A recombinant human IgM promotes myelin repair after a single, very low dose
Department of Neurology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA. Journal of Neuroscience Research
(Impact Factor: 2.59).
04/2007; 85(5):967-76. DOI: 10.1002/jnr.21217
A recombinant human monoclonal IgM, rHIgM22, promotes the synthesis of new myelin when used to treat several animal models of demyelination. rHIgM22 binds to myelin and the surface of oligodendrocytes and accumulates at central nervous system lesions in vivo. The minimal dose of monoclonal IgM required to promote remyelination has a direct bearing on the proposed mechanism of action. A dose ranging study using rHIgM22 was performed in mice with chronic virus-induced demyelination, a model of chronic progressive multiple sclerosis. The lowest tested dose of rHIgM22 effective at promoting spinal cord remyelination was a single 500-ng intraperitoneal bolus injection. A time course study of spinal cord repair performed in chronically demyelinated mice revealed that remyelination plateaued by 5 weeks following treatment with rHIgM22. Two doses of rHIgM22 spaced 5 weeks apart did not increase the extent of remyelination over a single dose. The half-life of rHIgM22 in the mouse systemic circulation was determined to be 15 hr; the human IgM serum concentration was close to zero by 48 hr following antibody administration. We propose that the specificity of rHIgM22 for myelin on living tissue targets the antibody to demyelinated lesions, initiating a long-term reparative effect on the central nervous system.
Available from: Jens Oliver Watzlawik
- "Polyclonal and monoclonal IgMs that bind to CNS antigens promote remyelination in the TMEV- and lysolecithin-induced animal models of MS , . A single low dose of rHIgM22 (25 µg/kg) promotes substantial remyelination of demyelinated lesions ,  suggesting that the effect of the IgM is amplified in some manner by endogenous mechanisms of remyelination. Strong evidence confirms that rHIgM22 crosses the blood brain barrier and targets the demyelinated lesion . "
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ABSTRACT: Promotion of remyelination is a major goal in treating demyelinating diseases such as multiple sclerosis (MS). The recombinant human monoclonal IgM, rHIgM22, targets myelin and oligodendrocytes (OLs) and promotes remyelination in animal models of MS. It is unclear whether rHIgM22-mediated stimulation of lesion repair is due to promotion of oligodendrocyte progenitor cell (OPC) proliferation and survival, OPC differentiation into myelinating OLs or protection of mature OLs. It is also unknown whether astrocytes or microglia play a functional role in IgM-mediated lesion repair.
We assessed the effect of rHIgM22 on cell proliferation in mixed CNS glial and OPC cultures by tritiated-thymidine uptake and by double-label immunocytochemistry using the proliferation marker, Ki-67. Antibody-mediated signaling events, OPC differentiation and OPC survival were investigated and quantified by Western blots.
rHIgM22 stimulates OPC proliferation in mixed glial cultures but not in purified OPCs. There is no proliferative response in astrocytes or microglia. rHIgM22 activates PDGFαR in OPCs in mixed glial cultures. Blocking PDGFR-kinase inhibits rHIgM22-mediated OPC proliferation in mixed glia. We confirm in isolated OPCs that rHIgM22-mediated anti-apoptotic signaling and inhibition of OPC differentiation requires PDGF and FGF-2. We observed no IgM-mediated effect in mature OLs in the absence of PDGF and FGF-2.
Stimulation of OPC proliferation by rHIgM22 depends on co-stimulatory astrocytic and/or microglial factors. We demonstrate that rHIgM22-mediated activation of PDGFαR is required for stimulation of OPC proliferation. We propose that rHIgM22 lowers the PDGF threshold required for OPC proliferation and protection, which can result in remyelination of CNS lesions.
Available from: Istvan Pirko
- "Intracerebral infection with Theiler's Murine Encephalomyelitis Virus (TMEV) of susceptible mouse strains results in chronic demyelinating disease with progressive neurologic dysfunction similar to progressive forms of multiple sclerosis . Treating this model with IgM class antibodies that bind to oligodendrocytes improves CNS remyelination . In contrast, a serum-derived human monoclonal antibody (sHIgM12) that binds to neurons, promotes robust neurite outgrowth to the same degree as laminin, and reduces the inhibitory effects of CNS myelin on neurite outgrowth . "
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ABSTRACT: Our laboratory demonstrated that a natural human serum antibody, sHIgM12, binds to neurons in vitro and promotes neurite outgrowth. We generated a recombinant form, rHIgM12, with identical properties. Intracerebral infection with Theiler's Murine Encephalomyelitis Virus (TMEV) of susceptible mouse strains results in chronic demyelinating disease with progressive axonal loss and neurologic dysfunction similar to progressive forms of multiple sclerosis. To study the effects of rHIgM12 on the motor function of TMEV-infected mice, we monitored spontaneous nocturnal activity over many weeks. Nocturnal behavior is a sensitive measure of rodent neurologic function because maximal activity changes are expected to occur during the normally active night time monitoring period. Mice were placed in activity boxes eight days prior to treatment to collect baseline spontaneous activity. After treatment, activity in each group was continuously recorded over 8 weeks. We chose a long 8-week monitoring period for two reasons: (1) we previously demonstrated that IgM induced remyelination is present by 5 weeks post treatment, and (2) TMEV-induced demyelinating disease in this strain progresses very slowly. Due to the long observation periods and large data sets, differences among treatment groups may be difficult to appreciate studying the original unfiltered recordings. To clearly delineate changes in the highly fluctuating original data we applied three different methods: (1) binning, (2) application of Gaussian low-pass filters (GF) and (3) polynomial fitting. Using each of the three methods we showed that compared to control IgM and saline, early treatment with rHIgM12 induced improvement in both horizontal and vertical motor function, whereas later treatment improved only horizontal activity. rHIgM12 did not alter activity of normal, uninfected mice. This study supports the hypothesis that treatment with a neuron-binding IgM not only protects neurons in vitro, but also influences functional motor improvement.
Available from: Jeffrey Lawrence Winters
- "We have demonstrated that rHIgM22 binds to oligodendrocytes and myelin and promotes CNS remyelination in virus- and toxin-induced models of MS. Spinal cord remyelination is induced after a single low dose (25 μg/mL) of rHIgM22 . It is remarkable that one peripheral (i.p.) treatment with a short-lived molecule (15 hr half life in mice) promotes maximal tissue repair within 5 weeks in a model of MS with little spontaneous repair. "
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ABSTRACT: The pathogenesis of multiple sclerosis (MS) remains elusive. Recent reports advocate greater involvement of B cells and immunoglobulins in the initiation and propagation of MS lesions at different stages of their ontogeny. The key role of B cells and immunoglobulins in pathogenesis was initially identified by studies in which patients whose fulminant attacks of demyelination did not respond to steroids experienced remarkable functional improvement following plasma exchange. The positive response to Rituximab in Phase II clinical trials of relapsing-remitting MS confirms the role of B cells. The critical question is how B cells contribute to MS. In this paper, we discuss both the deleterious and the beneficial roles of B cells and immunoglobulins in MS lesions. We provide alternative hypotheses to explain both damaging and protective antibody responses.
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