A5065156283- Immune cells in cancer
- Complement system in diseases
- Multiple Sclerosis Research Studies
- Sphingolipid Metabolism and Signaling
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Cancer Immunotherapy and Biomarkers
- Immunotherapy and Immune Responses
- T-cell and B-cell Immunology
- Cell Adhesion Molecules Research
- Neuroinflammation and Neurodegeneration Mechanisms
- Immune Response and Inflammation
- Galectins and Cancer Biology
- Immune Cell Function and Interaction
- Phytochemistry and Biological Activities
- Renal Diseases and Glomerulopathies
- Cytokine Signaling Pathways and Interactions
- Pneumonia and Respiratory Infections
- Monoclonal and Polyclonal Antibodies Research
- Bacterial Infections and Vaccines
- Signaling Pathways in Disease
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Peripheral Neuropathies and Disorders
- interferon and immune responses
- Adenosine and Purinergic Signaling
- Carbohydrate Chemistry and Synthesis
Novartis (Switzerland)
2014-2025
Novartis Institutes for BioMedical Research
2008-2023
Harvard University
2003-2006
Brigham and Women's Hospital
2003-2006
Max Planck Institute of Neurobiology
2000-2005
Max Planck Society
2001-2005
Dana-Farber Cancer Institute
2005
University of California, Berkeley
2005
Millennium Engineering and Integration (United States)
2005
VA Palo Alto Health Care System
2005
Dysregulation of the alternative complement pathway (AP) predisposes individuals to a number diseases including paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and C3 glomerulopathy. Moreover, glomerular Ig deposits can lead complement-driven nephropathies. Here we describe discovery highly potent, reversible, selective small-molecule inhibitor factor B, serine protease that drives central amplification loop AP. Oral administration prevents KRN-induced arthritis in...
Abstract We have explored the use of minocycline, a tetracycline with antiinflammatory properties, to treat chronic relapsing‐remitting experimental allergic encephalomyelitis, an animal model multiple sclerosis. Therapeutic treatment minocycline dramatically suppresses ongoing disease activity and limits progression. Disease suppression is associated immune deviation in periphery inflammatory cascade central nervous system. This association demonstrated by inhibition microglial activation...
Data from multiple sclerosis (MS) and the MS rodent model, experimental autoimmune encephalomyelitis (EAE), highlighted an inflammation-dependent synaptopathy at basis of neurodegenerative damage causing irreversible disability in these disorders. This is characterized by imbalance between glutamatergic GABAergic transmission has been proposed to be a potential therapeutic target. Siponimod (BAF312), selective sphingosine 1-phosphate1,5 receptor modulator, currently under investigation...
BAF312 (Siponimod) is a dual agonist at the sphingosine-1 phosphate receptors, S1PR1 and S1PR5. This drug currently undergoing clinical trials for treatment of secondary progressive multiple sclerosis (MS). Here, we investigated effects on isolated astrocyte microglia cultures as well in slice culture models demyelination. Mouse human astrocytes were treated with S1PR modulators changes levels pERK, pAkt, calcium signalling internalization cytokine was using Western blotting,...
Abstract Surface molecules that are differentially expressed on Th1 and Th2 cells may be useful in regulating specific immune responses vivo. Using a panel of mAbs, we have identified murine CD226 as specifically the surface differentiated but not or Th0 cells. Although is constitutively CD8 cells, it up-regulated CD4 upon activation. differentiation results enhanced expression, whereas expression down-regulated polarization. We demonstrate involved regulation T cell activation; vivo...
Abstract Experimental autoimmune encephalomyelitis (EAE) induced by sensitization with myelin oligodendrocyte glycoprotein (MOG) is a T cell-dependent disease that reproduces the inflammatory demyelinating pathology of multiple sclerosis. We report an encephalitogenic cell response to MOG can be either or alternatively suppressed as consequence immunological cross-reactivity, “molecular mimicry” extracellular IgV-like domain milk protein butyrophilin (BTN). In Dark Agouti rat, active...
We studied the immunological basis for very potent encephalitogenicity of myelin/oligodendrocyte glycoprotein (MOG), a minor component myelin in CNS that is widely used to induce experimental autoimmune encephalomyelitis (EAE). For this purpose, we generated mutant mouse lacking functional mog gene. This MOG-deficient presents no clinical or histological abnormalities, permitting us directly assess role MOG as target autoantigen EAE. In contrast WT mice, which developed severe EAE following...
Multiple sclerosis is a chronic disease of the central nervous system (CNS) characterized by inflammation, demyelination, and axonal loss. The immunopathogenesis demyelination in multiple involves an autoantibody response to myelin oligodendrocyte glycoprotein (MOG), type I transmembrane protein located at surface CNS myelin. Here we present crystal structures extracellular domain MOG (MOG Igd ) 1.45-Å resolution complex with antigen-binding fragment (Fab) MOG-specific demyelinating...
Abstract The etiology of multiple sclerosis (MS) is believed to involve environmental factors, but their identity and mode action are unknown. In this study, we demonstrate that Ab specific for the extracellular Ig-like domain myelin oligodendrocyte glycoprotein (MOG) cross-reacts with a homologous N-terminal bovine milk protein butyrophilin (BTN). Analysis paired samples MS sera cerebrospinal fluid (CSF) identified BTN-specific response in CNS differed its epitope specificity from...
Sphingosine 1-phosphate (S1P) lyase has recently been implicated as a therapeutic target for the treatment of multiple sclerosis (MS), based on studies in genetic mouse model. Potent active site directed inhibitors enzyme are not known so far. Here we describe discovery (4-benzylphthalazin-1-yl)-2-methylpiperazin-1-yl]nicotinonitrile 5 high-throughput screen using biochemical assay, and its further optimization. This class compounds was found to inhibit catalytic activity S1PL by binding...
Abstract T-cell activation and expansion in the tumor microenvironment (TME) are critical for antitumor immunity. Neutrophils TME acquire a complement-dependent suppressor phenotype that is characterized by inhibition of proliferation through mechanisms distinct from those myeloid-derived cells. In this study, we used ascites fluid supernatants (ASC) patients with ovarian cancer as an authentic component to evaluate effects ASC on neutrophil function neutrophil-driven immune suppression....
Fractalkine is the only as yet known member of a novel class chemokines. Besides its Cys‐X‐X‐X‐Cys motif, fractalkine exhibits features which have not been described for any other chemokine family, including unusual size (397 amino acids human, 395 mouse) and possession transmembrane anchor, from soluble form may be released by extracellular cleavage. This report demonstrates abundant mRNA protein expression in neuronal cells. The unaffected experimentally induced inflammation central nervous tissue.
The alternative pathway (AP) of the complement system is a key contributor to pathogenesis several human diseases including age-related macular degeneration, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and various glomerular diseases. serine protease factor B (FB) node in AP integral formation C3 C5 convertase. Despite prominent role FB AP, selective orally bioavailable inhibitors, beyond our own efforts, have not been reported previously. Herein we...
Antibodies directed against onconeuronal antigens provide a specific diagnostic marker for paraneoplastic neurological syndromes (PNS) and suggest that these autoantigens are targeted during disease pathogenesis. However, so far attempts to generate autoimmune models of PNS have been unsuccessful. Here we show the adoptive transfer T-cells autologous antigen Pnma1 cause encephalomyelitis in Dark Agouti (DA) rat. The sequence rat Ma1 (rPnma1) was determined by RT-PCR using primers human...
Sphingosine-1-phosphate (S1P) lyase is considered as a drug target in autoimmune diseases based on the protective effect of reducing activity enzyme animal models inflammation. Since S1P deficiency mice causes severe, lethal phenotype, it was interest to investigate any pathological alterations associated with only partially reduced may be encountered upon pharmacological inhibition. Both genetic reduction and inhibition low-molecular-weight compound rats consistently resulted podocyte-based...
Autoimmune diseases of the central nervous system (CNS) like multiple sclerosis (MS) are characterized by inflammation and demyelinated lesions in white grey matter regions. While is present at all stages MS, it more pronounced relapsing forms disease, whereas progressive MS (PMS) shows significant neuroaxonal damage atrophy. Hence, disease-modifying treatments beneficial patients with have limited success PMS. BAF312 (siponimod) a novel sphingosine-1-phosphate receptor modulator shown to...
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurring suppurating lesions of the intertriginous areas, resulting in substantial impact on patients' QOL. HS pathogenesis remains poorly understood. An autoimmune component has been proposed, but disease-specific autoantibodies, autoantigens, or autoreactive T cells have yet to be described. In this study, we identify high prevalence IgM, IgG, and IgA antibodies directed against Nε-carboxyethyl lysine...
Quantitative magnetization transfer magnetic resonance imaging (qMT-MRI) can be used to improve detection of white matter tissue damage in multiple sclerosis (MS) and animal models thereof. To study the correlation between MT parameters damage, ratio (MTR), parameter f* (closely related bound proton fraction) transverse relaxation time T(2B) lesions a model focal experimental autoimmune encephalomyelitis (EAE) were measured on 7T scanner data compared with histological markers indicative for...