients with MS. 9,10 However, timing of G-CSF administration may impact disease severity. 40, 41 Zavala et al 40 used G-CSF in MBP-not PLP-immunized mice, at different times then used in our study. They reported that G-CSF treatment before immunization with MPB or during peak of disease (from days 10 or 20 post immunization) significantly reduced disease severity.…”

CXCL12 Limits Inflammation by Localizing Mononuclear Infiltrates to the Perivascular Space during Experimental Autoimmune Encephalomyelitis

“…Alternatively, the enhanced expression of inflammatory cytokines observed during AMD3100 treatment may indicate that these cells are normally exposed to anti-inflammatory mediators within the perivascular space or that close interactions between T cells and macrophages at this site direct their mutual effector activities. Expressions of the anti-inflammatory cytokines IL-10 and IL-4 have been localized to perivascular macrophages within active MS lesions (64,65). These and other factors could influence the inflammatory responses of mononuclear cells as they migrate out of the blood and into the CNS parenchyma.…”

CCL22-Producing CD8α− Myeloid Dendritic Cells Mediate Regulatory T Cell Recruitment in Response to G-CSF Treatment

“…These data assign a key role to CD8a Interestingly, some biological agents already used in the clinics for other applications display such properties. Thus, treatment with G-CSF provides protection against various experimental autoimmune diseases, including lupus nephritis, experimental autoimmune encephalomyelitis, colitis, and type 1 diabetes (T1D) (1)(2)(3)(4)(5). T1D is an autoimmune disease characterized by the infiltration in the pancreatic islets of autoreactive T cells that target insulinproducing b cells.…”