Journal article
Complement C3-Targeted Therapy: Replacing Long-Held Assertions with Evidence-Based Discovery
Trends in immunology, Vol.38(6), pp.383-394
06/2017
DOI: 10.1016/j.it.2017.03.003
PMCID: PMC5447467
PMID: 28416449
Abstract
Complement dysregulation underlies several inflammatory disorders, and terminal complement inhibition has thus far afforded significant clinical gains. Nonetheless, emerging pathologies, fueled by complement imbalance and therapy-skewing genetic variance, underscore the need for more comprehensive, disease-tailored interventions. Modulation at the level of C3, a multifaceted orchestrator of the complement cascade, opens up prospects for broader therapeutic efficacy by targeting multiple pathogenic pathways modulated by C3-triggered proinflammatory crosstalk. Notably, C3 intervention is emerging as a viable therapeutic strategy for renal disorders with predominantly complement-driven etiology, such as C3 glomerulopathy (C3G). Using C3G as a paradigm, we argue that concerns about the feasibility of long-term C3 intervention need to be placed into perspective and weighed against actual therapeutic outcomes in prospective clinical trials.
Proteins of the complement cascade together form a key innate immune sensor that mediates immunosurveillance and tissue homeostasis through extensive crosstalk with other pattern recognition systems. However, deregulation of complement responses can fuel a vicious cycle of tissue injury and inflammation.
C5 blockade has proven effective for treating some complement-mediated diseases, but it has also revealed new pathogenic mechanisms that remain unaddressed.
C3G is a rare renal disorder driven by aberrant complement activation and dysregulation of complement responses on the glomerular basement membrane (GBM).
Blockade of the central component C3 is emerging as a therapeutic modality for C3G. Assertions related to potential risks and complications during prolonged C3 intervention need to be replaced by evidence-based discovery and clinical data.
Details
- Title: Subtitle
- Complement C3-Targeted Therapy: Replacing Long-Held Assertions with Evidence-Based Discovery
- Creators
- Dimitrios C Mastellos - Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAEdimara S Reis - Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADaniel Ricklin - Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USARichard J Smith - Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA, USAJohn D Lambris - Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Resource Type
- Journal article
- Publication Details
- Trends in immunology, Vol.38(6), pp.383-394
- DOI
- 10.1016/j.it.2017.03.003
- PMID
- 28416449
- PMCID
- PMC5447467
- NLM abbreviation
- Trends Immunol
- ISSN
- 1471-4906
- eISSN
- 1471-4981
- Publisher
- Elsevier Ltd
- Grant note
- name: US National Institutes of Health, award: AI003040, AI068730, DK110023; DOI: 10.13039/100000001, name: National Science Foundation, award: 1423304; name: European Commission 7th Framework Programme, award: 602699
- Language
- English
- Date published
- 06/2017
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
- Record Identifier
- 9984007161402771
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