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| Open AccessMesenchymal stromal cell apoptosis is required for their therapeutic function
Mesenchymal stromal cells (MSCs) demonstrate therapeutic benefits in multiple diseases, but the mechanisms remain unclear as infused MSCs do not persist in the body. Here, the authors show that MSC apoptosis is an important mechanistic element, as MSCs rendered genetically incapable of apoptosis lose their ability to ameliorate disease.
- Swee Heng Milon Pang
- , Joshua D’Rozario
- & Tracy S. P. Heng
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Article
| Open AccessTransient mTOR inhibition rescues 4-1BB CAR-Tregs from tonic signal-induced dysfunction
Chimeric antigen receptor engineering in T cells has been shown to be of great potential therapeutic benefit in a range of immune pathologies, although the functionality of such cell therapies can be limited due to tonic signalling and the induction of dysfunction. Here the authors show transient inhibition of mTOR can rescue their 41-BB-CAR-Tregs from tonic signalling-induced dysfunction.
- Baptiste Lamarthée
- , Armance Marchal
- & Julien Zuber
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Article
| Open AccessCancer immune therapy with PD-1-dependent CD137 co-stimulation provides localized tumour killing without systemic toxicity
The toxicity arising from generalised stimulation of T cells restricts applicability of CD137 agonists in cancer immune therapy. Here authors show that a bispecific antibody blocking PD-1 while activating CD137 efficiently restricts T cell activation to the tumour microenvironment, resulting in efficient tumour control and reduced liver toxicity.
- Yunqian Qiao
- , Yangmin Qiu
- & Xuan Wang
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Article
| Open AccessCD73-mediated adenosine production by CD8 T cell-derived extracellular vesicles constitutes an intrinsic mechanism of immune suppression
Ectonucleotidases associated to regulatory T cells are known modulators in the inflammatory environment. Here the authors describe CD8 T cell-derived extracellular vesicles bearing CD73 and suggest they function as an additional intrinsic modulator of immune responses.
- Enja Schneider
- , Riekje Winzer
- & Eva Tolosa
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Article
| Open AccessIntegrin-αV-mediated activation of TGF-β regulates anti-tumour CD8 T cell immunity and response to PD-1 blockade
Response to PD-1 checkpoint blockade is unpredictable in lung cancer patients. Here authors show in human lung and mouse tumour models that low or absent αV integrin expression leads to better tumour growth control by anti-PD-1 via reduced TGF-β activation and hence increased infiltration of anti-tumour CD8+ T cells.
- Ines Malenica
- , Julien Adam
- & Fathia Mami-Chouaib
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Article
| Open AccessEndogenous control of inflammation characterizes pregnant women with asymptomatic or paucisymptomatic SARS-CoV-2 infection
SARS-CoV-2 infection of expecting mothers has been reported. Here the authors profile the peripheral blood from 14 pregnant women with asymptomatic or mild SARS-CoV-2 infection to find grossly normal immune cell composition but heterogenous induction of pro-inflammatory cytokines, thereby implicating possible therapeutic targets for virus-induced damages during pregnancy.
- Sara De Biasi
- , Domenico Lo Tartaro
- & Andrea Cossarizza
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Article
| Open AccessDevelopment of a fixed module repertoire for the analysis and interpretation of blood transcriptome data
The blood transcriptome of human subjects can be profiled on an almost routine basis in translational research settings. Here the authors show that a fixed and well-characterized repertoire of transcriptional modules can be employed as a reusable framework for the analysis, visualization and interpretation of such data
- Matthew C. Altman
- , Darawan Rinchai
- & Damien Chaussabel
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Article
| Open AccessPLGA-particle vaccine carrying TLR3/RIG-I ligand Riboxxim synergizes with immune checkpoint blockade for effective anti-cancer immunotherapy
PLGA based cancer immunotherapy incorporating antigen and TLR ligands has resulted in enhancement of the anti-tumour response. Here, the authors explore the use of a defined double stranded RNA adjuvant, Riboxxim, and test its incorporation with PLGA immunotherapy in the context of in vivo tumour models and show enhanced induction of the anti-tumour response.
- Julia Koerner
- , Dennis Horvath
- & Marcus Groettrup
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Article
| Open AccessTargeting human Acyl-CoA:cholesterol acyltransferase as a dual viral and T cell metabolic checkpoint
Shared metabolic pathways could allow simultaneous manipulation of T cells, viruses and tumours. Here the authors show targeting cholesterol esterification restrains hepatitis B in vitro, whilst bolstering exhausted antigen-specific T cell responses from human liver and hepatocellular carcinoma.
- Nathalie M. Schmidt
- , Peter A. C. Wing
- & Mala K. Maini
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Article
| Open AccessImmune cellular networks underlying recovery from influenza virus infection in acute hospitalized patients
The immunological parameters that define severe influenza disease are not clear within human real time infections. Here the authors compare a severe influenza infection cohort with an influenza vaccinated cohort to understand correlates of severe influenza disease.
- Thi H. O. Nguyen
- , Marios Koutsakos
- & Katherine Kedzierska
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Article
| Open AccessTherapeutic B-cell depletion reverses progression of Alzheimer’s disease
Alzheimer’s disease is characterized by progressive dementia and amyloid beta plaque deposition. Here the authors show in three relevant transgenic animal models that accumulation of activated B cells is central to AD pathology and depletion of B cells interferes with both histological and behavioural manifestations of the disease.
- Ki Kim
- , Xin Wang
- & Arya Biragyn
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Article
| Open AccessDefective dystrophic thymus determines degenerative changes in skeletal muscle
Immune cells are known to aggravate the inflammatory impact of Duchene muscular dystrophy. Here, the authors describe impaired thymic development and suggest thymic involution in this model of disease is linked to disease acceleration due to impaired immunological tolerance.
- Andrea Farini
- , Clementina Sitzia
- & Yvan Torrente
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Article
| Open AccessCirculating mucosal-associated invariant T cells identify patients responding to anti-PD-1 therapy
Immune checkpoint inhibition (ICI) shows potential for cancer therapies, but response rates vary. Here, the authors use single-cell analyses to show that, in a 28 patient cohort, patients stratified by mucosal-associated invariant T (MAIT) percentages show different response rates, and ICI responders have more MAIT cells expressing CXCR4 and granzyme B.
- Sara De Biasi
- , Lara Gibellini
- & Andrea Cossarizza
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Article
| Open AccessImplication of TIGIT+ human memory B cells in immune regulation
Regulatory B cells have been shown to play critical roles in the modulation of the immune system. Here, the authors implicate TIGIT expression in B cells with the process of immuno-regulation.
- Md Mahmudul Hasan
- , Sumi Sukumaran Nair
- & SangKon Oh
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Article
| Open AccessCheckpoint inhibition through small molecule-induced internalization of programmed death-ligand 1
Programmed death-ligand 1 (PD-L1) is involved in the inhibition of antigen specific T cells via ligation of programmed death 1 (PD-1). Here, the authors show checkpoint inhibition by use of small molecule inhibition of PD-L1 which in a humanised mouse model was shown to restore T cell responses and reduced tumour burden.
- Jang-June Park
- , Emily P. Thi
- & Chris B. Moore
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Article
| Open AccessHost immunity modulates the efficacy of microbiota transplantation for treatment of Clostridioides difficile infection
Transfer of a host’s microbiota by faecal microbiota transplantation has shown benefit in the context of recurrent Clostridioides difficle infection. Here the authors shows the inflammatory status of the recipient can impact on engraftment and the efficacy of the introduced microbiota in a model of C.difficile infection.
- Eric R. Littmann
- , Jung-Jin Lee
- & Michael C. Abt
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Article
| Open AccessEndogenous antisense RNA curbs CD39 expression in Crohn’s disease
CD39 is an ectonucleotidase associated with immunoregulatory function. Here authors show regulation of CD39 expression by an endogenous antisense RNA moiety transcribed from the 3‘ end of CD39/ENTPD1 which when itself is silenced results in amelioration of pathology in an animal model of colitis.
- Rasika P. Harshe
- , Anyan Xie
- & Maria Serena Longhi
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Article
| Open AccessCharacterization of neutralizing antibody with prophylactic and therapeutic efficacy against SARS-CoV-2 in rhesus monkeys
Here the authors characterize a monoclonal antibody from a COVID-19 convalescent patient that interferes with SARS-CoV-2 spike binding to ACE2 and has prophylactic and therapeutic activity in non-human primates. Antibody-dependent enhancement of infection is prevented by mutating the Fc region of the antibody.
- Shuang Wang
- , Yun Peng
- & Datao Liu
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Article
| Open AccessWhole blood immunophenotyping uncovers immature neutrophil-to-VD2 T-cell ratio as an early marker for severe COVID-19
COVID-19 severity is associated with cytokine levels and lymphopenia, but the role of immune cell subsets is not well understood. Here the authors immunophenotype whole blood samples from 54 COVID-19 patients and find that the immature neutrophil-to-VD2 T-cell ratio is associated with severe COVID-19.
- Guillaume Carissimo
- , Weili Xu
- & Lisa FP Ng
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Article
| Open AccessEnhancing mucosal immunity by transient microbiota depletion
Tissue resident CD8 + T cells present at mucosal surfaces are poised to elicit function in situ, however approaches to boost their number in the gastrointestinal mucosa has been limited. Here the authors combine the use of Listeria monocytogenese and transient depletion of the intestinal microbiome to boost the resident CD8 + T cell response.
- Simone Becattini
- , Eric R. Littmann
- & Eric G. Pamer
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Article
| Open AccessMG53 suppresses interferon-β and inflammation via regulation of ryanodine receptor-mediated intracellular calcium signaling
TRIM proteins are known to play critical roles in the context of viral infection. Here the authors establish MG53 (TRIM72) suppresses IFN and inflammation by modulation of ryanodine receptor related intracellular calcium induction.
- Matthew Sermersheim
- , Adam D. Kenney
- & Jianjie Ma
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Article
| Open AccessLymphocyte predominant cells detect Moraxella catarrhalis-derived antigens in nodular lymphocyte-predominant Hodgkin lymphoma
Nodular lymphocyte-predominant Hodgkin lymphoma with IgD+ lymphocyte-predominant (LP) cells is a rare clinical distinct lymphoma subset of B-cell origin. Here the authors show that antigens expressed by Moraxella catarrhalis are recognized by B cell receptors of IgD+ LP cells, suggesting the contribution of chronic antigen stimulation to lymphomagenesis.
- Lorenz Thurner
- , Sylvia Hartmann
- & Michael Pfreundschuh
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Article
| Open AccessHigh throughput pMHC-I tetramer library production using chaperone-mediated peptide exchange
Peptide-MHC (pMHC) tetramers are important tools for probing T cell repertoire and adaptive immune responses. Here the authors use a molecular chaperone, TAPBPR, to develop a high-throughput, multiplexible platform for pMHC tetramer generation to facilitate simultaneous assessments of T cell repertoire/antigen specificity and transcriptome.
- Sarah A. Overall
- , Jugmohit S. Toor
- & Nikolaos G. Sgourakis
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Article
| Open AccessThe mechanistic and functional profile of the therapeutic anti-IgE antibody ligelizumab differs from omalizumab
Immunoglobulin E (IgE) plays a central role in allergic responses, yet therapeutic targeting of IgE with antibodies such as omalizumab is met with various limitations. Here the authors characterize the molecular properties and crystal structure of a new anti-IgE antibody, ligelizumab, for mechanistic insights related to its enhanced suppression activity.
- Pascal Gasser
- , Svetlana S. Tarchevskaya
- & Alexander Eggel
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Article
| Open AccessIgA subclasses have different effector functions associated with distinct glycosylation profiles
Immunoglobulin A (IgA) has two subclasses, IgA1 and IgA2, but differential effects on inflammation are unclear. Here the authors show that IgA2, when compared with IgA1, has stronger pro-inflammatory functions associated with changed glycosylation and higher disease scores in patients with rheumatoid arthritis.
- Ulrike Steffen
- , Carolien A. Koeleman
- & Georg Schett
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Article
| Open AccessObesity and disease severity magnify disturbed microbiome-immune interactions in asthma patients
Here, the authors characterize immunological and microbiome alterations in a cohort of obese asthmatics, finding that disease severity negatively correlates with fecal abundance of Akkermansia muciniphila, and show in a mouse model that administration of A. muciniphila reduces airway hyper-reactivity and airway inflammation.
- David Michalovich
- , Noelia Rodriguez-Perez
- & Liam O’Mahony
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Article
| Open AccessmiRNA142-3p targets Tet2 and impairs Treg differentiation and stability in models of type 1 diabetes
miRNA142-3p and Tet2 are separately known to regulate Treg. Here the authors show that miRNA142-3p targets Tet2 and by this opposes Treg differentiation in autoimmune diabetes.
- Martin G. Scherm
- , Isabelle Serr
- & Carolin Daniel
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Article
| Open AccessMissing self triggers NK cell-mediated chronic vascular rejection of solid organ transplants
‘Missing self’ is a mode of natural killer (NK) cell activation aimed to detect the lack of HLA-I molecules on infected or neoplastic cells. Here, the authors show that mismatch between donor HLA-I and cognate receptors on recipient NK cells mediates microvascular inflammation-associated graft rejection, a pathology that is preventable by mTOR inhibition.
- Alice Koenig
- , Chien-Chia Chen
- & Olivier Thaunat
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Article
| Open AccessRepurposing endogenous immune pathways to tailor and control chimeric antigen receptor T cell functionality
Engineered T cells work as living therapeutics, but are prone to hyperreactivity and exhaustion. Here the authors improve CAR T cell antitumor responses by simultaneously targeting a CAR to TCR locus and IL-12 to PD1 locus, placing the transgenes under a naturally regulated transcriptional network while disrupting unwanted signals.
- Mohit Sachdeva
- , Brian W. Busser
- & Julien Valton
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Article
| Open AccessFramework engineering to produce dominant T cell receptors with enhanced antigen-specific function
Increasing TCR cell surface expression can potentiate T cell responses to low-concentrations of antigen. Here the authors identify aminoacids in human TCR variable domains that impact its surface expression, and demonstrate how editing these residues can improve T cell activation and effector function without altering antigen specificity.
- Sharyn Thomas
- , Fiyaz Mohammed
- & Hans J. Stauss
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Article
| Open AccessHuman PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology
Causally linking a mutation to clinical phenotypes in rare hereditary diseases is both challenging and illuminating. Here the authors identify PI3Kɣ mutations in a patient with immune dysregulation, and recapitulate the phenotypes in PI3Kɣ-deficient mice by exposing them to natural microbiota from pet-shop mice.
- Andrew J. Takeda
- , Timothy J. Maher
- & Carrie L. Lucas
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Article
| Open AccessTumor-reprogrammed resident T cells resist radiation to control tumors
Lymphocytes are considered one of the most radiosensitive cell types in the body. Here the authors show that unlike circulating lymphocytes, tumor-infiltrating T cells survive therapeutic doses of irradiation, remaining functional and contributing to radiotherapy induced anti-tumor immunity.
- Ainhoa Arina
- , Michael Beckett
- & Ralph R. Weichselbaum
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Article
| Open AccessIdentification of drug-specific public TCR driving severe cutaneous adverse reactions
Severe cutaneous adverse reactions (SCAR) is a T cell-mediated, potentially lethal drug hypersensitivity (DH). Here, the authors identify a carbamazepine-specific TCR common among patients with carbamazepine-induced SCAR that confers SCAR-like pathology in mice upon carbamazepine exposure, thereby implicating specific TCRs in DH etiology.
- Ren-You Pan
- , Mu-Tzu Chu
- & Shuen-Iu Hung
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Article
| Open AccessMass cytometry reveals systemic and local immune signatures that distinguish inflammatory bowel diseases
Distinguishing clinical subtypes of IBD is critical for optimal treatments, outcome prediction, and better understanding of disease pathogenesis. Here the authors phenotype blood and intestinal immune cells by mass cytometry and identify signatures associated with distinct disease states.
- Samuel J. S. Rubin
- , Lawrence Bai
- & Aida Habtezion
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Article
| Open AccessFunctional rare and low frequency variants in BLK and BANK1 contribute to human lupus
Function-altering variants of immune-related genes cause rare autoimmune syndromes, whereas their contribution to common autoimmune diseases remains uncharacterized. Here the authors show that rare variants of lupus-associated genes are present in the majority of lupus patients and healthy controls, but only the variants found in lupus patients alter gene function.
- Simon H. Jiang
- , Vicki Athanasopoulos
- & Carola G. Vinuesa
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Article
| Open AccessMolecular and functional heterogeneity of IL-10-producing CD4+ T cells
Tr1 cells are considered an immunosuppressive CD4 T cell population producing IL-10. Here the authors show that IL-10 is insufficient for Tr1 immunosuppression, define surface markers and transcriptional program of the immunosuppressive subset within Tr1, and reveal its deficiency in patients with IBD.
- Leonie Brockmann
- , Shiwa Soukou
- & Samuel Huber
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Article
| Open AccessBroad CD8+ T cell cross-recognition of distinct influenza A strains in humans
Mutations within immunological epitope containing regions of influenza A virus can impair the established immune response between influenza strains and could impact rational vaccine design. Here Grant et al. examine the presence, structural impact and cross reactivity of two human immunodominant influenza epitope variants.
- Emma J. Grant
- , Tracy M. Josephs
- & Katherine Kedzierska
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Article
| Open AccessPDL2+ CD11b+ dermal dendritic cells capture topical antigen through hair follicles to prime LAP+ Tregs
Antigen present and presented in the structures of the skin can result in immune responses that elicit tolerance, protective immunity or allergy, depending on the immunological context. Here the authors describe a key role for the hair follicle and CD11b+ dendritic cells in the priming of local antigenic tolerance.
- Leticia Tordesillas
- , Daniel Lozano-Ojalvo
- & M. Cecilia Berin
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Article
| Open AccessInnate and adaptive signals enhance differentiation and expansion of dual-antibody autoreactive B cells in lupus
Conventional B cells express clonally specific antigen receptors, but a small subset of B cells from patients and mice with systematic lupus erythematosus simultaneously expresses two distinct antigen receptors. Here the authors show that these dual-specificity B cells have higher levels of MHC-II, depend on IL-21 for expansion, and mount stronger memory response.
- Allison Sang
- , Thomas Danhorn
- & Roberta Pelanda
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Article
| Open AccessMicrobial metabolite sensor GPR43 controls severity of experimental GVHD
The microbial metabolite sensor GPR43 has been previously shown to be a crucial modulator of immune responses. Here the authors show GPR43 is required for controlling disease pathology severity in the context of experimental models of GVHD.
- Hideaki Fujiwara
- , Melissa D. Docampo
- & Pavan Reddy
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Article
| Open AccessStatin as a novel pharmacotherapy of pulmonary alveolar proteinosis
Pulmonary alveolar proteinosis (PAP) is associated with defective macrophage clearance of surfactant. Here, the authors show that patients with PAP have altered cholesterol-to-phospholipid ratio in their surfactant, and that more importantly, statin therapy and reduction of cholesterol accumulation in macrophages can ameliorate PAP in both humans and mice.
- Cormac McCarthy
- , Elinor Lee
- & Bruce C. Trapnell
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Article
| Open AccessMyeloid apolipoprotein E controls dendritic cell antigen presentation and T cell activation
Cholesterol homeostasis can modulate immunity via multiple pathways. Here the authors show that apolipoprotein E, an important regulator of cholesterol, produced by myeloid cells can regulate T cell activation by controlling the antigen presentation activity of dendritic cells in both humans and mice.
- Fabrizia Bonacina
- , David Coe
- & Giuseppe D. Norata
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Article
| Open AccessThe chimeric TAC receptor co-opts the T cell receptor yielding robust anti-tumor activity without toxicity
Chimeric antigen receptors (CARs) are effective tools for directing T cell killing of tumors, but may cause adverse side effects. Here the authors show that coupling of antigen-recognition and CD3-binding in a modular format induces more efficient anti-tumour responses but reduced toxicity when compared with current CARs.
- Christopher W. Helsen
- , Joanne A. Hammill
- & Jonathan L. Bramson
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Correspondence
| Open AccessTrace N-glycans including sulphated species may originate from various plasma glycoproteins and not necessarily IgG
- Gordan Lauc
- , Frano Vučković
- & Manfred Wuhrer
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Article
| Open AccessIntermedin protects against sepsis by concurrently re-establishing the endothelial barrier and alleviating inflammatory responses
Sepsis is a life-threatening condition. Here, the authors show that intermedin alleviates organ injury and decreases mortality in septic mice by concurrently alleviating vascular leakage and inflammatory responses. Patients with high intermedin levels exhibit a low risk of shock, lower severity scores, and greatly improved survival outcomes.
- Fei Xiao
- , Denian Wang
- & Wei Zhang
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Article
| Open AccessCorticosteroid suppression of antiviral immunity increases bacterial loads and mucus production in COPD exacerbations
Corticosteroid therapy is frequently used for chronic obstructive pulmonary disease (COPD) but its use is associated with increased risk of pneumonia. Here the authors show that corticosteroid use impairs innate and adaptive immunity to rhinovirus infection, which is restored by exogenous IFNβ.
- Aran Singanayagam
- , Nicholas Glanville
- & Sebastian L. Johnston
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Article
| Open AccessTreating cat allergy with monoclonal IgG antibodies that bind allergen and prevent IgE engagement
Allergen-specific immunotherapy is used to treat patients affected by acute immunoglobulin E (IgE) responses, but the function mechanism is unclear. Here the authors show that the administration of two cat allergen-specific IgGs reduces allergic responses in mouse models and helps ameliorate clinical symptoms in a phase 1b clinical trial.
- J. M. Orengo
- , A. R. Radin
- & G. D. Yancopoulos
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Article
| Open AccessSmall tumor necrosis factor receptor biologics inhibit the tumor necrosis factor-p38 signalling axis and inflammation
Anti-TNF therapy has improved the treatment of inflammatory disease but can predispose to infection and malignancy. Here the authors show an anti-TNF biologic peptide that functionally and selectively targets the TNF-p38 pathway in multiple models of inflammation.
- Violet R. Mukaro
- , Alex Quach
- & Antonio Ferrante
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Article
| Open AccessBAFF-neutralizing interaction of belimumab related to its therapeutic efficacy for treating systemic lupus erythematosus
Blocking B-cell activating factor (BAFF), an important soluble factor for B-cell responses, with specific antibodies is approved for treating autoimmune disorders. Here the authors show, with structural data, that antibody-BAFF interactions not only interrupt BAFF–receptor-binding, but also induce the formation of a less active BAFF polymer.
- Woori Shin
- , Hyun Tae Lee
- & Yong-Seok Heo