Anti-inflammatory cytokine gene therapy decreases sensory and motor dysfunction in experimental Multiple Sclerosis: MOG-EAE behavioral and anatomical symptom treatment with cytokine gene therapy

Abstract

Multiple Sclerosis (MS) is an autoimmune inflammatory disease that presents clinically with a range of symptoms including motor, sensory, and cognitive dysfunction as well as demyelination and lesion formation in brain and spinal cord. A variety of animal models of MS have been developed that share many of the pathological hallmarks of MS including motor deficits (ascending paralysis), demyelination and axonal damage of central nervous system (CNS) tissue. In recent years, neuropathic pain has been recognized as a prevalent symptom of MS in a majority of patients. To date, there have been very few investigations into sensory disturbances in animal models of MS. The current work contains the first assessment of hind paw mechanical allodynia (von Frey test) over the course of a relapsing-remitting myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis (MOG-EAE) rat model of MS and establishes the utility of this model in examining autoimmune induced sensory dysfunction. We demonstrate periods of both decreased responsiveness to touch that precedes the onset of hind limb paralysis, and increased responsiveness (allodynia) that occurs during the period of motor deficit amelioration traditionally referred to as symptom remission. Furthermore, we tested the ability of our recently characterized antiinflammatory IL-10 gene therapy to treat the autoimmune inflammation induced behavioral symptoms and tissue histopathological changes. This therapy is shown here to reverse inflammation induced paralysis, to reduce disease associated reduction in sensitivity to touch, to prevent the onset of allodynia, to reverse disease associated loss of body weight, and to suppress CNS glial activation associated with disease progression in this model.

Anti-inflammatory effect by lentiviral-mediated overexpression of IL-10 or IL-1 receptor antagonist in rat glial cells and macrophages

“…[19][20][21][22] IL-1ra acts as a true receptor antagonist by binding to the signalling IL-1 type I receptor thereby preventing binding of both IL-1a and IL-1b to their cell surface receptor and subsequent IL-1 actions. 23 IL-10 has a broader spectrum of anti-inflammatory activities because it suppresses the production of a whole number of pro-inflammatory cytokines (for example, interferon-g, IL-1a, IL-1b, IL-2, IL-6, IL-8 and TNF-a) and nitric oxide in different cell types, including glial cells, and B-and T-lymphocytes.…”

Neuropathic Pain in Multiple Sclerosis–Current Therapeutic Intervention and Future Treatment Perspectives

“…Moreover, reactive gliosis and a significant increase in the expression of the inflammatory cytokines in the dorsal root ganglia of EAE animals correlates with the onset of neuropathic pain behaviors in EAE rodents (57). In line with the important role of inflammation for pain development, gene therapy with anti-inflammatory IL-10 in EAE animals improved motor and sensory function, prevented allodynia, and reduced glial activation in the lumbar spinal cord (62).…”

“…Most likely, the therapeutic effect of rapamycin in EAE is dependent on its immunosuppressive activity involving inhibition of effector T-cells, expansion of regulatory T-cells, and inhibition of glial cell activation (80,81) -all processes shown to contribute to the pathology of MS-associated chronic neuropathic pain. In line with this, anti-inflammatory cytokine gene therapy reduced EAE disease course and prevented mechanical allodynia (62). In addition, fingolimod, an immune suppressive drug that reduces MS relapse rates and lesion frequency (82), has been shown to promote pain alleviation in animals with peripheral nerve injury-mediated pain conditions (83).…”

Insights into the Role of Neuroinflammation in the Pathogenesis of Multiple Sclerosis

“…For some people, MS is characterised by periods of relapse and remission while, for others, the disease exhibits a progressive pattern. Due to the spectrum of symptoms and clinical manifestations, it is not surprising that the life of MS patients may become unpredictable [4,8,[11][12][13].…”

“…The bureau estimates that about 48% of the MS sufferers in Australia exhibit profound limitations to their activity and autonomy. The neurological deficits of MS sufferers are an expanding list that progresses towards severe sensory dysfunction, often accompanied by the presence of cognitive dysregulation and neuropathic pain [3][4][5]. Some authors have also described peripheral neuropathy [3].…”