A recombinant human IgM promotes myelin repair after a single, very low dose
ABSTRACT 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.
- SourceAvailable from: Hans Ulrich LutzAutoimmunity Reviews 07/2008; 7(6):405-9. DOI:10.1016/j.autrev.2008.03.005 · 7.10 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Schwann cells are the myelinating glial cells of the peripheral nervous system and exert important regenerative functions revealing them as central repair components of many peripheral nerve pathologies. Intravenous immunoglobulins (IVIG) are widely used to treat autoimmune and inflammatory diseases including immune-mediated neuropathies. Nevertheless, promotion of peripheral nerve regeneration is currently an unmet therapeutical goal. We therefore examined whether immunoglobulins affect glial cell homeostasis, differentiation, and Schwann cell dependent nerve regenerative processes. The responses of different primary Schwann cell culture models to IVIG were investigated: immature or differentiation competent Schwann cells, myelinating neuron/glial cocultures, and dorsal root ganglion explants. Immature or differentiating Schwann cells were used to study cellular proliferation, morphology, and gene/protein expression. Myelination rates were determined using myelinating neuron/glia cocultures, whereas axonal outgrowth was assessed using non-myelinating dorsal root ganglion explants. We found that IVIG specifically bind to Schwann cells and detected CD64 Fc receptor expression on their surface. In response to IVIG binding, Schwann cells reduced proliferation rates and accelerated growth of cellular protrusions. Furthermore, we observed that IVIG treatment transiently boosts myelin gene expression and myelination-related signaling pathways of immature cells, whereas in differentiating Schwann cells, myelin expression is enhanced on a long-term scale. Importantly, myelin gene upregulation was not detected upon application of IgG1 control antibodies. In addition, we demonstrate for the first time that Schwann cells secrete interleukin-18 upon IVIG stimulation and that this cytokine instructs these cells to promote axonal growth. We conclude that IVIG can positively influence the Schwann cell differentiation process and that it enhances their regenerative potential.Journal of Neuroinflammation 05/2015; 12(1):107. DOI:10.1186/s12974-015-0331-7 · 4.90 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The immune system generates antibodies and antigen-specific T-cells as basic elements of the immune networks that differentiate self from non-self in a finely tuned manner. The antigen-specific nature of immune responses ensures that normal immune activation contains non-self when tolerating self. Here we review the B-1 subset of lymphocytes which produce self-reactive antibodies. By analyzing the IgM class of natural antibodies that recognize antigens from the nervous system, we emphasize that natural antibodies are biomarkers of how the immune system monitors the host. The immune response activated against self can be detrimental when triggered in an autoimmune genetic background. In contrast, tuning immune activity with natural antibodies is a potential therapeutic strategy.Future Neurology 01/2015; 10(1):25-39. DOI:10.2217/fnl.14.62