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1.
Cytokine ; 162: 156091, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36481478

RESUMO

RATIONALE: Type 2 (T2) asthma is characterized by airflow limitations and elevated levels of blood and sputum eosinophils, fractional exhaled nitric oxide, IgE, and periostin. While eosinophils are associated with exacerbations, the contribution of eosinophils to lung inflammation, remodeling and function remains largely hypothetical. OBJECTIVES: To determine the effect of T2 cytokines IL-4, IL-13 and IL-5 on eosinophil biology and compare the impact of depleting just eosinophils versus inhibiting all aspects of T2 inflammation on airway inflammation. METHODS: Human eosinophils or endothelial cells stimulated with IL-4, IL-13 or IL-5 were assessed for gene changes or chemokine release.Mice exposed to house dust mite extract received anti-IL-4Rα (dupilumab), anti-IL-5 or control antibodies and were assessed for changes in lung histological and inflammatory endpoints. MEASUREMENTS AND MAIN RESULTS: IL-4 or IL-13 stimulation of human eosinophils and endothelial cells induced gene expression changes related to granulocyte migration; whereas, IL-5 induced changes reflecting granulocyte differentiation.In a mouse model, blocking IL-4Rα improved lung function by impacting multiple effectors of inflammation and remodeling, except peripheral eosinophil counts, thereby disconnecting blood eosinophils from airway inflammation, remodeling and function. Blocking IL-5 globally reduced eosinophil counts but did not impact inflammatory or functional measures of lung pathology. Whole lung transcriptome analysis revealed that IL-5 or IL-4Rα blockade impacted eosinophil associated genes, whereas IL-4Rα blockade also impacted genes associated with multiple cells, cytokines and chemokines, mucus production, cell:cell adhesion and vascular permeability. CONCLUSIONS: Eosinophils are not the sole contributor to asthma pathophysiology or lung function decline and emphasizes the need to block additional mediators to modify lung inflammation and impact lung function.


Assuntos
Asma , Pneumonia , Animais , Humanos , Camundongos , Asma/metabolismo , Quimiocinas/metabolismo , Citocinas/metabolismo , Células Endoteliais/metabolismo , Inflamação/metabolismo , Interleucina-13/metabolismo , Pulmão/metabolismo , Pneumonia/metabolismo , Interleucina-4/farmacologia
2.
Dis Model Mech ; 16(10)2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37718909

RESUMO

Sezary syndrome (SS) is a rare, aggressive leukemic variant of cutaneous T-cell lymphoma (CTCL) that lacks adequate therapeutic options and representative small-animal models. Here, we demonstrate that IL-15 is a critical CTCL growth factor. Importantly, an immunodeficient knock-in mouse model genetically engineered to express human IL-15 uniquely supported the growth of SS patient samples relative to conventional immunodeficient mouse strains. SS patient-derived xenograft (PDX) models recapacitated key pathological features of the human disease, including skin infiltration and spread of leukemic cells to the periphery, and maintained the dependence on human IL-15 upon serial in vivo passaging. Detailed molecular characterization of the engrafted cells by single-cell transcriptomic analysis revealed congruent neoplastic gene expression signatures but distinct clonal engraftment patterns. Overall, we document an important dependence of Sezary cell survival and proliferation on IL-15 signaling and the utility of immunodeficient humanized IL-15 mice as hosts for SS - and potentially other T and NK cell-derived hematologic malignancies - PDX model generation. Furthermore, these studies advocate the thorough molecular understanding of the resultant PDX models to maximize their translational impact.


Assuntos
Linfoma Cutâneo de Células T , Síndrome de Sézary , Neoplasias Cutâneas , Humanos , Animais , Camundongos , Neoplasias Cutâneas/metabolismo , Interleucina-15 , Linfoma Cutâneo de Células T/patologia , Síndrome de Sézary/metabolismo , Síndrome de Sézary/patologia , Linfócitos/metabolismo , Microambiente Tumoral
3.
Sci Transl Med ; 15(678): eabo0205, 2023 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-36630481

RESUMO

The common γ chain (γc; IL-2RG) is a subunit of the interleukin (IL) receptors for the γc cytokines IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. The lack of appropriate neutralizing antibodies recognizing IL-2RG has made it difficult to thoroughly interrogate the role of γc cytokines in inflammatory and autoimmune disease settings. Here, we generated a γc cytokine receptor antibody, REGN7257, to determine whether γc cytokines might be targeted for T cell-mediated disease prevention and treatment. Biochemical, structural, and in vitro analysis showed that REGN7257 binds with high affinity to IL-2RG and potently blocks signaling of all γc cytokines. In nonhuman primates, REGN7257 efficiently suppressed T cells without affecting granulocytes, platelets, or red blood cells. Using REGN7257, we showed that γc cytokines drive T cell-mediated disease in mouse models of graft-versus-host disease (GVHD) and multiple sclerosis by affecting multiple aspects of the pathogenic response. We found that our xenogeneic GVHD mouse model recapitulates hallmarks of acute and chronic GVHD, with T cell expansion/infiltration into tissues and liver fibrosis, as well as hallmarks of immune aplastic anemia, with bone marrow aplasia and peripheral cytopenia. Our findings indicate that γc cytokines contribute to GVHD and aplastic anemia pathology by promoting these characteristic features. By demonstrating that broad inhibition of γc cytokine signaling with REGN7257 protects from immune-mediated disorders, our data provide evidence of γc cytokines as key drivers of pathogenic T cell responses, offering a potential strategy for the management of T cell-mediated diseases.


Assuntos
Anemia Aplástica , Doença Enxerto-Hospedeiro , Subunidade gama Comum de Receptores de Interleucina , Linfócitos T , Animais , Camundongos , Anemia Aplástica/metabolismo , Anticorpos Monoclonais/metabolismo , Citocinas/metabolismo , Doença Enxerto-Hospedeiro/metabolismo , Transdução de Sinais , Linfócitos T/metabolismo , Linfócitos T/patologia , Subunidade gama Comum de Receptores de Interleucina/antagonistas & inibidores , Subunidade gama Comum de Receptores de Interleucina/metabolismo , Primatas
4.
Mol Cell Biol ; 42(1): e0046721, 2022 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-34723652

RESUMO

A subset of hospitalized COVID-19 patients, particularly the aged and those with comorbidities, develop the most severe form of the disease, characterized by acute respiratory disease syndrome (ARDS), coincident with experiencing a "cytokine storm." Here, we demonstrate that cytokines which activate the NF-κB pathway can induce activin A. Patients with elevated activin A, activin B, and FLRG at hospital admission were associated with the most severe outcomes of COVID-19, including the requirement for mechanical ventilation, and all-cause mortality. A prior study showed that activin A could decrease viral load, which indicated there might be a risk to giving COVID-19 patients an inhibitor of activin. To evaluate this, the role for activin A was examined in a hamster model of SARS-CoV-2 infection, via blockade of activin A signaling. The hamster model demonstrated that use of an anti-activin A antibody did not worsen the disease and there was no evidence for increase in lung viral load and pathology. The study indicates blockade of activin signaling may be beneficial in treating COVID-19 patients experiencing ARDS.


Assuntos
Ativinas/sangue , Anticorpos Monoclonais Humanizados/uso terapêutico , Tratamento Farmacológico da COVID-19 , Proteínas Relacionadas à Folistatina/sangue , SARS-CoV-2/efeitos dos fármacos , Adulto , Idoso , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , COVID-19/mortalidade , COVID-19/virologia , Linhagem Celular , Células Cultivadas , Cricetinae , Método Duplo-Cego , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacos , Taxa de Sobrevida
5.
Nat Microbiol ; 6(1): 73-86, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33340034

RESUMO

Non-human primate models will expedite therapeutics and vaccines for coronavirus disease 2019 (COVID-19) to clinical trials. Here, we compare acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in young and old rhesus macaques, baboons and old marmosets. Macaques had clinical signs of viral infection, mild to moderate pneumonitis and extra-pulmonary pathologies, and both age groups recovered in two weeks. Baboons had prolonged viral RNA shedding and substantially more lung inflammation compared with macaques. Inflammation in bronchoalveolar lavage was increased in old versus young baboons. Using techniques including computed tomography imaging, immunophenotyping, and alveolar/peripheral cytokine response and immunohistochemical analyses, we delineated cellular immune responses to SARS-CoV-2 infection in macaque and baboon lungs, including innate and adaptive immune cells and a prominent type-I interferon response. Macaques developed T-cell memory phenotypes/responses and bystander cytokine production. Old macaques had lower titres of SARS-CoV-2-specific IgG antibody levels compared with young macaques. Acute respiratory distress in macaques and baboons recapitulates the progression of COVID-19 in humans, making them suitable as models to test vaccines and therapies.


Assuntos
COVID-19/veterinária , Callithrix/imunologia , Pulmão/imunologia , Macaca mulatta/imunologia , Doenças dos Macacos/virologia , Papio/imunologia , SARS-CoV-2/imunologia , Imunidade Adaptativa , Animais , Anticorpos Antivirais/imunologia , Lavagem Broncoalveolar , Líquido da Lavagem Broncoalveolar , COVID-19/diagnóstico por imagem , COVID-19/imunologia , COVID-19/patologia , Feminino , Humanos , Imunidade Celular/imunologia , Imunoglobulina G/imunologia , Inflamação/patologia , Pulmão/virologia , Masculino , Doenças dos Macacos/imunologia , Células Mieloides/imunologia , Carga Viral , Eliminação de Partículas Virais
6.
Sci Immunol ; 5(54)2020 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-33443029

RESUMO

Deficiency in interleukin-36R (IL-36R) antagonist caused by loss-of-function mutations in IL-36RN leads to DITRA (deficiency of IL-36 receptor antagonist), a rare inflammatory human disease that belongs to a subgroup of generalized pustular psoriasis (GPP). We report a functional genetic mouse model of DITRA with enhanced IL-36R signaling analogous to that observed in patients with DITRA, which provides new insight into our understanding of the IL-36 family of molecules in regulating barrier integrity across multiple tissues. Humanized DITRA-like mice displayed increased skin inflammation in a preclinical model of psoriasis, and in vivo blockade of IL-36R pathway using anti-human IL-36R antibody ameliorated imiquimod-induced skin pathology as both prophylactic and therapeutic treatments. Deeper characterization of the humanized DITRA-like mice revealed that deregulated IL-36R signaling promoted tissue pathology during intestinal injury and led to impairment in mucosal restoration in the repair phase of chronic dextran sulfate sodium (DSS)-induced colitis. Blockade of IL-36R pathway significantly ameliorated DSS-induced intestinal inflammation and rescued the inability of DITRA-like mice to recover from mucosal damage in vivo. Our results indicate a central role for IL-36 in regulating proinflammatory responses in the skin and epithelial barrier function in the intestine, suggesting a new therapeutic potential for targeting the IL-36R axis in psoriasis and at the later stages of intestinal pathology in inflammatory bowel disease.


Assuntos
Dermatite/etiologia , Dermatite/metabolismo , Gastroenterite/etiologia , Gastroenterite/metabolismo , Receptores de Interleucina-1/metabolismo , Transdução de Sinais , Animais , Biomarcadores , Dermatite/patologia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Gastroenterite/patologia , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos , Pele/metabolismo , Pele/patologia
7.
Science ; 370(6520): 1110-1115, 2020 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-33037066

RESUMO

An urgent global quest for effective therapies to prevent and treat coronavirus disease 2019 (COVID-19) is ongoing. We previously described REGN-COV2, a cocktail of two potent neutralizing antibodies (REGN10987 and REGN10933) that targets nonoverlapping epitopes on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. In this report, we evaluate the in vivo efficacy of this antibody cocktail in both rhesus macaques, which may model mild disease, and golden hamsters, which may model more severe disease. We demonstrate that REGN-COV-2 can greatly reduce virus load in the lower and upper airways and decrease virus-induced pathological sequelae when administered prophylactically or therapeutically in rhesus macaques. Similarly, administration in hamsters limits weight loss and decreases lung titers and evidence of pneumonia in the lungs. Our results provide evidence of the therapeutic potential of this antibody cocktail.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , COVID-19/terapia , Animais , COVID-19/prevenção & controle , Combinação de Medicamentos , Macaca mulatta , Mesocricetus
8.
Sci Transl Med ; 12(525)2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31915305

RESUMO

T cell activation is initiated upon binding of the T cell receptor (TCR)/CD3 complex to peptide-major histocompatibility complexes ("signal 1"); activation is enhanced by engagement of a second "costimulatory" receptor, such as the CD28 receptor on T cells binding to its cognate ligand(s) on the target cell ("signal 2"). CD3-based bispecific antibodies act by replacing conventional signal 1, linking T cells to tumor cells by binding a tumor-specific antigen (TSA) with one arm of the bispecific and bridging to TCR/CD3 with the other. Although some of these so-called TSAxCD3 bispecifics have demonstrated promising antitumor efficacy in patients with cancer, their activity remains to be optimized. Here, we introduce a class of bispecific antibodies that mimic signal 2 by bridging TSA to the costimulatory CD28 receptor on T cells. We term these TSAxCD28 bispecifics and describe two such bispecific antibodies: one specific for ovarian and the other for prostate cancer antigens. Unlike CD28 superagonists, which broadly activate T cells and resulted in profound toxicity in early clinical trials, these TSAxCD28 bispecifics show limited activity and no toxicity when used alone in genetically humanized immunocompetent mouse models or in primates. However, when combined with TSAxCD3 bispecifics, they enhance the artificial synapse between a T cell and its target cell, potentiate T cell activation, and markedly improve antitumor activity of CD3 bispecifics in a variety of xenogeneic and syngeneic tumor models. Combining this class of CD28-costimulatory bispecific antibodies with the emerging class of TSAxCD3 bispecifics may provide well-tolerated, off-the-shelf antibody therapies with robust antitumor efficacy.


Assuntos
Anticorpos Biespecíficos/imunologia , Antígenos CD28/imunologia , Complexo CD3/imunologia , Neoplasias/imunologia , Animais , Antígenos de Neoplasias/imunologia , Linhagem Celular Tumoral , Proliferação de Células , Citocinas/metabolismo , Citotoxicidade Imunológica , Feminino , Células HEK293 , Humanos , Sinapses Imunológicas/metabolismo , Ativação Linfocitária/imunologia , Macaca fascicularis , Camundongos , Neoplasias/patologia , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Invest Ophthalmol Vis Sci ; 47(1): 377-85, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16384988

RESUMO

PURPOSE: The aim of this study was to identify the changes in the primate visual system after a single session of photodynamic therapy (PDT) in an intact nonhuman primate retina. METHODS: As part of a larger study, PDT (wavelength 689 nm, 50 J/cm2, 600 mW/cm2, 83 seconds, 4-mm spot size) with verteporfin (6 mg/m2 intravenous infusion) was performed in one eye each of two cynomolgus monkeys. Fundus photography, fluorescein angiography (FA), indocyanine green angiography (ICG), optical coherence tomography (OCT), and multifocal electroretinography (mfERG) were performed at baseline and 12 time points (1-283 days) after PDT. In addition, retinal histopathologic findings were evaluated at 9 months. RESULTS: Various morphologic changes, including whitening of the treated area, RPE proliferation, closure of the choroidal vasculature, and subretinal edema (followed by foveolar thinning) were observed. Most of the changes persisted and were detectable in histopathologic evaluation at 9 months. Reductions of the mfERG amplitude, followed by varying degrees of recovery from the treated and the border regions, were observed. This was accompanied by progressive delay of P1 peak time up to 3 months after treatment, followed by complete recovery at 9 months. In addition, the nontreated area showed amplitude and timing mfERG deficits, which underwent gradual (but not complete) recovery. CONCLUSIONS: In a primate model, under standard clinical parameters, a single PDT treatment resulted in various dynamic morphologic and functional retinal changes detectable for up to 9 months after treatment. The significance of the observed changes and possible ways of pharmacologic interference with PDT adverse effects are discussed.


Assuntos
Arteriopatias Oclusivas/induzido quimicamente , Doenças da Coroide/induzido quimicamente , Corioide/irrigação sanguínea , Edema Macular/induzido quimicamente , Fotoquimioterapia/efeitos adversos , Retina/efeitos dos fármacos , Animais , Arteriopatias Oclusivas/diagnóstico , Corioide/patologia , Doenças da Coroide/diagnóstico , Eletrorretinografia/efeitos dos fármacos , Feminino , Angiofluoresceinografia , Seguimentos , Verde de Indocianina , Macaca fascicularis , Edema Macular/diagnóstico , Fármacos Fotossensibilizantes/efeitos adversos , Porfirinas/efeitos adversos , Retina/patologia , Tomografia de Coerência Óptica , Verteporfina
10.
Sci Rep ; 6: 23204, 2016 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-26979938

RESUMO

The expansion of a hexanucleotide (GGGGCC) repeat in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Both the function of C9ORF72 and the mechanism by which the repeat expansion drives neuropathology are unknown. To examine whether C9ORF72 haploinsufficiency induces neurological disease, we created a C9orf72-deficient mouse line. Null mice developed a robust immune phenotype characterized by myeloid expansion, T cell activation, and increased plasma cells. Mice also presented with elevated autoantibodies and evidence of immune-mediated glomerulonephropathy. Collectively, our data suggest that C9orf72 regulates immune homeostasis and an autoimmune response reminiscent of systemic lupus erythematosus (SLE) occurs in its absence. We further imply that haploinsufficiency is unlikely to be the causative factor in C9ALS/FTD pathology.


Assuntos
Autoanticorpos/biossíntese , Autoimunidade , Glomerulonefrite Membranoproliferativa/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Animais , Autoanticorpos/sangue , Proteína C9orf72 , Citocinas/sangue , Feminino , Glomerulonefrite Membranoproliferativa/sangue , Glomerulonefrite Membranoproliferativa/imunologia , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Ativação Linfocitária , Tecido Linfoide/patologia , Macrófagos/imunologia , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasmócitos/imunologia , Análise de Sequência de RNA , Transcriptoma
12.
Sci Rep ; 5: 17943, 2015 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-26659273

RESUMO

Bispecific antibodies, while showing great therapeutic potential, pose formidable challenges with respect to their assembly, stability, immunogenicity, and pharmacodynamics. Here we describe a novel class of bispecific antibodies with native human immunoglobulin format. The design exploits differences in the affinities of the immunoglobulin isotypes for Protein A, allowing efficient large-scale purification. Using this format, we generated a bispecific antibody, REGN1979, targeting the B cell marker, CD20, and the CD3 component of the T cell receptor, which triggers redirected killing of B cells. In mice, this antibody prevented growth of B cell tumors and also caused regression of large established tumors. In cynomolgus monkeys, low doses of REGN1979 caused prolonged depletion of B cells in peripheral blood with a serum half-life of approximately 14 days. Further, the antibody induced a deeper depletion of B cells in lymphoid organs than rituximab. This format has broad applicability for development of clinical bispecific antibodies.


Assuntos
Anticorpos Biespecíficos/imunologia , Citotoxicidade Celular Dependente de Anticorpos , Linfócitos B/imunologia , Citotoxicidade Imunológica , Neoplasias/imunologia , Neoplasias/patologia , Linfócitos T/imunologia , Sequência de Aminoácidos , Animais , Anticorpos Biespecíficos/química , Anticorpos Biespecíficos/isolamento & purificação , Anticorpos Biespecíficos/farmacologia , Antígenos CD20/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Complexo CD3/imunologia , Linhagem Celular Tumoral , Cromatografia de Afinidade , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Imunofenotipagem , Macaca fascicularis , Camundongos , Camundongos Knockout , Camundongos SCID , Modelos Moleculares , Dados de Sequência Molecular , Neoplasias/terapia , Fenótipo , Conformação Proteica , Alinhamento de Sequência , Linfócitos T/metabolismo , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/imunologia
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