Scott Zamvil | University of California | San Francisco, CA
San Francisco, CA
New Haven, CT
Portland, OR
Phoenix, AZ
Dallas, TX
Seattle, WA
Los Angeles, CA
Cleveland, OH
St. Louis, MO
New York, NY
Buffalo, NY
Rochester, NY
Baltimore, MD
Montreal, Canada
ITN020AI
Completed
Multiple sclerosis (MS), the most common central nervous system (CNS) demyelinating disease, is thought to be mediated in part by CNS autoantigen-specific MHC class II-restricted Th1 cells. With development of treatments that reduce the risk of relapse and development of sustained disability, earlier treatment is encouraged. However, currently approved immunomodulatory therapies are partially effective, administered parenterally and associated with significant side effects and potential toxicities. In contrast, HMG CoA reductase inhibitors "statins" are administered orally, are well tolerated and have few toxicities. Recent studies in experimental autoimmune encephalomyelitis (EAE), a model for MS, have indicated that atorvastatin has immunomodulatory activity that may be beneficial in MS treatment. Atorvstatin promoted the differentiation of Th0 cells into Th2 cells that in adoptive transfer protected recipient mice from EAE induction. Thus, induction of regulatory T cells is one mechanism for statin-mediated immune tolerance. Atorvastatin treatment after the first attack of chronic relapsing remitting EAE reversed paralysis. Atorvastatin inhibited IFN-gamma-inducible expression of MHC class II molecules and CD40, CD80 and CD86 costimulatory molecules on nonprofessional APC. Statins also inhibit CNS APC (microglia and astrocytes) from producing nitric oxide synthetase (iNOS) and TNF-alpha, suggesting that they may also have a neuroprotective role that could be beneficial in MS.
A clinically isolated syndrome (CIS) refers to the first clinical attack attributed to CNS demyelination that precedes the clinical diagnosis of MS. The primary goals of this proposal are to: 1) determine whether atorvastatin treatment will reduce the risk of conversion to MS in patients that have experienced a CIS and are at high risk to develop MS, and (2) determine if atorvastatin treatment causes immune deviation. Nine MS centers that are highly experienced in MS clinical research will participate in this randomized double-masked, placebo-controlled phase II trial. One hundred and twenty six patients (63 in each arm) will be enrolled. These patients will have had a CIS within one month of enrollment and at least two T2 bright lesions of the screening brain MRI. Patients will be treated for one year with the approved 80 mg dose or placebo. The primary endpoint will be conversion to MS by clinical or MRI events according to MacDonald's criteria. Immune function will be assessed by several different parameters including CNS autoantigen-specific proliferation, Th1 and Th1 cytokines by ELISA, T cell differentiation/activation markers and expression of MHC class II and costimulatory molecules on APC by FACS. Substudies will involve evaluation of MHC class II transactivator expression and analysis of markers for oxidative injury. Our proposed studies involve collaboration with ITN microarray, real-time PCR and ELISPOT Core Facilities. This study is highly relevant to immune tolerance. The results from this clinical trial may be relevant to treatment of other organ-specific Th1-mediated autoimmune diseases, including insulin-dependent diabetes mellitus and rheumatoid arthritis.
McKinney EF, Cuthbertson I, Harris KM, Smilek D, Connor C, Manferrari G, Carr EJ, Zamvil SS, Smith KGC (2021). A CD8 + NK cell transcriptomic signature associated with clinical outcome in relapsing remitting multiple sclerosis. Nat Commun, 12 (1), 635.
DOI:
http://dx.doi.org/10.1038/s41467-020-20594-2,
PMID:
33504809
,
PMCID:
PMC7840761
,
PubMed,
ReprintPelletier D, Gao Z, Zamvil SS, Waubant E, Mowry EM, Howell MD (2016). Vitamin D in clinically isolated syndrome: evidence for possible neuroprotection. Eur J Neurol, 23 (2), 327-32.
Waubant E, Pelletier D, Mass M, Cohen JA, Kita M, Cross A, Bar-Or A, Vollmer T, Racke M, Stüve O, Schwid S, Goodman A, Kachuck N, Preiningerova J, Weinstock-Guttman B, Calabresi PA, Miller A, Mokhtarani M, Ikle D, Murphy S, Kopetskie H, Ding L, Rosenberg E, Spencer C, Zamvil SS, ITN020AI Study Management Team, ITN STAyCIS Study Group (2012). Randomized controlled trial of atorvastatin in clinically isolated syndrome. Neurology, 78 (15), 1171-8.
DOI:
http://dx.doi.org/10.1212/WNL.0b013e31824f7fdd,
PMID:
22459680
,
PMCID:
PMC3320055
,
PubMed,
Reprint