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The direct modulation of T cell responses is an emerging therapeutic strategy with the potential to modulate undesired immune responses including, autoimmune disease, and allogeneic cells transplantation. We have previously demonstrated that poly(lactide-co-glycolide) particles were able to modulate T cell responses indirectly through antigen-presenting cells (APCs). In this report, we investigated the design of nanoparticles that can directly interact and modulate T cells by coating the membranes from APCs onto nanoparticles to form membrane-coated nanoparticles (MCNPs). Proteins within the membranes of the APCs, such as Major Histocompatibility Complex class II and co-stimulatory factors, were effectively transferred to the MCNP. Using alloreactive T cell models, MCNP derived from allogeneic dendritic cells were able to stimulate proliferation, which was not observed with membranes from syngeneic dendritic cells and influenced cytokine secretion. Furthermore, we investigated the engineering of the membranes either on the dendritic cells or postfabrication of MCNP. Engineered membranes could be to promote antigen-specific responses, to differentially activate T cells, or to directly induce apoptosis. Collectively, MCNPs represent a tunable platform that can directly interact with and modulate T cell responses.
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Doenças Autoimunes , Nanopartículas , Humanos , Linfócitos T , Células Dendríticas , Proteínas/metabolismoRESUMO
SS is a chronic systemic autoimmune disease characterized by decreased exocrine gland function. A variety of other disease manifestations may also be present, including general constitutional symptoms and extraglandular features. A multidisciplinary approach focused on both local and systemic medical therapies is needed as the disease has a wide clinical spectrum. The current treatment for SS is mainly symptomatic. However, there is evidence that systemic drugs are effective in controlling extraglandular manifestations of the disease. Overall evidence for the role of conventional immunosuppressive therapy is limited. A number of attempts to use biologic therapies have led to variable results. Biologic agents targeting B cells, such as rituximab, epratuzumab and belimumab, have shown promising results, but further studies are needed to validate the findings. Early-phase studies with abatacept and alefacept proved that T cell stimulation inhibition is another potentially effective target for SS treatment. Modulation or inhibition of other targets such as IFN, IL-6 and Toll-like receptor are also currently being investigated. We have summarized the available evidence regarding the efficacy of biologic treatments and discuss other potential therapies targeting pathways or molecules recognized as being involved in the pathogenesis of SS.
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Fatores Biológicos/uso terapêutico , Produtos Biológicos/uso terapêutico , Terapia Biológica/métodos , Síndrome de Sjogren/terapia , Adulto , Animais , Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Fator Ativador de Células B/antagonistas & inibidores , Citocinas/antagonistas & inibidores , Métodos Epidemiológicos , Humanos , Camundongos , Terapia de Alvo Molecular/métodos , Linfócitos T/efeitos dos fármacosRESUMO
Harnessing the immune system to fight cancer has become a reality with the clinical success of immune-checkpoint blockade (ICB) antibodies against PD(L)-1 and CTLA-4. However, not all cancer patients respond to ICB. Thus, there is a need to modulate the immune system through alternative strategies for improving clinical responses to ICB. The CD3-T cell receptor (TCR) is the canonical receptor complex on T cells. It provides the "first signal" that initiates T cell activation and determines the specificity of the immune response. The TCR confers the binding specificity whilst the CD3 subunits facilitate signal transduction necessary for T cell activation. While the mechanisms through which antigen sensing and signal transduction occur in the CD3-TCR complex are still under debate, recent revelations regarding the intricate 3D structure of the CD3-TCR complex might open the possibility of modulating its activity by designing targeted drugs and tools, including aptamers. In this review, we summarize the basis of CD3-TCR complex assembly and survey the clinical and preclinical therapeutic tools available to modulate CD3-TCR function for potentiating cancer immunotherapy.
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Asthma is a chronic inflammatory disease around the world. Extracellular adenosine triphosphate works as a dangerous signal in responding to cellular stress, irritation, or inflammation. It has also been reported its association with the pathogenicity in asthma, with increased level in lungs of asthmatics. Pannexin-1 is one of the routes that contributes to the release of adenosine triphosphate form intracellular to extracellular. The aim of this study was to apply pannexin-1 peptide antagonist 10Panx1 into adeno-associated viral (AAV) vectors on ovalbumin (OVA)-induced asthmatic mouse model. The results demonstrated that this treatment was able to reduce the adenosine triphosphate level in bronchoalveolar lavage fluid and downregulate the major relevant to the symptom of asthma attack, airway hyperresponsiveness to methacholine. The histological data also gave a positive support with decreased tissue remodeling and mucus deposition. Other asthmatic related features, including eosinophilic inflammation and OVA-specific T helper type 2 responses, were also decreased by the treatment. Beyond the index of inflammation, the proportion of effector and regulatory T cells was examined to survey the potential mechanism behind. The data provided a slightly downregulated pattern in lung GATA3+ CD4 T cells. However, an upregulated population of CD25+FoxP3+ CD4 T cells was seen in spleens. These data suggested that exogeneous expression of 10Panx1 peptide was potential to alleviated asthmatic airway inflammation, and this therapeutic effect might be from 10Panx1-mediated disruption of T cell activation or differentiation. Collectively, AAV vector-mediated 10Panx1 expression could be a naval therapy option to develop.
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Alérgenos , Asma , Animais , Camundongos , Trifosfato de Adenosina , Alérgenos/farmacologia , Asma/terapia , Asma/tratamento farmacológico , Líquido da Lavagem Broncoalveolar , Conexinas/genética , Conexinas/uso terapêutico , Citocinas/metabolismo , Modelos Animais de Doenças , Inflamação/terapia , Inflamação/patologia , Pulmão/metabolismo , Camundongos Endogâmicos BALB C , Proteínas do Tecido Nervoso , Ovalbumina/toxicidadeRESUMO
In spite of the efficacy of combinational antiretroviral treatment (cART), HIV-1 persists in the host and infection is associated with chronic inflammation, leading to an increased risk of comorbidities, such as cardiovascular diseases, neurocognitive disorders, and cancer. Myeloid cells, mainly monocytes and macrophages, have been shown to be involved in the immune activation observed in HIV-1 infection. However, less attention has been paid to neutrophils, the most abundant circulating myeloid cell, even though neutrophils are strongly involved in tissue damage and inflammation in several chronic diseases, in particular, autoimmune diseases. Herein, we performed a longitudinal characterization of neutrophil phenotype and we evaluated the interplay between neutrophils and T cells in the model of pathogenic SIVmac251 experimental infection of cynomolgus macaques. We report that circulating granulocytes consists mainly of immature CD10- neutrophils exhibiting a prime phenotype during primary and chronic infection. We found that neutrophil priming correlates with CD8+ T cell activation. Moreover, we provide the evidence that neutrophils are capable of modulating CD4+ and CD8+ T-cell proliferation and IFN-γ production in different ways depending on the time of infection. Thus, our study emphasizes the role of primed immature neutrophils in the modulation of T-cell responses in SIV infection.
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Neutrófilos/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Interferon gama/metabolismo , Ativação Linfocitária , Macaca fascicularis , Neutrófilos/metabolismo , Síndrome de Imunodeficiência Adquirida dos Símios/sangue , Vírus da Imunodeficiência Símia/metabolismoRESUMO
Serum and glucocorticoid-regulated kinase 1 (SGK1) is a serine/threonine kinase belonging to the protein kinase A, G, and C (AGC) family. Upon initiation of the phosphoinositide 3-kinase (PI3K) signaling pathway, mammalian target of rapamycin complex 2 (mTORC2) and phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylate the hydrophobic motif and kinase domain of SGK1, respectively, inducing SGK1 activation. SGK1 modulates essential cellular processes such as proliferation, survival, and apoptosis. Hence, dysregulated SGK1 expression can result in multiple diseases, including hypertension, cancer, autoimmunity, and neurodegenerative disorders. This review provides a current understanding of SGK1, particularly in sodium transport, cancer progression, and autoimmunity. In addition, we summarize the developmental status of SGK1 inhibitors, their structures, and respective potencies evaluated in pre-clinical experimental settings. Collectively, this review highlights the significance of SGK1 and proposes SGK1 inhibitors as potential drugs for treatment of clinically relevant diseases.
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Graft-vs. host disease (GVHD), both acute and chronic are among the chief non-relapse complications of allogeneic transplantation which still cause substantial morbidity and mortality despite significant advances in supportive care over the last few decades. The prevention of GVHD therefore remains critical to the success of allogeneic transplantation. In this review we briefly discuss the pathophysiology and immunobiology of GVHD and the current standards in the field which remain centered around calcineurin inhibitors. We then discuss important translational advances in GVHD prophylaxis, approaching these various platforms from a mechanistic standpoint based on the pathophysiology of GVHD including in-vivo and ex-vivo T-cell depletion alongwith methods of selective T-cell depletion, modulation of T-cell co-stimulatory pathways (checkpoints), enhancing regulatory T-cells (Tregs), targeting T-cell trafficking as well as cytokine pathways. Finally we highlight exciting novel pre-clinical research that has the potential to translate to the clinic successfully. We approach these methods from a pathophysiology based perspective as well and touch upon strategies targeting the interaction between tissue damage induced antigens and T-cells, regimen related endothelial toxicity, T-cell co-stimulatory pathways and other T-cell modulatory approaches, T-cell trafficking, and cytokine pathways. We end this review with a critical discussion of existing data and novel therapies that may be transformative in the field in the near future as a comprehensive picture of GVHD prophylaxis in 2020. While calcineurin inhibitors remain the standard, post-transplant eparinsphamide originally developed to facilitate haploidentical transplantation is becoming an attractive alternative to traditional calcinuerin inhibitor based prophylaxis due to its ability to reduce severe forms of acute and chronic GVHD without compromising other outcomes, even in the HLA-matched setting. In addition T-cell modulation, particularly targeting some important T-cell co-stimulatory pathways have resulted in promising outcomes and may be a part of GVHD prophylaxis in the future. Novel approaches including targeting early events in GVHD pathogenesis such as interactions bvetween tissue damage associated antigens and T-cells, endothelial toxicity, and T-cell trafficking are also promising and discussed in this review. GVHD prophylaxis in 2020 continues to evolve with novel exicitng therapies on the horizon based on a more sophisticated understanding of the immunobiology of GVHD.
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Doença Enxerto-Hospedeiro/prevenção & controle , Animais , Terapia Combinada , Gerenciamento Clínico , Suscetibilidade a Doenças , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Padrão de Cuidado , Pesquisa Translacional Biomédica , Imunologia de Transplantes , Transplante HomólogoRESUMO
Maternal milk is nature's first functional food. It plays a crucial role in the development of the infant's gastrointestinal (GI) tract and the immune system. Extracellular vesicles (EVs) are a heterogeneous population of lipid bilayer enclosed vesicles released by cells for intercellular communication and are a component of milk. Recently, we discovered that human milk EVs contain a unique proteome compared to other milk components. Here, we show that physiological concentrations of milk EVs support epithelial barrier function by increasing cell migration via the p38 MAPK pathway. Additionally, milk EVs inhibit agonist-induced activation of endosomal Toll like receptors TLR3 and TLR9. Furthermore, milk EVs directly inhibit activation of CD4+ T cells by temporarily suppressing T cell activation without inducing tolerance. We show that milk EV proteins target key hotspots of signalling networks that can modulate cellular processes in various cell types of the GI tract.
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Vesículas Extracelulares/metabolismo , Sistema de Sinalização das MAP Quinases , Leite Humano/citologia , Mucosa Bucal/fisiologia , Adulto , Linhagem Celular , Vesículas Extracelulares/imunologia , Feminino , Humanos , Mucosa Bucal/imunologia , Linfócitos T/imunologia , Receptor 3 Toll-Like/metabolismo , Receptor Toll-Like 9/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
T cell modulation in the clinical background of autoimmune diseases or allogeneic cell and organ transplantations with concurrent preservation of their natural immunological functions (e.g., pathogen defense) is the major obstacle in immunology. An anti-human CD4 antibody (MAX.16H5) was applied intravenously in clinical trials for the treatment of autoimmune diseases (e.g., rheumatoid arthritis) and acute late-onset rejection after transplantation of a renal allograft. The response rates were remarkable and no critical allergic problems or side effects were obtained. During the treatment of autoimmune diseases with the murine MAX.16H5 IgG1 antibody its effector mechanisms with effects on lymphocytes, cytokines, laboratory and clinical parameters, adverse effects as well as pharmacodynamics and kinetics were studied in detail. However, as the possibility of developing immune reactions against the murine IgG1 Fc-part remains, the murine antibody was chimerized, inheriting CD4-directed variable domains of the MAX.16H5 IgG1 connected to a human IgG4 backbone. Both antibodies were studied in vitro and in specific humanized mouse transplantation models in vivo with a new scope. By ex vivo incubation of an allogeneic immune cell transplant with MAX.16H5 a new therapy strategy has emerged for the first time enabling both the preservation of the graft-vs.-leukemia (GVL) effect and the permanent suppression of the acute graft-vs.-host disease (aGVHD) without conventional immunosuppression. In this review, we especially focus on experimental data and clinical trials obtained from the treatment of autoimmune diseases with the murine MAX.16H5 IgG1 antibody. Insights gained from these trials have paved the way to better understand the effects with the chimerized MAX.16H5 IgG4 as novel therapeutic approach in the context of GVHD prevention.
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Antígenos CD4/imunologia , Epitopos/imunologia , Tolerância Imunológica , Imunoglobulina G/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Imunoglobulina G/uso terapêutico , Interleucina-6/sangue , Cooperação Linfocítica , CamundongosRESUMO
BACKGROUND: Renal Cell Carcinoma (RCC) is the most common tumor originating from the kidneys. In comparison to other solid tumors, RCC is poorly sensitive to conventional therapeutic modalities. As such, metastatic RCC (mRCC) continues to be associated with high rates of morbidity and mortality. Targeted agents have shown remarkable progress in RCC management with improved patients' outcomes, but rarely induce complete response and patients develop resistance to therapy eventually. However, it is well known that RCC represents one of the most immunogenic cancers and is able to evoke immune response naturally, thus prompted the emergence of several immunotherapeutic strategies in the management of RCC with variable degrees of success. Modulating the immune system with cytokines, vaccines, and T-cell modulating agents offer hope for the patients with RCC. CONCLUSION: This review critically summarizes the state of the art in RCC therapeutic regimen with immunomodulation agents. We will focus on the clinical data and ongoing clinical trials exploring the use of immunotherapy with different agents for RCC. In addition, different novel immunotherapeutic agents are being investigated for their combination therapy with other immune therapies or other modalities. Prospects (e.g., potential future immunological targets, combination regimens, appropriate sequencing) for immune therapies of RCC are also set forth in this work.