Commentary
Abstract
Chimeric antigen receptor (CAR) T cells are an effective therapy for relapsed or refractory pediatric B cell leukemia. Analysis of the starting material, the T cells collected from the patient prior to CAR manufacture, reveals possible biomarkers of cells destined to perform poorly in patients. Long-term follow-up shows that long periods of B cell aplasia, a marker of in vivo CAR activity, are associated with longer remission but also a higher chance of antigen-negative relapse. The role of transplantation as consolidative therapy is unclear in this nonrandomized data, but clearly warrants further study.
Authors
David M. Barrett
Abstract
The Epstein-Barr virus (EBV) is estimated to infect a large part of the population and is associated with a variety of human tumors; therefore, EBV is an important target for vaccine development. In this issue of the JCI, Rühl et al. developed a promising heterologous prime-boost vaccination strategy for EBV-associated malignancies and symptomatic primary infection. The authors show that two prime-boost regimens, using either dendritic cells or an adenovirus approach targeting nuclear antigen EBNA1 followed by a modified vaccinia virus Ankara (MVA) booster, induced significant T cell–mediated, EBV-specific immune control and Ab production. These findings suggest that administration of heterologous prime-boost vaccinations targeting EBNA1 may result in potent CD4+ and CD8+ T cell–mediated EBV immune control and may be a promising clinical approach.
Authors
Sandhya Sharma, Rayne H. Rouce
Abstract
The equilibrium of signaling through activating and inhibitory receptors dictates whether a given NK cell will execute cellular cytotoxicity. In this issue of the JCI, Kamiya et al. describe a novel approach to efficiently inhibiting surface expression of the inhibitory receptor CD94/NK group 2 member A (NKG2A) through retention of the protein in the endoplasmic reticulum. In adoptive transfer experiments into tumor-bearing immunodeficient mice, NKG2Anull NK cells were significantly more effective at eliminating HLA-E–expressing tumor cells than NKG2A+ NK cells. This study provides proof of concept for a new immunotherapeutic approach using NKG2Anull NK cells.
Authors
Frank Cichocki, Jeffrey S. Miller
Abstract
Cancer stem cells sustain propagation of the deadly primary brain cancer glioblastoma. Glioblastoma stem cells (GSCs) characterized by a mesenchymal phenotype are aggressive and resistant to therapies and represent a crucial therapeutic target. In this issue of the JCI, Chen et al. show that the intracellular levels of aldehyde dehydrogenase 1A3 (ALDH1A3), known as a functional marker of mesenchymal GSCs, are regulated posttranslationally by ubiquitin-specific protease 9X–mediated (USP9X-mediated) deubiquitination. Increased expression of USP9X stabilizes ALDH1A3, enabling GSCs to exhibit mesenchymal traits and the malignant phenotype. Thus, the USP9X-ALDH1A3 axis may offer a novel therapeutic target in glioblastoma.
Authors
Hiroaki Wakimoto
Abstract
Eosinophilic esophagitis (EoE) is a recently described disease in which exposure to specific foods and allergens leads to type 2 inflammation, epithelial barrier dysfunction, and difficulty in swallowing. In the current issue of the JCI, Wen and colleagues investigate tissue T cell heterogeneity in patients with EoE using single-cell RNA sequencing (scRNA-seq). Esophageal epithelium from individuals with EoE convtained a prominent population of Th2 cells not seen in controls. The short-chain fatty acid (SCFA) receptor FFAR3 was found to be highly expressed in EoE Th2 cells. Experiments presented here provide evidence that SCFAs may promote type 2 inflammation in allergic diseases such as EoE and asthma. This study provides an early example of scRNA-seq for identifying relevant cell populations and mechanisms underlying allergic diseases.
Authors
Walter L. Eckalbar, David J. Erle
Abstract
The role of urokinase-type plasminogen activator receptor (uPAR) in kidney physiology and pathology has attracted considerable attention. The protein uPAR has dual functions: as a key regulator of plasmin generation and a component of the innate immune system. In the current issue, Wei and colleagues describe a transgenic mouse expressing Plaur RNA in glomerular podocytes. The mice manifested podocyte injury, including c-Src phosphorylation, proteinuria, and focal segmental glomerulosclerosis (FSGS). Plaur-transgenic mice on a β3 integrin–deficient background were protected from podocyte injury. Renal biopsies from subjects with FSGS, but not those with other glomerular diseases, manifested increased c-Src phosphorylation in podocytes. These findings suggest a novel injury mechanism in FSGS, with possible implications for new treatment strategies.
Authors
Jeffrey B. Kopp, Jurgen Heymann
Abstract
In this issue of the JCI, Casas et al. define a previously unknown role of the NADPH oxidase catalytic subunit NOX5 in cerebral infarction. Using a mouse expressing human NOX5 in the endothelium, the investigators show that NOX5 is activated and plays a deleterious role in promoting edema, infarction, and ultimately, worsened neurological function following cerebral ischemia. They provide evidence that this is due to the breakdown of the blood-brain barrier (BBB) and that a unique pharmacological inhibitor of NOX5, ML090, if given early, around the time of reoxygenation, can maintain BBB integrity. Future studies of NOX5 inhibition in humans, particularly in the setting of thrombolysis, are warranted.
Authors
Luciana Simão do Carmo, Bradford C. Berk, David G. Harrison
Abstract
Survivors of sepsis and other forms of critical illness frequently experience significant and disabling cognitive and affective disorders. Inflammation, ischemia, and glial cell dysfunction contribute to this persistent brain injury. In this issue of the JCI, Hippensteel et al. show that endothelial injury in animal models of sepsis or endotoxemia leads to shedding of heparan fragments from the endothelial glycocalyx. These fragments directly sequester brain-derived neurotrophic factor and impair hippocampal long-term potentiation, an electrophysiologic correlate of memory. The authors further explore the specific characteristics of heparan fragments that bind neurotrophins and the presence of these fragments in the circulation of patients who survive sepsis. This study highlights an important mechanism by which vascular injury can impair brain function.
Authors
Benjamin H. Singer
Abstract
Motoneurons are particularly sensitive to mutations in mitofusin-2 (MFN2) that cause the neurological disorder Charcot-Marie-Tooth disease type 2A (CMT2A). MFN2 is a mitochondrial outer membrane protein that, together with its homologue MFN1, fuses mitochondria in most tissues. In this issue of the JCI, Zhou and colleagues show that increasing MFN1 expression in neurons can curtail neurological defects in a CMT2A mouse model. These results show that the ratio of MFN1 to MFN2 can explain the tissue specificity of CMT2A and indicate that augmentation of MFN1 in the nervous system has potential as a possible therapeutic strategy for CMT2A.
Authors
Keiko Iwata, Luca Scorrano
Abstract
Chronic unresolved inflammation contributes to the development of nonalcoholic steatohepatitis (NASH), a disorder characterized by lipotoxicity, fibrosis, and progressive liver dysfunction. In this issue of the JCI, Han et al. report that maresin 1 (MaR1), a proresolving lipid mediator, mitigates NASH by reprograming macrophages to an antiinflammatory phenotype. Mechanistically, they identified retinoic acid–related orphan receptor α (RORα) as both a target and autocrine regulator of MaR1 production. Because NASH is associated with many widely occurring metabolic diseases, including obesity and type 2 diabetes, identification of this endogenous protective pathway could have broad therapeutic implications.
Authors
Matthew Spite
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Copyright © 2019 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)