Therapeutic monoclonal antibodies (mAbs) are potent new tools for a molecular targeted approach to modify the course of multiple sclerosis (MS). Besides natalizumab, which was approved in 2006, three ...other mAbs (alemtuzumab, rituximab and daclizumab) were successfully tested in Phase II MS trials. In this review, introductory notes on the development and systematic nomenclature of therapeutic mAbs in general, set the stage for a detailed discussion of the four mAbs mentioned. We summarize non-MS indications, expression and function of target antigens, scientific rationales for MS therapy, putative modes of action and pharmacological aspects. Particularly, we provide a critical discussion of clinical MS trials, including protocols and interim analyses of trials currently underway. The natalizumab section pays special attention to the clinical handling of safety issues and the diagnostic use of neutralizing antibodies. We finally develop a scenario for how each of the four mAbs might evolve into the market of MS therapeutics within the coming years.
Posttranslational modification with SUMO is known to regulate the activity of transcription factors, but how SUMOylation of individual proteins might influence immunity is largely unexplored. The ...NFAT transcription factors play an essential role in antigen receptor-mediated gene regulation. SUMOylation of NFATc1 represses IL-2 in vitro, but its role in T cell-mediated immune responses in vivo is unclear. To this end, we generated a novel transgenic mouse in which SUMO modification of NFATc1 is prevented. Avoidance of NFATc1 SUMOylation ameliorated experimental autoimmune encephalomyelitis as well as graft-versus-host disease. Elevated IL-2 production in T cells promoted T reg expansion and suppressed autoreactive or alloreactive immune responses. Mechanistically, increased IL-2 secretion counteracted IL-17 and IFN-γ expression through STAT5 and Blimp-1 induction. Then, Blimp-1 repressed IL-2 itself, as well as the induced, proliferation-associated survival factor Bcl2A1. Collectively, these data demonstrate that prevention of NFATc1 SUMOylation fine-tunes T cell responses toward lasting tolerance. Thus, targeting NFATc1 SUMOylation presents a novel and promising strategy to treat T cell-mediated inflammatory diseases.
Interferon-β1b in multiple sclerosis Buttmann, Mathias; Rieckmann, Peter
Expert review of neurotherapeutics,
20/3/1/, Letnik:
7, Številka:
3
Journal Article
Recenzirano
In 1993, interferon (IFN)-β
1b
for subcutaneous injection became the first US FDA-approved immunomodulatory treatment for multiple sclerosis, a chronic inflammatory disease of the CNS. In this review ...of IFN-β
1b
, we first present a short introduction to multiple sclerosis and currently available therapeutics. We then summarize current knowledge about the biochemical structure of IFN-β
1b
, as well as pharmacokinetics and pharmacodynamics, including data on putative mechanisms underlying therapeutic as well as adverse effects. Furthermore, a critical review of ongoing and recently published clinical trials investigating IFN-β
1b
in multiple sclerosis will be provided. Main topics are: trials investigating IFN-β
1b
after a first clinical event, at higher dosages or in comparison to once-weekly subcutaneous IFN-β
1a
injections, 16 years of long-term follow-up, IFN-β
1b
in Japanese patients, the role of neutralizing antibodies, biomarkers for the prediction of therapy response, IFN-β
1b
and pregnancy, and IFN-β
1b
treatment of children with multiple sclerosis. Finally, we discuss how novel drugs, especially monoclonal antibodies and orally administered immunosuppressants, might soon challenge the position of this well-established agent on the multiple sclerosis therapeutics market.
Abstract A novel type of encephalomyelitis was first described as chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) in 2010 and few additional ...patients were reported since then. Partially due to its unknown aetiology and a lack of pathognomonic features some have suggested that CLIPPERS may not represent a distinct disease, but rather a syndrome with different underlying aetiologies. Here we report a 49-year-old German female who presented with a number of clinical and paraclinical features described as typical for CLIPPERS, while additionally showing symptoms and findings compatible with primary angiitis of the CNS (PACNS). This case may establish a previously unnoted link between two poorly understood autoimmune conditions of the CNS.
OBJECTIVETo investigate if patients with neuromyelitis optica spectrum disorder (NMOSD) develop subclinical visual pathway impairment independent of acute attacks.
METHODSA total of 548 ...longitudinally assessed full-field visual evoked potentials (VEP) of 167 patients with NMOSD from 16 centers were retrospectively evaluated for changes of P100 latencies and P100-N140 amplitudes. Rates of change in latencies (RCL) and amplitudes (RCA) over time were analyzed for each individual eye using linear regression and compared using generalized estimating equation models.
RESULTSThe rates of change in the absence of optic neuritis (ON) for minimal VEP intervals of ≥3 months between baseline and last follow-up were +1.951 ms/y (n = 101 eyes; SD = 6.274; p = 0.012) for the P100 latencies and −2.149 µV/y (n = 64 eyes; SD = 5.013; p = 0.005) for the P100-N140 amplitudes. For minimal VEP intervals of ≥12 months, the RCL was +1.768 ms/y (n = 59 eyes; SD = 4.558; p = 0.024) and the RCA was −0.527 µV/y (n = 44 eyes; SD = 2.123; p = 0.111). The history of a previous ON >6 months before baseline VEP had no influence on RCL and RCA. ONs during the observational period led to mean RCL and RCA of +11.689 ms/y (n = 16 eyes; SD = 17.593; p = 0.003) and −1.238 µV/y (n = 11 eyes; SD = 3.708; p = 0.308), respectively.
CONCLUSIONThis first longitudinal VEP study of patients with NMOSD provides evidence of progressive VEP latency delay occurring independently of acute ON. Prospective longitudinal studies are needed to corroborate these findings and help to interpret the clinical relevance.
Dimethyl fumarate (DMF) is approved for disease-modifying treatment of patients with relapsing-remitting multiple sclerosis. Animal experiments suggested that part of its therapeutic effect is due to ...a reduction of T-cell infiltration of the central nervous system (CNS) by uncertain mechanisms. Here we evaluated whether DMF and its primary metabolite monomethyl fumarate (MMF) modulate pro-inflammatory intracellular signaling and T-cell adhesiveness of nonimmortalized single donor human brain microvascular endothelial cells at low passages. Neither DMF nor MMF at concentrations of 10 or 50 µM blocked the IL-1β-induced nuclear translocation of NF-kappaB/p65, whereas the higher concentration of DMF inhibited the nuclear entry of p65 in human umbilical vein endothelium cultured in parallel. DMF and MMF also did not alter the IL-1β-stimulated activation of p38 MAPK in brain endothelium. Furthermore, neither DMF nor MMF reduced the basal or IL-1β-inducible expression of ICAM-1. In accordance, both fumaric acid esters did not reduce the adhesion of activated Jurkat T cells to brain endothelium under basal or inflammatory conditions. Therefore, brain endothelial cells probably do not directly mediate a potential blocking effect of fumaric acid esters on the inflammatory infiltration of the CNS by T cells.
EAE serves as an animal model for multiple sclerosis and is initiated by autoreactive T cells that infiltrate the CNS. Recognition of myelin‐associated Ags within the CNS leads to activation of the ...transcription factor family NFAT. Here, we demonstrate an essential role for NFAT in disease induction, as the combined lack of NFAT1 (NFATc2) and NFAT2 (NFATc1) completely protected mice. Single deficiency of either NFAT1 or NFAT2 ameliorated the course of EAE, and NFAT2 ablation resulted in an obstructed proinflammatory reaction. However, NFAT1 deficit led to an anti‐inflammatory response with nonpathogenic Th17 and Th2 cells concurrently secreting IL‐17, IL‐4, and IL‐10. Both IL‐4 and IL‐10 contributed to disease protection. In Nfat1−/− CD4+ T cells, the expression of anti‐inflammatory lymphokines was mediated by NFAT2, thus directly enabling protective IL expression. Consequently, blocking NFAT in toto may be an option for immunosuppressive therapy. More importantly, selective NFAT1 blockade could represent a safe long‐term immunomodulatory treatment approach for multiple sclerosis patients, potentially avoiding the adverse effects of global immunosuppression.
Cognitive impairment (CI) affects 40–65% of multiple sclerosis (MS) patients. This study attempted evaluating the effects of fingolimod and interferon beta-1b (IFN β-1b) on CI progression, magnetic ...resonance imaging (MRI) and clinical outcomes in relapsing–remitting MS (RRMS) patients over 18 months. The GOLDEN study was a pilot study including RRMS patients with CI randomised (2:1) to fingolimod (0.5 mg daily)/IFN β-1b (250 µg every other day). CI was assessed via Rao’s Brief Repeatable Battery and Delis–Kaplan Executive Function System test. MRI parameters, Expanded Disability Status Scale scores and relapses were measured. Overall, 157 patients were randomised, of whom 30 discontinued the study (fingolimod, 8.49%; IFN β-1b, 41.18%;
p
≤ 0.0001). Patients randomised to fingolimod had more severe clinical and MRI disease characteristics at baseline compared with IFN β-1b. At Month (M) 18, both treatment groups showed improvements in all cognitive parameters. At M18, relapse rate, total number and volume of T2/T1 gadolinium-enhancing lesions were higher with IFN β-1b, as well as the percentage brain volume change during the study. Safety and tolerability of both treatments were similar to previous studies. Both treatments showed improvements in cognitive parameters. Fingolimod demonstrated significantly better effects on MRI parameters and relapse rate. Imbalance in baseline characteristics and the drop-out pattern may have favoured IFN β-1b. A longer duration trial may be needed to observe the complete expression of differential effects on CI scales reflecting the between-groups differences on MRI. Although limited in size, the GOLDEN study confirms the favourable benefit–risk profile of fingolimod reported in previous studies.
The third part of this in-depth review series on the treatment of multiple sclerosis (MS) with monoclonal antibodies covers the years 2010-2012. The natalizumab section gives a progressive multifocal ...leukoencephalopathy update, focusing on clinically relevant aspects. Furthermore, it outlines problems around natalizumab cessation and current evidence on therapeutic strategies thereafter. Finally, it reviews evidence on Janus-faced modes of natalizumab action besides anti-inflammatory effects, including proinflammatory effects. The section on alemtuzumab critically analyzes recent Phase III results and discusses which patients might be best suited for alemtuzumab treatment, and reviews the long-term immunological impact of this anti-CD52 antibody. The daclizumab section critically summarizes results from the Phase IIb SELECT/SELECTION trial and introduces the Phase III program. The section on anti-CD20 antibodies reviews Phase II results on ocrelizumab and ofatumumab, and discusses current perspectives of these antibodies for MS therapy. Promising recent Phase II results on the anti-IL-17A antibody secukinumab (AIN457) are outlined and a short update on tabalumab (LY2127399) is given. Other highlighted antibodies currently being tested in MS patients include GNbAC1, BIIB033, MOR103 and MEDI-551. Finally, the authors give an update on the role monoclonal antibodies could play in the therapeutic armamentarium for MS in the medium term.
The neuronal ceroid lipofuscinoses constitute a group of fatal inherited lysosomal storage diseases that manifest in profound neurodegeneration in the CNS. Visual impairment usually is an early ...symptom and selective degeneration of retinal neurons has been described in patients suffering from distinct disease subtypes. We have previously demonstrated that palmitoyl protein thioesterase 1 deficient (Ppt1-/-) mice, a model of the infantile disease subtype, exhibit progressive axonal degeneration in the optic nerve and loss of retinal ganglion cells, faithfully reflecting disease severity in the CNS. Here we performed spectral domain optical coherence tomography (OCT) in Ppt1-/- and ceroid lipofuscinosis neuronal 3 deficient (Cln3-/-) mice, which are models of infantile and juvenile neuronal ceroid lipofuscinosis, respectively, in order to establish a non-invasive method to assess retinal alterations and monitor disease severity in vivo.
Blue laser autofluorescence imaging revealed increased accumulation of autofluorescent storage material in the inner retinae of 7-month-old Ppt1-/- and of 16-month-old Cln3-/- mice in comparison with age-matched control littermates. Additionally, optical coherence tomography demonstrated reduced thickness of retinae in knockout mice in comparison with age-matched control littermates. High resolution scans and manual measurements allowed for separation of different retinal composite layers and revealed a thinning of layers in the inner retinae of both mouse models at distinct ages. OCT measurements correlated well with subsequent histological analysis of the same retinae.
These results demonstrate the feasibility of OCT to assess neurodegenerative disease severity in mouse models of neuronal ceroid lipofuscinosis and might have important implications for diagnostic evaluation of disease progression and therapeutic efficacy in patients. Moreover, the non-invasive method allows for longitudinal studies in experimental models, reducing the number of animals used for research.
PDF
