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Microtubule-stabilizing agents delay the onset of EAE through inhibition of migration

David O'Sullivan1, John H Miller, Peter T Northcote

  • 1Centre for Biodiscovery, Schools of Biological Sciences and Chemical and Physical Sciences, Victoria University of Wellington, Wellington, New Zealand.

Immunology and Cell Biology
|September 25, 2013
PubMed

Insights

Microtubule-stabilizing agents (MSA) protect against experimental autoimmune encephalomyelitis (EAE) by inhibiting immune cell migration into the central nervous system (CNS) and preventing proliferation. Combination therapies with synergistic MSA enhance protection at lower doses.

Area of Science:

  • Immunology
  • Neuroscience
  • Pharmacology

Background:

  • Microtubule-stabilizing agents (MSA) are anti-proliferative compounds previously shown to delay disease onset and reduce cumulative disease in experimental autoimmune encephalomyelitis (EAE).
  • The precise mechanisms by which MSA exert their protective effects in EAE remain incompletely understood.

Purpose of the Study:

  • To investigate the mechanisms of action of MSA in EAE.
  • To determine if the protective effects of MSA are solely due to their anti-proliferative activity.
  • To explore the potential for synergistic effects between different MSA.

Main Methods:

  • Comparison of MSA administration before or after peak antigen-specific proliferation in an EAE model.
  • In vivo migration assays to assess immune cell infiltration into the central nervous system (CNS).
  • Evaluation of combination therapy using different MSA (peloruside A and ixabepilone).

Main Results:

  • Treatment with MSA before peak proliferation inhibited antigen-specific responses in the spleen, while treatment after peak proliferation did not.
  • Despite differences in proliferation inhibition, both treatment timings resulted in similar protection against EAE.
  • MSA were shown to inhibit immune cell infiltration into the CNS.
  • Combination treatment with low doses of two different MSA (peloruside A and ixabepilone) enhanced efficacy and synergized in vivo.

Conclusions:

  • The protective effect of MSA in EAE is not solely attributed to anti-proliferative activity.
  • MSA suppress EAE through at least two mechanisms: prevention of proliferation and inhibition of immune cell migration into the CNS.
  • Combination therapy with synergizing MSA offers enhanced protection at lower therapeutic doses, suggesting a promising therapeutic strategy for EAE.

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