Predictability of FTY720 efficacy in experimental autoimmune encephalomyelitis by in vivo macrophage tracking: clinical implications for ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging.
OBJECTIVE
To examine the efficacy of FTY720 as a new agent to reduce inflammatory activity in an animal model of multiple sclerosis (MS) by in vivo macrophage tracking.


METHODS
FTY720 was used for treatment of rats in a model of chronic relapsing experimental autoimmune encephalomyelitis (EAE) at an oral dose of 0.3 mg/kg/day. Magnetic resonance imaging (MRI) based on in vivo tracking of macrophages labeled with ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles, immunohistological staining (IHC), and neurological readouts was used to study the burden of disease in treated and untreated animals.


RESULTS
While untreated animals showed severe paralysis of the hind paws, intense accumulation of macrophages in brain tissue, and areas of blood-brain barrier (BBB) disruption, FTY720-treated animals displayed no signs of inflammatory activity or neurological impairment. These observations were made for both acute phase and first relapse.


CONCLUSIONS
Tracking of macrophages by MRI provides direct evidence of the immunomodulatory efficacy of FTY720 in the EAE model and correlates well with neurological symptoms and histology.
Rausch
Martin
M
Novartis Institute for Biomedical Research, Basel, Switzerland. martin.rausch@pharma.novartis.com
Hiestand
Peter
P
Foster
Carolyn A
CA
Baumann
Diana R
DR
Cannet
Catherine
C
Rudin
Markus
M
D000208:Acute Disease; D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D003287:Contrast Media; D003911:Dextrans; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000175:diagnosis* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D052203:Ferrosoferric Oxide; D000068876:Fingolimod Hydrochloride; D006571:Heterocyclic Compounds; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007501:Iron; D008264:Macrophages / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D058185:Magnetite Nanoparticles; D009942:Organometallic Compounds; D010087:Oxides; D011409:Propylene Glycols / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D043562:Receptors, G-Protein-Coupled / Q000819:agonists; D049312:Receptors, Lysophospholipid; D012008:Recurrence; D013110:Sphingosine
D003287:Contrast Media; D003911:Dextrans; D006571:Heterocyclic Compounds; D007166:Immunosuppressive Agents; D058185:Magnetite Nanoparticles; D009942:Organometallic Compounds; D010087:Oxides; D011409:Propylene Glycols; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; C097921:ferumoxtran-10; C050823:gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate; D007501:Iron; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D052203:Ferrosoferric Oxide