scholarly journals Novel Approaches for Immunosuppression in Graves’ Hyperthyroidism and Associated Orbitopathy

2020 ◽  
Vol 9 (Suppl. 1) ◽  
pp. 17-30 ◽  
Author(s):  
Alan Chun Hong Lee ◽  
George J. Kahaly
Keyword(s):  
Monoclonal Antibody ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Cell Interaction ◽  
Thyrotropin Receptor ◽  
Recent Onset ◽  
Immunological Mechanisms ◽  
Interleukin 6 Receptor ◽  
Novel Treatment Strategies ◽  
Receptor Monoclonal Antibody

<b><i>Background:</i></b> Both Graves’ hyperthyroidism (GH) and Graves’ orbitopathy (GO) are associated with significant adverse health consequences. All conventional treatment options have limitations regarding efficacy and safety. Most importantly, they do not specifically address the underlying immunological mechanisms. We aim to review the latest development of treatment approaches in these two closely related disorders. <b><i>Summary:</i></b> Immunotherapies of GH have recently demonstrated clinical efficacy in preliminary studies. They include ATX-GD-59, an antigen-specific immunotherapy which restores immune tolerance to the thyrotropin receptor; iscalimab, an anti-CD40 monoclonal antibody which blocks the CD40-CD154 costimulatory pathway in B-T cell interaction; and K1-70, a thyrotropin receptor-blocking monoclonal antibody. Novel treatment strategies have also become available in GO. Mycophenolate significantly increased the overall response rate combined with standard glucocorticoid (GC) treatment compared to GC monotherapy. Tocilizumab, an anti-interleukin 6 receptor monoclonal antibody, displayed strong anti-inflammatory action in GC-resistant cases. Teprotumumab, an anti-insulin-like growth factor 1 receptor monoclonal antibody, resulted in remarkable improvement in terms of disease activity, proptosis, and diplopia. Further, rituximab appears to be useful in active disease of recent onset without impending dysthyroid optic neuropathy. <b><i>Key Messages:</i></b> Therapeutic advances will continue to optimize our management of GH and associated orbitopathy in an effective and safe manner.

scholarly journals Myeloma Bone Disease: Update on Pathogenesis and Novel Treatment Strategies

Pharmaceutics ◽  
2018 ◽  
Vol 10 (4) ◽  
pp. 202 ◽  
Author(s):  
Sonia Vallet ◽  
Julia-Marie Filzmoser ◽  
Martin Pecherstorfer ◽  
Klaus Podar
Keyword(s):  
Bone Disease ◽  
Molecular Mechanisms ◽  
Bone Fractures ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Nf Kappa B ◽  
Skeletal Involvement ◽  
Myeloma Bone Disease ◽  
Skeletal Related Events ◽  
Novel Treatment Strategies

Bone disease, including osteolytic lesions and/or osteoporosis, is a common feature of multiple myeloma (MM). The consequences of skeletal involvement are severe pain, spinal cord compressions, and bone fractures, which have a dramatic impact on patients’ quality of life and, ultimately, survival. During the past few years, several landmark studies significantly enhanced our insight into MM bone disease (MBD) by identifying molecular mechanisms leading to increased bone resorption due to osteoclast activation, and decreased bone formation by osteoblast inhibition. Bisphosphonates were the mainstay to prevent skeletal-related events in MM for almost two decades. Excitingly, the most recent approval of the receptor activator of NF-kappa B ligand (RANKL) inhibitor, denosumab, expanded treatment options for MBD, for patients with compromised renal function, in particular. In addition, several other bone-targeting agents, including bone anabolic drugs, are currently in preclinical and early clinical assessment. This review summarizes our up-to-date knowledge on the pathogenesis of MBD and discusses novel state-of-the-art treatment strategies that are likely to enter clinical practice in the near future.

scholarly journals CRISPR/Cas9-engineered Drosophila knock-in models to study VCP diseases

2021 ◽  
Author(s):  
Jordan M. Wall ◽  
Ankita Basu ◽  
Elizabeth R.M. Zunica ◽  
Olga S. Dubuisson ◽  
Kathryn Pergola ◽  
...  
Keyword(s):  
Treatment Options ◽  
Treatment Strategies ◽  
Model Organism ◽  
Organelle Biogenesis ◽  
Protein Aggregate ◽  
Phenotypic Differences ◽  
Aaa Atpase ◽  
Novel Treatment Strategies ◽  
Unexpected Findings

Valosin containing protein (VCP) is a hexameric type II AAA ATPase required for several cellular processes including ER-associated degradation, organelle biogenesis, autophagy and membrane fusion. VCP contains three domains: a regulatory N-terminal domain and two ATPase domains (D1 and D2). Mutations in the N-terminal and D1 domains are associated with several degenerative diseases, including Multisystem Proteinopathy (MSP-1) and ALS. However, patients with VCP mutations vary widely in their pathology and clinical penetrance, making it difficult to devise effective treatment strategies. Having a deeper understanding of how each mutation affects VCP function could enhance the prediction of clinical outcomes and design of personalized treatment options. Over-expressing VCP patient mutations in Drosophila has been shown to mimic many pathologies observed in human patients. The power of a genetically tractable model organism coupled with well-established in vivo assays and a relatively short life cycle make Drosophila an attractive system to study VCP disease pathogenesis and novel treatment strategies. Using CRISPR/Cas9, we have generated individual Drosophila knock-in mutants that include nine hereditary VCP disease mutations. We validate that these models display many hallmarks of VCP-mediated degeneration, including progressive decline in mobility, protein aggregate accumulation and defects in lysosomal and mitochondrial function. We also made some novel and unexpected findings, including laminopathies and sex-specific phenotypic differences in several mutants. Taken together, the Drosophila VCP disease models we have generated in this study will be useful for studying the etiology of individual VCP patient mutations and for testing potential genetic and/or pharmacological therapies.

Effects of SA237, a humanized anti-interleukin-6 receptor monoclonal antibody, on pre- and postnatal development in cynomolgus monkey

2017 ◽  
Vol 109 (11) ◽  
pp. 843-856 ◽  
Author(s):  
Ryuichi Katagiri ◽  
Kana Ishihara-Hattori ◽  
Werner Frings ◽  
Jun Amano ◽  
Antje Fuchs ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Postnatal Development ◽  
Interleukin 6 ◽  
Cynomolgus Monkey ◽  
Interleukin 6 Receptor ◽  
Receptor Monoclonal Antibody

scholarly journals Current Concepts of Hyperinflammation in Chronic Granulomatous Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Nikolaus Rieber ◽  
Andreas Hector ◽  
Taco Kuijpers ◽  
Dirk Roos ◽  
Dominik Hartl
Keyword(s):  
Chronic Granulomatous Disease ◽  
Fungal Infections ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Antimicrobial Treatment ◽  
Inflammasome Activation ◽  
Granulomatous Disease ◽  
Therapeutic Implications ◽  
Immunological Mechanisms ◽  
Surface Redox

Chronic granulomatous disease (CGD) is the most common inherited disorder of phagocytic functions, caused by genetic defects in the leukocyte nicotinamide dinucleotide phosphate (NADPH) oxidase. Consequently, CGD phagocytes are impaired in destroying phagocytosed microorganisms, rendering the patients susceptible to bacterial and fungal infections. Besides this immunodeficiency, CGD patients suffer from various autoinflammatory symptoms, such as granuloma formation in the skin or urinary tract and Crohn-like colitis. Owing to improved antimicrobial treatment strategies, the majority of CGD patients reaches adulthood, yet the autoinflammatory manifestations become more prominent by lack of causative treatment options. The underlying pathomechanisms driving hyperinflammatory reactions in CGD are poorly understood, but recent studies implicate reduced neutrophil apoptosis and efferocytosis, dysbalanced innate immune receptors, altered T-cell surface redox levels, induction of Th17 cells, the enzyme indolamine-2,3-dioxygenase (IDO), impaired Nrf2 activity, and inflammasome activation. Here we discuss immunological mechanisms of hyperinflammation and their potential therapeutic implications in CGD.

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