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Ben Segal

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Primary Appointment: Neurology Department
Primary PIBS Dept.: Immunology
PubMed Name: Segal B.M.; Segal B.
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 DESCRIPTION OF RESEARCH
  Multiple Sclerosis and Animal Models of Inflammatory Demyelinating Disease:
We use animal models and clinical samples from patients with MS and other neurological disorders to study the influence of the CNS microenvironment on the development of local inflammatory responses and, conversely, the influence of immune mediators on neuronal and glial survival and regeneration. Many projects focus on the human disease multiple sclerosis (MS, the second most common cause of neurological disability in young adults) and its animal model, experimental autoimmune encephalomyelitis (EAE). MS is believed to be an autoimmune disease in which CD4+ T cells mount an aberrant attack against proteins in the myelin sheath. In the EAE model, mice injected with CD4+ T cells reactive against myelin proteins develop neuroinflammatory lesions and neurological deficits that simulate MS. We are investigating the mechanisms by which leukocyte subsets, chemokines and cytokines act together to induce demyelination and neuronal loss in EAE. Specific topics that we are currently investigating include the mechanism by which the growth factor, granulocyte macrophage-colony stimulating factor (GM-CSF), promotes disease activity in EAE and MS, and how GM-CSF antagonists can be used as therapeutic agents in MS. Another project concerns the immunoregulatory roles of macrophages and dendritic cells that infiltrate the CNS and produce iNOS or arginase-1 during EAE and MS. We are testing our hypothesis that these cells trigger “spontaneous” remissions from disease and that interventions to promote their expansion and trafficking to the CNS will be therapeutically beneficial.

Part of our efforts are devoted to translating discoveries made in animal models to clinical studies. This involves the analysis of peripheral blood and cerebrospinal fluid mononuclear cells that are collected from patients with MS or other neurological diseases and healthy controls. We are interested in identifying biomarkers that: (i) correlate with clinical relapse or progression, (ii) correlate with MRI lesion burden or new MRI lesion development, (iii) predict responsiveness to specific disease modifying drugs. Ongoing studies are demonstrating that certain chemokines are dysregulated in progressive forms of MS, and are associated with cognitive deficits, disability accumulation and brain atrophy.

Immune Mediated Neuroregeneration:
We are also studying how alternative types of immune responses can actually drive repair of the damaged CNS. We recently developed an animal model of immune mediated nerve fiber regeneration following crush injury to the optic nerve. In preliminary studies we have identified a unique subset of neutrophils that stimulate transected axons to regenerate. We are currently investigating their mechanism of action. We are hopeful that th insights gained from this research will ultimately inform the development of novel drugs that regulate pro-regenerative neutrophil subsets to stimulate axonal regrowth, while minimizing bystander tissue damage, in a spectrum of neurological disorders, including traumatic brain and spinal cord injury, ALS and MS.