Methylthioadenosine reverses brain autoimmune disease.
OBJECTIVE
To assess the immunomodulatory activity of methylthioadenosine (MTA) in rodent experimental autoimmune encephalomyelitis (EAE) and in patients with multiple sclerosis.


METHODS
We studied the effect of intraperitoneal MTA in the acute and chronic EAE model by quantifying clinical and histological scores and by performing immunohistochemistry stains of the brain. We studied the immunomodulatory effect of MTA in lymphocytes from EAE animals and in peripheral blood mononuclear cells from healthy control subjects and multiple sclerosis patients by assessing cell proliferation and cytokine gene expression, by real-time polymerase chain reaction, and by nuclear factor-kappaB modulation by Western blot.


RESULTS
We found that MTA prevents acute EAE and, more importantly, reverses chronic-relapsing EAE. MTA treatment markedly inhibited brain inflammation and reduced brain damage. Administration of MTA suppressed T-cell activation in vivo and in vitro, likely through a blockade in T-cell signaling resulting in the prevention of inhibitor of kappa B (IkappaB-alpha) degradation and in the impaired activation transcription factor nuclear factor-kappaB. Indeed, MTA suppressed the production of proinflammatory genes and cytokines (interferon-gamma, tumor necrosis factor-alpha, and inducible nitric oxide synthase) and increased the production of antiinflammatory cytokines (interleukin-10).


CONCLUSIONS
MTA has a remarkable immunomodulatory activity and may be beneficial for multiple sclerosis and other autoimmune diseases.
Moreno
Beatriz
B
Neuroscience and Gene Therapy Division, Center for Applied Medical Research, University of Navarra, Navarra, Spain.
Hevia
Henar
H
Santamaria
Monica
M
Sepulcre
Jorge
J
Muñoz
Javier
J
García-Trevijano
Elena R
ER
Berasain
Carmen
C
Corrales
Fernando J
FJ
Avila
Matias A
MA
Villoslada
Pablo
P
D000328:Adult; D017668:Age of Onset; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000737:chemistry / Q000627:therapeutic use*; D008214:Lymphocytes / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010835:Phytohemagglutinins / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D018709:Statistics, Nonparametric; D013872:Thionucleosides / Q000737:chemistry / Q000627:therapeutic use*
D016564:Amyloid beta-Protein Precursor; D016207:Cytokines; D007155:Immunologic Factors; D010835:Phytohemagglutinins; D012333:RNA, Messenger; D013872:Thionucleosides; D052247:Nitric Oxide Synthase Type II