scholarly journals B Cells and Antibodies as Targets of Therapeutic Intervention in Neuromyelitis Optica Spectrum Disorders

2021 ◽  
Vol 14 (1) ◽  
pp. 37
Author(s):  
Jan Traub ◽  
Leila Husseini ◽  
Martin S. Weber
Keyword(s):  
B Cells ◽  
Neuromyelitis Optica ◽  
Plasma Cells ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Therapeutic Interventions ◽  
Complement Factor ◽  
Major Subset ◽  
Spectrum Disorders

The first description of neuromyelitis optica by Eugène Devic and Fernand Gault dates back to the 19th century, but only the discovery of aquaporin-4 autoantibodies in a major subset of affected patients in 2004 led to a fundamentally revised disease concept: Neuromyelits optica spectrum disorders (NMOSD) are now considered autoantibody-mediated autoimmune diseases, bringing the pivotal pathogenetic role of B cells and plasma cells into focus. Not long ago, there was no approved medication for this deleterious disease and off-label therapies were the only treatment options for affected patients. Within the last years, there has been a tremendous development of novel therapies with diverse treatment strategies: immunosuppression, B cell depletion, complement factor antagonism and interleukin-6 receptor blockage were shown to be effective and promising therapeutic interventions. This has led to the long-expected official approval of eculizumab in 2019 and inebilizumab in 2020. In this article, we review current pathogenetic concepts in NMOSD with a focus on the role of B cells and autoantibodies as major contributors to the propagation of these diseases. Lastly, by highlighting promising experimental and future treatment options, we aim to round up the current state of knowledge on the therapeutic arsenal in NMOSD.

Treatment options in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorders

2021 ◽  
Vol 27 ◽  
Author(s):  
Paulus Rommer ◽  
Uwe K Zettl
Keyword(s):  
Multiple Sclerosis ◽  
Side Effects ◽  
Neuromyelitis Optica ◽  
Treatment Options ◽  
Spectrum Disorder ◽  
Neuromyelitis Optica Spectrum Disorder ◽  
Neuromyelitis Optica Spectrum Disorders ◽  
The Past ◽  
Drug Classes ◽  
Spectrum Disorders

: There are few diseases with as many therapeutic advances in recent years as in multiple sclerosis. Nine different drug classes with more than a dozen approved therapies are now available. Similarly, there have been unimaginable advances in understanding neuromyelitis optica (now neuromyelitis optica spectrum disorder [NMOSD]) over the past 15 years. Building on the knowledge gained, the first therapies have been approved in recent years. In this review, we aim to present all therapies approved for the treatment of MS or NMOSD. The different forms of application, different approval criteria and most important side effects will be presented. This work is intended for physicians who are interested in MS and NMOSD therapies and want to get a first overview and does not replace the respective guidelines of the regulatory authorities.

scholarly journals Towards Personalization in the Curative Treatment of Gastric Cancer

2020 ◽  
Vol 10 ◽  
Author(s):  
Astrid E. Slagter ◽  
Marieke A. Vollebergh ◽  
Edwin P. M. Jansen ◽  
Johanna W. van Sandick ◽  
Annemieke Cats ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Standard Of Care ◽  
Molecular Characteristics ◽  
Perioperative Chemotherapy ◽  
Current Standard ◽  
Common Cancer ◽  
Resectable Gastric Cancer

Gastric cancer is the fifth most common cancer worldwide and has a high mortality rate. In the last decades, treatment strategy has shifted from an exclusive surgical approach to a multidisciplinary strategy. Treatment options for patients with resectable gastric cancer as recommended by different worldwide guidelines, include perioperative chemotherapy, pre- or postoperative chemoradiotherapy and postoperative chemotherapy. Although gastric cancer is a heterogeneous disease with respect to patient-, tumor-, and molecular characteristics, the current standard of care is still according to a one-size-fits-all approach. In this review, we discuss the background of the different treatment strategies in resectable gastric cancer including the current standard, the specific role of radiotherapy, and describe the current areas of research and potential strategies for personalization of therapy.

scholarly journals SWAP-70 deficiency causes high-affinity plasma cell generation despite impaired germinal center formation

Blood ◽  
2008 ◽  
Vol 111 (5) ◽  
pp. 2714-2724 ◽  
Author(s):  
Laurence Quemeneur ◽  
Veronique Angeli ◽  
Michael Chopin ◽  
Rolf Jessberger
Keyword(s):  
B Cells ◽  
Plasma Cell ◽  
Cell Activation ◽  
Plasma Cells ◽  
Actin Binding ◽  
B Cell Activation ◽  
Interacting Protein ◽  
Memory Response ◽  
High Affinity

Germinal centers (GCs) are lymphoid tissue structures central to the generation of long-lived, high-affinity, antibody-forming B cells. However, induction, maintenance, and regulation of GCs are not sufficiently understood. The F-actin–binding, Rac-interacting protein SWAP-70 is strongly expressed in activated B cells like those in B follicles. Recent work suggests that SWAP-70 is involved in B-cell activation, migration, and homing. Therefore, we investigated the role of SWAP-70 in the T-dependent immune response, in GC formation, and in differentiation into plasma and memory B cells. Compared with wt, sheep red blood cell (SRBC)–, or NP-KLH–immunized SWAP-70−/− mice have strongly reduced numbers of GCs and GC-specific B cells. However, SWAP-70−/− NP-specific B cells accumulate outside of the B follicles, and SWAP-70−/− mice show more plasma cells in the red pulp and in the bone marrow, and increased NP-specific Ig and antibody-forming B cells. Yet the memory response is impaired. Thus, SWAP-70 deficiency uncouples GC formation from T-dependent antibody and long-lived plasma cell production and causes extrafollicular generation of high-affinity plasma cells, but does not adequately support the memory response.

scholarly journals Crucial Role of Tumor Necrosis Factor Receptor 1 Expression on Nonhematopoietic Cells for B Cell Localization within the Splenic White Pulp

1998 ◽  
Vol 187 (4) ◽  
pp. 469-477 ◽  
Author(s):  
Maria Tkachuk ◽  
Stephan Bolliger ◽  
Bernhard Ryffel ◽  
Gerd Pluschke ◽  
Theresa A. Banks ◽  
...  
Keyword(s):  
B Cells ◽  
Tumor Necrosis ◽  
Plasma Cells ◽  
Tumor Necrosis Factor Receptor ◽  
White Pulp ◽  
Splenic White Pulp ◽  
Initial Activation ◽  
Deficient Mice ◽  
Necrosis Factor

During immune responses the initial activation of B cells takes place in T cell zones of periarteriolar lymphoid sheaths (PALS) of the splenic white pulp. After initial activation, B cells migrate into the primary follicles and, in association with follicular dendritic cells (FDCs), undergo clonal expansion and differentiation giving rise to germinal centers (GCs). Peanut agglutinin binding (PNA+) cells of the GC differentiate further into memory or plasma cells. Here we report that in tumor necrosis factor receptor 1–deficient mice (TNFR1−/−), the location of B cells was altered and that plasma cells were abnormally distributed in the splenic PALS. In contrast to lymphotoxin α–deficient mice (LTα−/−), bone marrow or fetal liver transplantation did not correct the abnormal organization of the spleen, location of B cells, the lack of an FDC network, nor the antibody response in TNFR1−/− mice. These results argue for a crucial role of TNFR1 expression on nonhematopoietic cells for the maintenance of the splenic architecture and proper B cell location. In addition, the lack in development of an FDC network after adoptive transfer suggests that either FDCs are not of bone marrow origin or that they depend on signals from nonhematopoietic cells for maturation.

scholarly journals Circulating Memory T Follicular Helper Cells in Patients with Neuromyelitis Optica/Neuromyelitis Optica Spectrum Disorders

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Xueli Fan ◽  
Yanfang Jiang ◽  
Jinming Han ◽  
Jingyao Liu ◽  
Yafen Wei ◽  
...  
Keyword(s):  
Neuromyelitis Optica ◽  
Potential Role ◽  
Neuromyelitis Optica Spectrum Disorders ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Cell Counts ◽  
Before And After ◽  
Spectrum Disorders ◽  
White Blood Cell Counts

Objective. This study aimed to examine the potential role of memory T follicular helper (Tfh) cells in patients with neuromyelitis optica/neuromyelitis optica spectrum disorders (NMO/NMOSD).Methods. The percentages of different subsets of circulating memory Tfh cells in 25 NMO/NMOSD patients before and after treatment as well as in 17 healthy controls were examined by flow cytometry. The levels of IL-21 and AQP4 Ab in plasma and CSF were measured by ELISA.Results. The percentages and numbers of circulating memory Tfh cells, ICOS+, CCR7−, CCR7−ICOS+, CCR7+, CCR7+ICOS+memory Tfh cells, and the levels of IL-21 in plasma and CSF were significantly increased in NMO/NMOSD patients. The percentages of CCR7−and CCR7−ICOS+memory Tfh cells were positively correlated with ARR, plasma IL-21, and AQP4 Ab levels. The percentages of CCR7+and CCR7+ICOS+memory Tfh cells were positively correlated with CSF white blood cell counts, proteins, and IL-21 levels. Treatment with corticosteroids significantly reduced the numbers of CCR7−ICOS+and CCR7+ICOS+memory Tfh cells as well as plasma IL-21 levels in patients with partial remission.Conclusions. Our findings indicate that circulating memory Tfh cells may participate in the relapse and development of NMO/NMOSD and may serve as a new therapeutic target.

scholarly journals Role of the Myokine Irisin on Bone Homeostasis: Review of the Current Evidence

2021 ◽  
Vol 22 (17) ◽  
pp. 9136
Author(s):  
Amanda Kornel ◽  
Danja J. Den Hartogh ◽  
Panagiota Klentrou ◽  
Evangelia Tsiani
Keyword(s):  
Bone Resorption ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Current Treatment ◽  
Current Evidence ◽  
Signaling Proteins ◽  
Bone Homeostasis ◽  
Menopausal Women ◽  
Post Menopausal

Bone is a highly dynamic tissue that is constantly adapting to micro-changes to facilitate movement. When the balance between bone building and resorption shifts more towards bone resorption, the result is reduced bone density and mineralization, as seen in osteoporosis or osteopenia. Current treatment strategies aimed to improve bone homeostasis and turnover are lacking in efficacy, resulting in the search for new preventative and nutraceutical treatment options. The myokine irisin, since its discovery in 2012, has been shown to play an important role in many tissues including muscle, adipose, and bone. Evidence indicate that irisin is associated with increased bone formation and decreased bone resorption, leading to reduced risk of osteoporosis in post-menopausal women. In addition, low serum irisin levels have been found in individuals with osteoporosis and osteopenia. Irisin targets key signaling proteins, promoting osteoblastogenesis and reducing osteoclastogenesis. The present review summarizes the existing evidence regarding the effects of irisin on bone homeostasis.

scholarly journals Pharmacodynamic modeling and exposure-response assessment of inebilizumab in subjects with neuromyelitis optica spectrum disorders

2021 ◽  
Author(s):  
Li Yan ◽  
Bing Wang ◽  
Dewei She ◽  
Ben Mitchel ◽  
Ryan Criste ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Neuromyelitis Optica ◽  
Drug Exposure ◽  
Response Assessment ◽  
Pharmacodynamic Modeling ◽  
Neuromyelitis Optica Spectrum Disorders ◽  
Spectrum Disorders ◽  
Disease Attack ◽  
The Impact

AIM: Neuromyelitis optica spectrum disorders (NMOSD) is an autoantibody-mediated, B cell-driven disease. Inebilizumab is a humanized, affinity-optimized, afucosylated IgG1 kappa monoclonal antibody that binds to the B cell specific surface antigen CD19, resulting in rapid, profound, and sustained depletion of circulating peripheral B cells in NMOSD subjects (pivotal study). The objective of this study was to conduct population modeling of B cell response following inebilizumab treatment in adult subjects with NMOSD, and to assess the impact of drug exposure to outcome. METHODS: A hematopoietic transit model was developed to describe the joint effects of reducing influx from pro-B cells and accelerating CD20+ B cell depletion in the blood by inebilizumab. Furthermore, the relationships between inebilizumab pharmacokinetic (PK) exposure and the primary efficacy endpoint and key secondary efficacy endpoints were evaluated. KEY RESULTS: At the 300 mg dose, there was no apparent relationship between efficacy (reduction in disease attack risk, risk of worsening from baseline in Expanded Disability Status Scale, cumulative total active MRI lesions, and the number of NMOSD-related in-patient hospitalizations) and PK exposure. Subjects with low, medium, and high PK exposure had a similar hazard ratio of NMOSD attack vs placebo group. CONCLUSIONS: The pharmacodynamic modeling confirmed effective depletion of B cells is achieved with a 300 mg intravenous dose of inebilizumab administered on Day 1 and Day 15 and every 6 months thereafter. The PK variability between patients had no apparent effect on clinical efficacy.

scholarly journals Struggling with recurrent Clostridium difficile infections: is donor faeces the solution?

2009 ◽  
Vol 14 (34) ◽  
Author(s):  
E van Nood ◽  
P Speelman ◽  
E J Kuijper ◽  
J J Keller
Keyword(s):  
Clostridium Difficile ◽  
Case Reports ◽  
Treatment Options ◽  
Intestinal Flora ◽  
Treatment Strategies ◽  
Case Series ◽  
Oral Vancomycin ◽  
Vancomycin Therapy ◽  
Evidence Based Treatment

Patients with recurrent Clostridium difficile infections (CDI) in hospitals and the community constitute an increasing treatment problem. While most patients with a first infection respond to either metronidazole or oral vancomycin, therapy in recurrent C. difficile infections tends to fail repeatedly. Lack of alternative treatment options can be a tremendous burden, both to patients and their treating physicians. Most guidelines recommend prolonged oral vancomycin pulse and or tapering schedules, but evidence-based treatment strategies are lacking. The role of immunoglobulins, whey prepared from vaccinated cows, probiotics or other antibiotics is unclear. Since 1958 several case series and case reports describe a treatment strategy where faecal infusions are successfully given for the treatment of recurrent CDI. Restoring intestinal flora has been historically thought of as the mechanism responsible for cure in these patients. In the literature, more than 150 patients have received faeces from a healthy donor, either infused through an enema, or through a nasoduodenal or nasogastric tube. We summarise the literature regarding treatment with donor faeces for recurrent CDI, and introduce the FECAL trial, currently open for inclusion.

scholarly journals Role of Glutamatergic Excitotoxicity in Neuromyelitis Optica Spectrum Disorders

2019 ◽  
Vol 13 ◽  
Author(s):  
Ana Paula Bornes da Silva ◽  
Débora Guerini Souza ◽  
Diogo Onofre Souza ◽  
Denise Cantarelli Machado ◽  
Douglas Kazutoshi Sato
Keyword(s):  
Neuromyelitis Optica ◽  
Neuromyelitis Optica Spectrum Disorders ◽  
Spectrum Disorders
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