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Lacroix, et al. (2002). Delivery of hyper-interleukin-6 to the injured spinal cord increases neutrophil and macrophage infiltration and inhibits axonal growth

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    Lacroix, et al. (2002). Delivery of hyper-interleukin-6 to the injured spinal cord increases neutrophil and macrophage infiltration and inhibits axonal growth

    Lacroix S, Chang L, Rose-John S and Tuszynski MH (2002). Delivery of hyper-interleukin-6 to the injured spinal cord increases neutrophil and macrophage infiltration and inhibits axonal growth. J Comp Neurol 454:213-28. Cytokine growth factors of the interleukin (IL)-6 family have recently been shown to play an important role in central nervous system (CNS) development, repair, and inflammation. These cytokines, which interact via specific membrane receptors, share a signal-transducing receptor subunit, glycoprotein 130 (gp130). Gp130 is expressed by motoneurons in the gray matter of the rat spinal cord and by several brainstem nuclei that project to the spinal cord including the red, reticular, and vestibular nuclei. In this study, we examined whether stimulation of gp130 signaling, with the use of grafts of fibroblasts genetically modified to deliver the fusion protein, hyper-IL-6 (H-IL-6), which consists of the cytokine growth factor, IL-6, and its alpha receptor, would elicit growth of injured spinal cord axons. Particular emphasis was placed on examining the potentially competing effects of growth factor versus proinflammatory influences of H-IL-6 in the context of spinal cord injury. Our results demonstrated that grafts delivering H-IL-6 induce a sixfold increase in the number of neutrophils (P < 0.05) and a twofold increase in the areas of spinal tissue occupied by macrophages and activated microglia [P < 0.01) at the site of the spinal cord injury when compared with control grafts. Of note, this augmentation in inflammatory cell infiltration correlated with a significant twofold increase in lesion size [P < 0.05) and a fourfold reduction in axonal growth [P < 0.01) at the lesion site. Thus, potential neurotrophic properties of this cytokine family of growth factors must be balanced against their inflammatory properties when considering therapeutic application to CNS injury. J. Comp. Neurol. 454:213-228, 2002.:Cytokine growth factors of the interleukin [IL)-6 family have recently been shown to play an important role in central nervous system [CNS) development, repair, and inflammation. These cytokines, which interact via specific membrane receptors, share a signal-transducing receptor subunit, glycoprotein 130 [gp130). Gp130 is expressed by motoneurons in the gray matter of the rat spinal cord and by several brainstem nuclei that project to the spinal cord including the red, reticular, and vestibular nuclei. In this study, we examined whether stimulation of gp130 signaling, with the use of grafts of fibroblasts genetically modified to deliver the fusion protein, hyper-IL-6 [H-IL-6), which consists of the cytokine growth factor, IL-6, and its alpha receptor, would elicit growth of injured spinal cord axons. Particular emphasis was placed on examining the potentially competing effects of growth factor versus proinflammatory influences of H-IL-6 in the context of spinal cord injury. Our results demonstrated that grafts delivering H-IL-6 induce a sixfold increase in the number of neutrophils [P < 0.05) and a twofold increase in the areas of spinal tissue occupied by macrophages and activated microglia [P < 0.01) at the site of the spinal cord injury when compared with control grafts. Of note, this augmentation in inflammatory cell infiltration correlated with a significant twofold increase in lesion size [P < 0.05) and a fourfold reduction in axonal growth [P < 0.01) at the lesion site. Thus, potential neurotrophic properties of this cytokine family of growth factors must be balanced against their inflammatory properties when considering therapeutic application to CNS injury. J. Comp. Neurol. 454:213-228, 2002.

    #2
    hyper-interleukin-6 - looking into prior research on it.


    Transneuronal delivery of hyper-interleukin-6 enables functional recovery after severe spinal cord injury in mice - 1/15/2021
    https://www.nature.com/articles/s41467-020-20112-4


    Headline Patrol: German Scientists Make Paralyzed Mice Walk Again by Sam Maddox - 2/2/2021
    https://u2fp.org/get-educated/our-vo...ice-walk-again


    The protein used to promote recovery is called hyper-interleukin-6, which seems to stimulate nerve cells to regenerate. To be technical, it’s an artificial cytokine; these are switching molecules necessary for the multitude of processes needed to restart axon growth. There are of course natural cytokines in the brain and spinal cord, but the designer version works much better than native ones -- it hooks up with an abundance of receptors found on almost all neurons.

    Here’s a section lifted from a Ruhr press release:
    "This is a so-called designer cytokine, which means it doesn't occur like this in nature and has to be produced using genetic engineering," explains Fischer. His research group already demonstrated in a previous study that hIL-6 can efficiently stimulate the regeneration of nerve cells in the visual system.

    The study focused on motonuerons, long nerve fibers such as the corticospinal tract that descend from the brain down the spinal cord and control major activities such as walking. The researchers used an inert virus to ferry the genetic blueprint for the hI-6 protein to the target cells; they noticed that their protein also found its way to affect some nerve fiber side-paths in the brain that are also important for movement but hard to reach otherwise.
    "Thus, gene therapy treatment of only a few nerve cells stimulated the axonal regeneration of various nerve cells in the brain and several motor tracts in the spinal cord simultaneously," says Fischer. "Ultimately, this enabled the previously paralyzed animals that received this treatment to start walking after two to three weeks. This came as a great surprise to us at the beginning, as it had never been shown to be possible before after full paraplegia."

    According to the published results, the scientists studied some mice that had been mutated to delete (or flox, as the paper states it) a molecule called PTEN. PTEN acts as a sort of brake on nerve growth; getting rid of it, therefore, frees up robust spinal cord nerve growth. Their floxed animals showed some regeneration even without the added cytokine, but no motor recovery. Adding the hIL-6 cytokine was much better, with regeneration of the crucial corticospinal cord and recovery of motor function in both hind legs, even though the drug was only given on one side of the brain cortex.

    The German team suggests the regenerative effect of their novel cytokine might be improved if combined with other therapies.
    . . . our finding that the transneuronal application of hIL-6 enables functional recovery opens possibilities to further improve the functional outcome by combining it with other strategies, such as neutralizing extracellular inhibitors at the lesion site, or bridging the lesion site with permissive grafts. Such combinatorial approaches, also in less severe injury models, may maximize axon regeneration and functional recovery after spinal cord injury, potentially also in humans.

    “Potentially also in humans.” That’s down the road a bit. It’s innovative work, shows a very cool mechanism of action, and we can imagine the upside as they move it forward. From the paper, with a nod to a chronic model:
    The research team is now investigating to what extent this or similar approaches can be combined with other measures to optimize the administration of hyper-Interleukin-6 further and achieve additional functional improvements. They are also exploring whether hyper-interleukin-6 still has positive effects in mice, even if the injury occurred several weeks previously. "This aspect would be particularly relevant for application in humans," says Fischer. "We are now breaking new scientific ground. These further experiments will show, among other things, whether it will be possible to transfer these new approaches to humans in the future."

    Let’s see more. A bigger animal model is necessary – we have all seen mischiefs of injured mice that got better using therapies that never panned out in humans. Also, while a spinal cord crush is severe, and important to this study, it’s not clearly relevant to the more typical contusion injury most people with SCI have. Lastly, the only question the SCI community really cares about is, will it work in the chronic stage of spinal cord injury? The scientists speculate that it could, so we will keep an eye on this lab and this line of work.

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