Patrice H. Lalive

Glatiramer acetate increases IL-1 receptor antagonist but decreases T cell-induced IL-1β in human monocytes and multiple sclerosis

Mechanisms of action as well as cellular targets of glatiramer acetate (GA) in multiple sclerosis (MS) are still not entirely understood. IL-1β is present in CNS-infiltrating macrophages and microglial cells and is an important mediator of inflammation in experimental autoimmune encephalitis (EAE), the MS animal model. A natural inhibitor of IL-1β, the secreted form of IL-1 receptor antagonist (sIL-1Ra) improves EAE disease course. In this study we examined the effects of GA on the IL-1 system. In vivo, GA treatment enhanced sIL-1Ra blood levels in both EAE mice and patients with MS, whereas IL-1β levels remained undetectable. In vitro, GA per se induced the transcription and production of sIL-1Ra in isolated human monocytes. Furthermore, in T cell contact-activated monocytes, a mechanism relevant to chronic inflammation, GA strongly diminished the expression of IL-1β and enhanced that of sIL-1Ra. This contrasts with the effect of GA in monocytes activated upon acute inflammatory conditions. Indeed, in LPS-activated monocytes, IL-1β and sIL-1Ra production were increased in the presence of GA. These results demonstrate that, in chronic inflammatory conditions, GA enhances circulating sIL-1Ra levels and directly affects monocytes by triggering a bias toward a less inflammatory profile, increasing sIL-1Ra while diminishing IL-1β production. This study sheds light on a mechanism that is likely to participate in the therapeutic effects of GA in MS.

MHC class II–restricted antigen presentation by plasmacytoid dendritic cells inhibits T cell–mediated autoimmunity

Although plasmacytoid dendritic cells (pDCs) express major histocompatibility complex class II (MHCII) molecules, and can capture, process, and present antigens (Ags), direct demonstrations that they function as professional Ag-presenting cells (APCs) in vivo during ongoing immune responses remain lacking. We demonstrate that mice exhibiting a selective abrogation of MHCII expression by pDCs develop exacerbated experimental autoimmune encephalomyelitis (EAE) as a consequence of enhanced priming of encephalitogenic CD4+ T cell responses in secondary lymphoid tissues. After EAE induction, pDCs are recruited to lymph nodes and establish MHCII-dependent myelin-Ag–specific contacts with CD4+ T cells. These interactions promote the selective expansion of myelin-Ag–specific natural regulatory T cells that dampen the autoimmune T cell response. pDCs thus function as APCs during the course of EAE and confer a natural protection against autoimmune disease development that is mediated directly by their ability to present of Ags to CD4+ T cells in vivo.

Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25+Foxp3+ regulatory T cells

Immune-mediated diseases of the CNS, such as multiple sclerosis and its animal model, experimental autoimmune encephalitis (EAE), are characterized by the activation of antigen-presenting cells and the infiltration of autoreactive lymphocytes within the CNS, leading to demyelination, axonal damage, and neurological deficits. Hepatocyte growth factor (HGF) is a pleiotropic factor known for both neuronal and oligodendrocytic protective properties. Here, we assess the effect of a selective overexpression of HGF by neurons in the CNS of C57BL/6 mice carrying an HGF transgene (HGF-Tg mice). EAE induced either by immunization with myelin oligodendrocyte glycoprotein peptide or by adoptive transfer of T cells was inhibited in HGF-Tg mice. Notably, the level of inflammatory cells infiltrating the CNS decreased, except for CD25+Foxp3+ regulatory T (Treg) cells, which increased. A strong T-helper cell type 2 cytokine bias was observed: IFN-γ and IL-12p70 decreased in the spinal cord of HGF-Tg mice, whereas IL-4 and IL-10 increased. Antigen-specific response assays showed that HGF is a potent immunomodulatory factor that inhibits dendritic cell (DC) function along with differentiation of IL-10–producing Treg cells, a decrease in IL-17–producing T cells, and down-regulation of surface markers of T-cell activation. These effects were reversed fully when DC were pretreated with anti-cMet (HGF receptor) antibodies. Our results suggest that, by combining both potentially neuroprotective and immunomodulatory effects, HGF is a promising candidate for the development of new treatments for immune-mediated demyelinating diseases associated with neurodegeneration such as multiple sclerosis.

Glatiramer acetate in the treatment of multiple sclerosis: emerging concepts regarding its mechanism of action.

Glatiramer acetate is a synthetic, random copolymer widely used as a first-line agent for the treatment of relapsing-remitting multiple sclerosis (MS). While earlier studies primarily attributed its clinical effect to a shift in the cytokine secretion of CD4+ T helper (Th) cells, growing evidence in MS and its animal model, experimental autoimmune encephalomyelitis (EAE), suggests that glatiramer acetate treatment is associated with a broader immunomodulatory effect on cells of both the innate and adaptive immune system. To date, glatiramer acetate-mediated modulation of antigen-presenting cells (APC) such as monocytes and dendritic cells, CD4+ Th cells, CD8+ T cells, Foxp3+ regulatory T cells and antibody production by plasma cells have been reported; in addition, most recent investigations indicate that glatiramer acetate treatment may also promote regulatory B-cell properties. Experimental evidence suggests that, among these diverse effects, a fostering interplay between anti-inflammatory T-cell populations and regulatory type II APC may be the central axis in glatiramer acetate-mediated immune modulation of CNS autoimmune disease. Besides altering inflammatory processes, glatiramer acetate could exert direct neuroprotective and/or neuroregenerative properties, which could be of relevance for the treatment of MS, but even more so for primarily neurodegenerative disorders, such as Alzheimer’s or Parkinson’s disease. In this review, we provide a comprehensive and critical overview of established and recent findings aiming to elucidate the complex mechanism of action of glatiramer acetate.

Is measurement of d-dimer useful in the diagnosis of cerebral venous thrombosis?

Background: The diagnosis of cerebral venous thrombosis (CVT) is a challenge because its clinical presentation is variable, brain CT may be normal, and MRI is not always available. Furthermore, early treatment may be effective. As d-dimer (DD) measurement is a sensitive test for the exclusion of venous thromboembolism, the authors studied whether this test could be useful in the diagnosis of CVT. Methods: A prospective study of 54 consecutive patients with headaches suggestive of CVT was conducted between October 2000 and September 2002. DD levels were tested for all patients in the emergency room before brain CT or MRI was performed. Results: Twelve (22%) of the 54 patients had CVT, and 10 (83%) of these 12 patients had DD level of >500 ng/mL (sensitivity of 83% and negative predictive value of 95%). Two patients with confirmed CVT and DD of <500 ng/mL had a history of chronic headache of >30 days’ duration. In the 42 patients without confirmed CVT, only 4 patients had DD level of >500 ng/mL (specificity of 90% and positive predictive value of 71%). Conclusions: DD test is useful in the diagnosis of acute CVT. A value below 500 ng/mL makes acute thrombosis unlikely.

Identification of new serum autoantibodies in neuromyelitis optica using protein microarrays

Neuromyelitis optica (NMO) or Devic’s disease is a severe demyelinating disease of the CNS affecting primarily optic nerves and spinal cord, secondary to a B-cell- and Ab-mediated autoimmune condition.1 This concept was recently bolstered by the demonstration of disease-specific NMO-Abs,2 and the apparent beneficial effect of B-cell depletion.3 Here, we used a protein microarray approach to profile the Ag reactivity of serum IgG from NMO patients. Sera from five patients fulfilling NMO criteria (Cases 2 through 6 described elsewhere3) and five healthy controls were tested. Because patients experienced relapses and progressive clinical impairment despite therapy, they received rituximab as an off-label, innovative treatment.3 A 20-year-old woman with NMO associated with a high relapse rate (19 relapses within the last 6 years) was blind, wheelchair bound, and had a mid-thoracic sensory level and urinary and stool incontinence. Following treatment with rituximab, she experienced improved strength and sensation in her legs. She had an attack of myelitis approximately 1 month after her first course of rituximab from which she recovered spontaneously without additional treatment. At 1 year follow up, her vision remained impaired but she recovered full strength in her legs, normal …

Opsoclonus-Myoclonus Syndrome in Anti–N-Methyl-D-Aspartate Receptor Encephalitis

BACKGROUND Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis has been recently reported as autoimmune/paraneoplastic encephalitis, affecting mostly young females. OBJECTIVE To describe opsoclonus-myoclonus syndrome in association with anti-NMDAR antibodies. DESIGN Case report. SETTING Geneva University Hospital. Patient A 23-year-old woman with opsoclonus-myoclonus syndrome. RESULTS Two weeks after an episode of gastroenteritis, the patient developed symptoms of depression associated with psychomotor slowing, progressive gait instability, and opsoclonus-myoclonus. Cerebrospinal fluid examination showed mild lymphocytic pleocytosis and intrathecal IgG synthesis with oligoclonal bands. The patients condition worsened rapidly to an akinetic mutism, followed by a period of agitation, delirium, and hallucinations. These gradually subsided; however, a frontal behavior and executive dysfunction persisted 5 months after symptom presentation. No tumor was found. Anti-NMDAR antibodies were found in the cerebrospinal fluid. CONCLUSIONS Opsoclonus-myoclonus may occur in patients with anti-NMDAR encephalitis. Prompt diagnosis of this disorder is important because after tumor removal and immunomodulatory therapies it has a relatively good prognosis.

Carotid plaque: comparison between visual and grey-scale median analysis

Plaque morphology plays an important prognostic role in the occurrence of cerebrovascular events. Echolucent and heterogeneous plaques, in particular, carry an increased risk of subsequent stroke. Most of the trials emphasizing the relationship between plaque echo structure and stroke risk are based on high-resolution ultrasound (US) using a visual method of classification. More recently, several studies have suggested that the computerized measurement of the grey-scale median (GSM) may evaluate carotid plaque echogenicity more objectively and accurately. We sought to compare these two types of evaluations. We studied 68 consecutive patients, with 86 carotid bifurcation plaques causing 30% to 99% stenosis on duplex scanning. We assessed the GSM of these plaques and compared it to the visually evaluated echogenicity using the five-type classification system with vessel lumen and adventitia as reference structures. Plaque heterogeneity was also studied in a subgroup of 47 patients with 60 carotid stenoses by comparing visual analysis with the GSM method. The mean GSM value of the plaques increased with the plaque type. The difference of echogenicity between the five types of plaques was statistically significant (p < 0.02). We found a good concordance between visual analysis and the GSM method regarding plaque heterogeneity. Our results suggest that the visual evaluation of plaque echogenicity and heterogeneity based on the five-type classification correlates well with the computerized measurement of the GSM. The visual evaluation of carotid plaque remains, therefore, a valuable method in daily clinical practice.

Hepatocyte growth factor: A regulator of inflammation and autoimmunity

Hepatocyte growth factor (HGF) is a pleiotropic cytokine that has been extensively studied over several decades, but was only recently recognized as a key player in mediating protection of many types of inflammatory and autoimmune diseases. HGF was reported to prevent and attenuate disease progression by influencing multiple pathophysiological processes involved in inflammatory and immune response, including cell migration, maturation, cytokine production, antigen presentation, and T cell effector function. In this review, we discuss the actions and mechanisms of HGF in inflammation and immunity and the therapeutic potential of this factor for the treatment of inflammatory and autoimmune diseases.

A phase IIa randomised clinical study of GNbAC1, a humanised monoclonal antibody against the envelope protein of multiple sclerosis-associated endogenous retrovirus in multiple sclerosis patients

Background: GNbAC1 is an immunoglobulin (IgG4) humanised monoclonal antibody against multiple sclerosis-associated retrovirus (MSRV)-Env, a protein of endogenous retroviral origin, expressed in multiple sclerosis (MS) lesions, which is pro-inflammatory and inhibits oligodendrocyte precursor cell differentiation. Objective: This is a randomised, double-blind placebo-controlled dose-escalation study followed by a six-month open-label phase to test GNbAC1 in MS patients. The primary objective was to assess GNbAC1 safety in MS patients, and the other objectives were pharmacokinetic and pharmacodynamic assessments. Methods: Ten MS patients were randomised into two cohorts to receive a single intravenous infusion of GNbAC1/placebo at doses of 2 or 6 mg/kg. Then all patients received five infusions of GNbAC1 at 2 or 6 mg/kg at four-week intervals in an open-label setting. Safety, brain magnetic resonance imaging (MRI), pharmacokinetics, immunogenicity, cytokines and MSRV RNA expression were studied. Results: All patients completed the study. GNbAC1 was well tolerated in all patients. GNbAC1 pharmacokinetics is dose-linear with mean elimination half-life of 27–37 d. Anti-GNbAC1 antibodies were not detected. Cytokine analysis did not indicate an adverse effect. MSRV-transcripts showed a decline after the start of treatment. Nine patients had stable brain lesions at MRI. Conclusion: The safety, pharmacokinetic profile, and pharmacodynamic responses to GNbAC1 are favourable in MS patients over a six-month treatment period.