Stanford Multiple Sclerosis and Neuroimmunology Research
Over decades, Stanford researchers have garnered international recognition for key discoveries about the mechanisms of action of neuroimmunological disorders, and for using those findings to expand the range of therapies for those disorders. In addition to creating a strong program in multiple sclerosis research, investigators in the division conduct research on many other disorders such as myasthenia gravis, the leukodystrophies, paraneoplastic disease, Guillain Barre syndrome, the effect of cancer on brain function and the interaction of the blood coagulation cascade with the nervous system. The role of the immune system in diseases ranging from amyotrophic lateral sclerosis to epilepsy are under intense investigation.
In recent years, Stanford has used its extensive MS tissue bank to catalog thousands of mRNAs and proteins that are involved in the progression of the disease. The researchers have found proteins whose presence is characteristic of each of the three main stages of disease: the acute stage, the chronic-active stage and the chronic silent stage. Blocking some of these proteins leads to improvement in a mouse model of MS.
Identification and characterization of proteins involved in MS has led to a new understanding of relapse and remission of MS. Stanford researchers identified the protein Osteopontin, and showed that it played a key role in the relapse of MS by binding to a4ß1 integrin to simulate the production of cytokines and inhibit apoptosis. Different integrins, particularly a5, are involved in the pathogenesis of amyotrophic lateral sclerosis.
Stanford researchers continue to investigate these and other possible avenues for discovering more effective treatments for MS, ALS and some of the forms of epilepsy.
Research in the Han lab mainly focuses on multiple sclerosis (MS), neuromyelitis optica (NMO) and other inflammatory demyelinating diseases of the CNS. The goal of our research is to better understand how to harness auto-reactive immune response, enhance remyelination, and fine-tune immune therapies to optimize clinical outcome in MS. We are a translational research laboratory, striving to apply our knowledge from bench to bedside. We utilize patient samples, animal models of MS and biochemical assays to decipher the molecular mechanisms involving MS pathogenesis.
A major focus of our laboratory is to understand how myeloid cells contribute to neuroinflammation and repair in MS. We have observed that myeloid cells can positively or negatively influence MS disease activity. In addition, we found that myeloid cells regulate the function of the blood-brain barrier, a gateway to the central nervous system. We are particularly interested in how myeloid cells play a role in progressive MS with the goal of developing myeloid cell-directed therapies.
Remyelination failure is a major cause of neurodegeneration in MS. A second research direction in our laboratory is to understand how the lipid second messenger, sphingosine-1-phosphate (S1P) signaling participates in oligodendrocyte maturation and remyelination.
Neuromyelitis optica (NMO) is a rare, inflammatory demyelinating disorder cause by auto-antibodies against aquaporin 4 and CNS antigens. We are actively recruiting NMO patients and controls as part of CIRCLES study for epidemiological and translational studies.
Lawrence Steinman, MD and his colleagues also made important discoveries about aB Crystallin. Steinman's laboratory demonstrated that the aB Crystallin protein plays a protective role in a mouse model of multiple sclerosis. When injected in mice, it can reverse paralysis. B Crystallin is a member of the SHSP superfamily, the most widespread set of molecular chaperones. Research at Stanford and elsewhere has shown that one of the strongest immune responses in patients with multiple sclerosis is against the aB Crystallin protein. Removal of this protein accelerates the autoimmune attack against the nervous system in various ways.
Research in Steinman's laboratory has been the foundation of the development of the most powerful drug yet approved for the relapsing and remitting form of MS, natalizumab (trade name Tysabari), which targets a4ß1 integrin. Recently Steinman also reported promising results on tests of a DNA vaccine to tame the immune system in relapsing and remitting MS. Results of the phase II clinical trials showed that the vaccine could suppress immune responses to myelin and decrease activity on brain scans. A fuller understanding of the dynamics of MS relapse and remission offers multiple possibilities for new drug targets, such osteopontin and aB Crystallin. The target of aB crystallin a receptor for acetylcholine was discovered, and new therapeutics are under development for diseases ranging from progressive MS to ulcerative colitis.
Steinman’s lab has developed techniques to enhance the efficacy of gene therapy in diseases like Duchenne’s Muscular Dystrophy.