Notable Research in MS is Underway
The John L. Trotter MS Center at Washington University Medical Center serves our community of patients through the partnership of Barnes-Jewish Hospital and Washington University School of Medicine.
Ongoing Research at The John L. Trotter MS Center
Multiple sclerosis (MS) is a complex disease of unknown etiology involving central nervous system (CNS) inflammation, demyelination, and axonal damage. MS is generally believed to be an autoimmune disease consisting in an adaptive immune response (T and/or B cell mediated) directed against CNS myelin components.
Dr. Cross is currently funded by grants from the National Institutes of Health, The Conrad N. Hilton Foundation and the National MS Society USA. Her laboratory studies utilize an animal model for MS (experimental autoimmune encephalomyelitis-EAE) to study the role of B cells, plasma cells and antibodies in inflammatory demyelination of the central nervous system. Other studies involve cutting edge imaging techniques to measure MS pathology in the central nervous system, and to observe neuropathological changes accompanying progressive disease in “real time”. Dr. Cross’ laboratory also investigates the effects of approved medications for MS, to better understand how they achieve efficacy.
Dr Piccio’s research investigates the role played by the immune system in MS pathogenesis and utilizes human specimens obtained from MS subjects as well as the EAE model. Her goals are to apply basic research findings to the clinic. Currently, Dr Piccio’s research focuses on two major areas: the Role of Innate Immune Cells and the Complex Interactions Between the Immune System and Metabolism in MS and EAE.
The goal of the Wu lab is to determine the requirements for antigen presentation during immune responses within the central nervous system. Several ongoing projects involve the use of an animal model system called experimental autoimmune encephalomyelitis (EAE). First, because there is strong clinical and experimental evidence that B cells contribute to MS via their role as antigen presenting cells, we have used a genetically engineered tool we have recently developed for the conditional expression of MHCII to explore the extent to which B cells alone can drive CD4 T cell auto-reactivity in vivo. We have found that antigen presentation by B cells alone is not sufficient to support passive EAE resulting from transfer of encephalitogenic CD4 T cells unless B cells also express antigen receptor specific for cognate antigen. Currently, we are exploring the mechanisms by which B cells regulate CD4 T cell function during EAE. Second, we are examining the role of dendritic cells (DCs), a special class of antigen presenting cell thought to be involved in the pathogenesis of central nervous system inflammation. Currently, EAE serves as the experimental basis for this work, although an initial collaboration with the Cross and Piccio labs is underway to extend this research focus into human clinical trials. Third, we have observed a role for the lipid binding protein apolipoprotein E (apoE) during EAE. We hypothesize that production of apoE by DCs and other innate cells functions to enhance myelin antigen capture and processing. To investigate the role of apoE in antigen presentation during EAE, we have used in vivo genetic manipulation of apoE. We have found changes in CD4 T cell myelin-reactivity in apoE-deficient mice that is associated with a reduction in severity of disease. We aim to continue to explore the mechanisms involved in apoE-mediated CD4 T cell responses using a variety of techniques, including cell culture, imaging, and flow cytometry. Funding for these studies currently comes from the NINDS and National Multiple Sclerosis Society.
Dr. Robyn Klein, Associate Professor in the departments of Internal Medicine, Pathology and Immunology, and Anatomy and Neurobiology, is currently funded by grants from the National Institutes of Health, the National Multiple Sclerosis Society and the Dana Foundation. Her laboratory utilizes both in vitro and in vivo models to define molecular mechanisms of leukocyte entry into the CNS, blood-brain barrier dysfunction and CNS repair including remyelination. The actions and regulation of chemokines, which play roles in all of these processes, is of particular interest, as well as innate immune mechanisms that may both promote and prevent neuropathology. The Klein lab website is: http://www.dbbs.wustl.edu/rib/kleinRobS
The Neuroimmunology Fellows:
Erin E. Longbrake, MD, PhD
- Piccio LM, Stark JL, Cross AH: Chronic Calorie Restriction Attenuates Experimental Autoimmune Encephalomyelitis. J Leuk Biol 84: 940-948, 2008
- Piccio LM, Buonsanti C, Schmidt RE, Rinker J, Panina-Bordignon P, Cella M, Colonna M, Cross AH: Identification of a novel soluble TREM-2 protein in the cerebrospinal fluid in association with central nervous system inflammation. Brain 2008; 131: 3081-3091. PMCID: PMC2577803
- Wilson, E.H., Harris, T.H., Mrass, P., John, B., Tait, E.D., Wu, G.F., Pepper, M., Wherry, E.J., Dzierzinkski, F., Roos, D., Haydon, P.G., Laufer, T.M., Weninger, W., Hunter, C.A. Behavior of parasite specific effector CD8+ T cells in the CNS and visualization of a kinesis-associated system of reticular fibers during infection Immunity. 2009 Feb 20; 30 (2): 300-11.
- Naismith RT, Piccio L, Lyons JA, Lauber J, Tutlam NT, Parks BJ, Trinkaus K, Song SK, Cross AH: Rituximab add-on therapy for breakthrough relapsing multiple sclerosis: a 52-week phase II trial. Neurology 2010; 74: 1860-1867 PMCID: PMC2882224
- Wu GF, Shindler KS, Allenspach EJ, Stephen TL, Thomas HL, Mikesell RJ,Cross AH, Laufer TM. Limited sufficiency of antigen presentation by dendritic cells in models of central nervous system autoimmunity. J Autoimmun 2011; 36:56-64.PMCID: PMC3053076
- Wang Y, Wang Q, Haldar JP, Yeh FC, Xie M, Sun P, Trinkaus K, Klein RS,Cross AH, Song S-K. Quantification of increased cellularity during inflammatory demyelination. Brain 2011; 134: 3587-9 PMCID: PMC3235568
- Klawiter EC, Xu J, Naismith RT, Benzinger TLS, Shimony JS, Lancia S, Snyder AZ, Trinkaus K, Song SK,Cross AH. Increased radial diffusivity in spinal cord lesions in neuromyelitis optica compared with multiple sclerosis. Mult Scler 2012;18: 1259-68. Doi:10.1177/1352458512436593. PMID: 22354742
- Luo J, Jagadeesan B,Cross AH, Yablonskiy DA. Gradient echo plural contrast imaging- signal model and derived contrasts: T2*, T1, Phase, SWI, T1f, FST2* and T2*-SWI. NeuroImage 2012;60:1073-82 PMCID: PMC3303959
- Yablonskiy DA, Luo J, Sukstanskii AL, Iyer A,Cross AH. Biophysical mechanisms of MRI signal frequency contrast in multiple sclerosis. Proc Natl Acad Sci USA. 2012; 109:14212-7. doi: 10.1073/pnas.1206037109.
- Archambault, A.S., Carrero, J.A., McGee, N.G., Sim, J., Wright, J., Raabe, T., Chen, P., Ding, H., Allenspach, E.J., Dragatsis, I., Laufer, T.M., and Wu, G.F. Conditional MHCII expression reveals a limited role for B cell antigen presentation in primary and secondary CD4 T cell responses. J Immunol. 2013;191:545-50. PMCID: PMC371153
- Satake, A., Schmidt, A.M., Archambault, A.S., Wu, G.F. and Kambayashi, T. Differential targeting of IL-2 and T cell receptor signaling pathways selectively expands regulatory T cells while inhibiting conventional T cells. J Autoimmun. 2013;44:13-20. PMCID: PMC3752416
- Fenoglio C, Ridolfi E, Cantoni C, de Riz M, Bonsi R, Serpente M, Villa C, Pietroboni AM, Naismith RT, Alvarez E, Bresolin N, Cross AH, Piccio LM, Galimberti D, Scarpini E. Decreased circulating miRNA levels in patients with primary progressive multiple sclerosis Mult Scler. 2013;19:1938-42. (PMCID pending)
- Piccio L, Cantoni C, Ramsbottom M, Mikesell B, Cremasco V, Haynes W, Dong LQ, Chan L, Galimberti D, Cross AH. Lack of adiponectin leads to increased lymphocyte activation and worse severity of a mouse model of multiple sclerosis. Eur J Immunol 2013; 43: 2089-2100. PMCID:PMC390153
- Naismith RT, Xu J, Klawiter EC, Lancia S, Tutlam NT, Wagner JM, Qian P, Trinkaus K, Song SK, Cross AH. Spinal cord tract diffusion tensor imaging reveals disability substrate in demyelinating disease. Neurology. 2013; 80:2201-9. PMCID:PMC3721096
- Shin S, Walz KA, Archambault AS, Sim J, Bollman BP, Koenigsknecht-Talboo J, Cross AH, Holtzman DM, Wu GF. Apolipoprotein E Mediation of Neuro-inflammation in a Murine Model of Multiple Sclerosis. J Neuroimmunol 2014; 271:8-17 PMCID: PMC4042395
- Barnett LG1, Simkins HM, Barnett BE, Korn LL, Johnson AL, Wherry EJ, Wu GF, Laufer TM. B cell antigen presentation in the initiation of follicular helper T cell and germinal center differentiation. J Immunol. 2014;192:3607-17. PMID: 24646739 (PMCID pending)
- Lin TH, Spees WM, Chiang CW, Trinkaus K, Cross AH,Song, SK. Diffusion fMRI detects white-matter dysfunction in mice with acute optic neuritis. Neurobiol Dis 2014;67:1-8. PMCID: PMC4035476
- Cruz-Orengo L, Daniels BP, Dorsey D, Basak SA, Grajales-Reyes JG, McCandless EE, Piccio L, Schmidt RE, Cross AH, Crosby SD, Klein RS. Enhanced sphingosine-1-phosphate receptor 2 expression underlies female CNS autoimmunity susceptibility. J Clin Invest, 2014; 124:2571-84. PMCID: PMC4089451
- Chiang CW, Wang Y, Sun P, Lin T-S, Trinkaus K, Cross AH, Song S-K. Quantifying white matter tract diffusion parameters in the presence of increased extra-fiber cellularity and vasogenic edema. NeuroImage 2014;101C:310-319. PMCID: PMC4165711
- Wen J, Cross AH, Yablonskiy D. On the role of physiological fluctuations in quantitative gradient echo MRI – Implications for GEPCI, QSM and SWI. Magn Res Med 2015; 73:195-203. PMCID: PMC4116475
- Wang Y, Sun P, Wang Q, Trinkaus K, Naismith RT, Cross AH, Song SK. Differentiation and quantification of inflammation, demyelination, and axon injury/loss in MS. Brain. 2015;138(Pt 5):1223-38. PMCID pending
- Longbrake EE, Cross AH. Dimethyl Fumarate Associated Lymphopenia in Clinical Practice. Mult Scler. 2015;21:796-7. PMCID: PMC4426020
- Parker, C.R., Archambault, A.S., Sim, J., Ferris, S.T., Mikesell, R.J., Koni, P.A., Shimoda, M., Linington, C., Russel, J.H., and Wu, G.F. B cell antigen presentation is sufficient to drive neuro-inflammation in an animal model of multiple sclerosis. J Immunol. 2015 Jun 1;194:5077-84.
- Wu, G.F., Brier, M.R., Parks, C.A.-L., Ances, B.M., and Van Stavern, G.P. An eye on brain integrity: Acute optic neuritis affects resting state functional connectivity. Invest Ophthalmol Vis Sci. Apr 2015;56:2541–2546.
- Cantoni C, Bollman B, Licastro D, Xie M, Mikesell R, Schmidt R, Yuede CM, Galimberti D, Olivecrona G, Klein RS, Cross AH, Otero K, Piccio L. TREM2 regulates microglial cell activation in response to demyelination in vivo. 2015;129:429-47.
Translational Work and Clinical Trials:
The John L. Trotter MS Center is committed to translating work done in the laboratory to the Clinic. Dr. Cross directs a clinical trial that was initiated at this institution, based upon prior work in the laboratories at Washington University. The trial is currently ongoing, and studies the effect of B cells and their products on disease activity in MS patients. Patients in the study, who all have ongoing MS disease activity despite taking FDA-approved medications, are depleted of circulating B cells for 6-12 months using a highly specific chemotherapeutic agent. MS activity in the brain is monitored by MRI. The imaging results are being analyzed by Dr. Robert Naismith.
More publications from the Center that report translational work and clinical trials include:
- Avasarala J, Cross AH, Trotter JL: Oligoclonal band number as a marker for prognosis in multiple sclerosis. Archives Neurol. 2001; 58: 2044-2045.
- Avasarala JR, Cross AH, Clifford DB, Singer B, Siegel, Abbey EE: Rapid Onset Mitoxantrone-induced Cardiotoxicity in Secondary Progressive Multiple Sclerosis. Multiple Sclerosis 2003; 9:59-62.
- Avasarala JR, Cross AH, Trinkaus K: Comparative assessment of Yale Single Question and Beck Depression Inventory Scale in screening for depression in multiple sclerosis. Multiple Sclerosis 2003; 9:307-310.
- Attarian HP, Brown KM, Duntley SP, Cross AH: The relationship of sleep disturbances to fatigue in multiple sclerosis. Arch. Neurol. 2004; 61: 535-538.
- Naismith RT, Trinkaus K, Cross AH: Phenotype and prognosis in African-Americans with multiple sclerosis: a retrospective chart review. Multiple Sclerosis 2006; 12: 775-781.
- Goodman AD, Cohen JA, Cross AH, Rizzo M, Vollmer T, Blight AR: Fampridine-SR in multiple sclerosis: a randomized, double-blind, placebo-controlled, dose-ranging study. Neurology 2008; 1134-41.
- Fenoglio C, Scalabrini D, Piccio L, deRiz M, Venturelli E, Cortini F, Villa C, Serpente M, Parks BJ, Rinker J, Bresolin N, Cross AH, Scarpini E, Galimberti D. Candidate gene analysis of selectin gene cluster in patients with multiple sclerosis. J Neurology 2009 256:832-3.
- De Jager PL, Jia X, Wang J, de Bakker PI, Ottoboni L, Aggarwal NT, Piccio L, Raychaudhuri S, Tran D, Aubin C, Briskin R, Romano S; International MS Genetics Consortium, Baranzini SE, McCauley JL, Pericak-Vance MA, Haines JL, Gibson RA, Naeglin Y, Uitdehaag B, Matthews PM, Kappos L, Polman C, McArdle WL, Strachan DP, Evans D, Cross AH, Daly MJ, Compston A, Sawcer SJ, Weiner HL, Hauser SL, Hafler DA, Oksenberg JR. Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nat. Genet. 2009; 41: 776-82.
- Naismith RT, Shepherd BJ, Weihl CC, Tutlam NT, Cross AH. Acute and bilateral blindness due to optic neuropathy associated with copper deficiency. Arch Neurol. 2009; 66: 1025-1027.
- Naismith RT, Tutlam N, Xu J, Klawiter EC, Shepherd, JB, Song, SK, Cross AH. Optical Coherence Tomography is Less Sensitive than Visual Evoked Potentials in Optic Neuritis Neurology 2009; 73: 46-52.
- Piccio L, Naismith RT, Trinkaus K, Klein RS, Parks BJ, Lyons JA, Cross AH. Changes in B- and T-lymphocyte and chemokine levels with rituximab treatment in multiple sclerosis. Arch Neurol 2010; 67(6):707-714.
- Klawiter EC, Benzinger TL, Roy A, Naismith RT, Parks BJ, Cross AH. Spinal cord ring enhancement in multiple sclerosis. Arch Neurol 2010; 67:1395-8. PMCID: PMC3057685
- Klawiter EC, Piccio L, Lyons JA, Mikesell R, O’Connor KC,Cross AH. Elevated intrathecal myelin oligodendrocyte glycoprotein antibodies in Multiple Sclerosis. Arch Neurol. 2010; 67: 1102-1108. PMCID: PMC3051403
- Qian P,Cross AH, Naismith RT. Lack of response to monoclonal antibody therapy in neuromyelitis optica. Ann Neurol 2011 68: 1207-1209
- Naismith RT, Xu J, Tutlam NT, Lancia S, Trinkaus K, Song SK,Cross AH. Diffusion Tensor Imaging in Acute Optic Neuropathies. Predictor of Clinical Outcomes. Arch Neurol 2012; 69: 65-71 doi:10.1001/archneurol.2011.243
- Qian P, Lancia S, Alvarez E, Klawiter EC,Cross AH, Naismith RT. Association of neuromyelitis optica with severe and intractable pain. Arch Neurol. 2012; 69:1482-7. PMID:22926050
- Alvarez E, Piccio L, Mikesell RJ, Klawiter EC, Parks BJ, Naismith RT, Cross AH. CXCL13 is a Biomarker of Inflammation in Multiple Sclerosis, Neuromyelitis Optica, and Other Neurological Conditions. Mult Scler J 2013 (in press)
- Naismith RT, Zu J, Klawiter EC, Lancia S, Tutlam N, Wagner J, Qian P, Trinkaus K, Song SK, Cross AH. Diffusion Tensor Imaging of Spinal Cord Tracts Reveals Disability Substrate in Demyelination. Neurology, 2013 (in press)