role of th1 and th17 cd4+ t cell subsets in the pathogenesis of ...

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1.7 ‐ STRATEGIC THERAPIES IN MS: RENDITION FROM EAE STUDIES?
Due to the complexity of CNS autoimmunity, only recently have researchers started to
understand MS pathology and EAE studies have been invaluable in the development of
each of the strategies described bellow and more. Positive results obtained in such of
these studies can be further confirmed with ones in MS and then follow to the clinical
trial phases. Naturally, many therapies have demonstrated to be of poor efficacy and
others with severe collateral effects. Nevertheless, EAE models are able to mimic the
relapse and remission phases of MS and, for that reason, are a precious tool to explore
the pathogenic mechanisms in order to design better strategies in MS treatment.
It is believed that immune cell migration, their adhesion to surface molecules of the
BBB and subsequent infiltration into the CNS parenchyma are crucial steps in the MS
and EAE pathogenesis (Engelhardt, 2008). In fact, the most famous therapeutic strategy
aiming at the targeting of the leukocyte trafficking across the BBB is by blocking the
alpha 4 subunit of the integrin VLA4 (very late antigen 4), a drug named Natalizumab.
This strategy results in the blockade of VLA‐4, expressed by T cells, binding to the
vascular cell‐adhesion molecule (VCAM‐1), expressed in the BBB endothelium, and is at
present the most potent drug approved so far in the treatment of relapsing‐remitting
MS. Another drug aiming at the targeting of leukocyte trafficking is the oral
immunosuppressant FTY720 (Fingolimod), a sphingosine‐1‐phosphate (S1P) analogue
that sequesters lymphocytes into the lymph nodes and therefore prevents immune cell
migration to the CNS. This drug is under investigation as a therapy and has
demonstrated a beneficial effect on disease activity in RR‐MS patients and in EAE
models (Miron et al., 2008).
As the humoral response also plays a role in MS, strategies aiming at B cells targeting
have been implemented. Rituximab is a chimeric murine‐human antibody against CD20 +
pre‐B cells and mature B cells, therefore interfering with the production of autoreactive
antibodies. The mixed cell targeting strategy counts with Alentuzumab as an example. It
is a humanized monoclonal antibody against CD52, a cell surface molecule present in T
cells, B cells and monocytes, and induces immediate cytolysis of these cells,