Remyelination-Promoting Human IgMs: Developing a Therapeutic Reagent for Demyelinating Disease

Abstract

Promoting remyelination following injury to the central nervous system (CNS) promises to be an effective neuroprotective strategy to limit the loss of surviving axons and prevent disability. Studies confirm that multiple sclerosis (MS) and spinal cord injury lesions contain myelinating cells and their progenitors. Recruiting these endogenous cells to remyelinate may be of therapeutic value. This review addresses the use of antibodies reactive to CNS antigens to promote remyelination. Antibody-induced remyelination in a virus-mediated model of chronic spinal cord injury was initially observed in response to treatment with CNS reactive antisera. Monoclonal mouse and human IgMs, which bind to the surface of oligodendrocytes and myelin, were later identified that were functionally equivalent to antisera. A recombinant form of a human remyelination-promoting IgM (rHIgM22) targets areas of CNS injury and promotes maximal remyelination within 5 weeks after a single low dose (25 µg/kg). The IgM isoform of this reparative antibody is required for in vivo function. We hypothesize that the IgM clusters membrane domains and

Proteomic Analysis of Demyelinated and Remyelinating Brain Tissue following Dietary Cuprizone Administration

“…In patients with chronic condition, repair of myelin is impaired. The steps leading to failure of repair in chronic lesions are not fully understood, although several possible mechanisms, including expression of inhibitory molecules and alterations in hormone levels, have been described (Back et al 2005;De Nicola et al 2006;Fernandez et al 2004;Warrington and Rodriguez 2008). The identification of important pathways or cellular functions involved in either promoting the repair of myelin or preventing the loss Table 2 Proteins at 3 weeks (T 3 ) and 6 weeks (T 6 ) of recovery with the largest abundance changes between treated and control brain tissues (q≤0.05; fold change ≥1.5; peptide number ≥2) of myelin could potentially lead to the development of novel therapeutics for this disease or other human dysmyelinated states (Rodriguez 2007).…”

Memorial: Roy Reed Peterson (1924 –2010), Emeritus Professor of Anatomy at Washington University School of Medicine

“…However, a previous study showed that rHIgM22 signaling was disrupted by cholesterol depletion, suggesting that the target of rHIgM22 may be associated with cholesterol‐enriched lipid rafts (Howe et al,2004). The fluorescence label intensity of rHIgM22 surface‐staining increases with OL maturation (Warrington and Rodriguez,2008). Therefore co‐localization studies of rHIgM22 and candidates were performed on cultures of mature (MBP‐positive) rat OLs.…”

“…The molecular mechanisms by which the IgM molecules promote remyelination are not understood. RHIgM22 has great potential to be a new therapeutic approach, because a single small dose of antibody was sufficient to induce extensive remyelination in vivo (Warrington et al,2007; Warrington and Rodriguez,2008). The first aim of this study was to identify potential signaling pathways, including cell surface molecules, involved in rHIgM22‐mediated signaling in OLs.…”

Surface plasmon resonance for high‐throughput ligand screening of membrane‐bound proteins

“…Approved antibody-based therapeutics are used to treat cancer, inflammatory diseases, transplantation recipients, infections and cardiovascular disease, and have a high rate of approval as drugs compared to small molecule based drugs [97]. By isolating mAbs from humans with monoclonal gammopathy, a condition in which the individual carries the mAb in high concentration for long periods of time, and focusing only on those individuals free of antibody-based disease, candidate mAbs can be isolated that have already been tested for long-term, high-dose, toxicity in at least one human [98,99]. Human mAbs from serum were selected based on cell surface binding and then assayed for efficacy in models of disease [100][101][102].…”