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1.
Front Immunol ; 12: 729189, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34603303

RESUMO

Several SARS-CoV-2 vaccines have received EUAs, but many issues remain unresolved, including duration of conferred immunity and breadth of cross-protection. Adjuvants that enhance and shape adaptive immune responses that confer broad protection against SARS-CoV-2 variants will be pivotal for long-term protection as drift variants continue to emerge. We developed an intranasal, rationally designed adjuvant integrating a nanoemulsion (NE) that activates TLRs and NLRP3 with an RNA agonist of RIG-I (IVT DI). The combination adjuvant with spike protein antigen elicited robust responses to SARS-CoV-2 in mice, with markedly enhanced TH1-biased cellular responses and high virus-neutralizing antibody titers towards both homologous SARS-CoV-2 and a variant harboring the N501Y mutation shared by B1.1.7, B.1.351 and P.1 variants. Furthermore, passive transfer of vaccination-induced antibodies protected naive mice against heterologous viral challenge. NE/IVT DI enables mucosal vaccination, and has the potential to improve the immune profile of a variety of SARS-CoV-2 vaccine candidates to provide effective cross-protection against future drift variants.


Assuntos
Adjuvantes Imunológicos/farmacologia , Anticorpos Antivirais/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Vacinas Sintéticas/imunologia , Imunidade Adaptativa/imunologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Chlorocebus aethiops , Proteção Cruzada/imunologia , Proteína DEAD-box 58 , Células HEK293 , Humanos , Imunidade Humoral/imunologia , Imunização Passiva , Camundongos , Camundongos Endogâmicos C57BL , Receptores Imunológicos/agonistas , Proteínas Recombinantes/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinação , Células Vero
3.
Immunology ; 164(2): 209-210, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34523728

RESUMO

Neurodegenerative diseases place a devastating burden on affected individuals and their families, and new treatments are desperately needed for these common immune-mediated inflammatory conditions. While large aggregates of abnormal proteins in the brain cause significant damage, it is becoming clear that smaller soluble protein aggregates can also contribute to disease, by both direct and indirect mechanisms. These soluble protein oligomers can be found in patients' serum. Here, we describe recent research that identifies effects of model oligomer molecules on peripheral blood T cells, therefore providing an additional mechanism by which neurodegeneration may be worsened through amplification of peripheral adaptive immune responses.


Assuntos
Encéfalo/imunologia , Doenças Neurodegenerativas/imunologia , Proteínas/imunologia , Linfócitos T/imunologia , Imunidade Adaptativa/imunologia , Humanos , Inflamação/imunologia
5.
Biosci Rep ; 41(8)2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34350941

RESUMO

An influenza-like virus named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for COVID-19 disease and spread worldwide within a short time. COVID-19 has now become a significant concern for public health. Obesity is highly prevalent worldwide and is considered a risk factor for impairing the adaptive immune system. Although diabetes, hypertension, cardiovascular disease (CVD), and renal failure are considered the risk factors for COVID-19, obesity is not yet well-considered. The present study approaches establishing a systemic association between the prevalence of obesity and its impact on immunity concerning the severe outcomes of COVID-19 utilizing existing knowledge. Overall study outcomes documented the worldwide prevalence of obesity, its effects on immunity, and a possible underlying mechanism covering obesity-related risk pathways for the severe outcomes of COVID-19. Overall understanding from the present study is that being an immune system impairing factor, the role of obesity in the severe outcomes of COVID-19 is worthy.


Assuntos
Imunidade Adaptativa/imunologia , COVID-19/patologia , Obesidade/imunologia , Obesidade/patologia , Humanos , Inflamação/patologia , Obesidade/epidemiologia , Fatores de Risco , SARS-CoV-2/imunologia
6.
Int J Mol Sci ; 22(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445668

RESUMO

Multiple sclerosis (MS) and Devic's disease (NMO; neuromyelitis optica) are autoimmune, inflammatory diseases of the central nervous system (CNS), the etiology of which remains unclear. It is a serious limitation in the treatment of these diseases. The resemblance of the clinical pictures of these two conditions generates a partial possibility of introducing similar treatment, but on the other hand, a high risk of misdiagnosis. Therefore, a better understanding and comparative characterization of the immunopathogenic mechanisms of each of these diseases are essential to improve their discriminatory diagnosis and more effective treatment. In this review, special attention is given to Th17 cells and Th17-related cytokines in the context of their potential usefulness as discriminatory markers for MS and NMO. The discussed results emphasize the role of Th17 immune response in both MS and NMO pathogenesis, which, however, cannot be considered without taking into account the broader perspective of immune response mechanisms.


Assuntos
Esclerose Múltipla/imunologia , Neuromielite Óptica/imunologia , Células Th17/imunologia , Imunidade Adaptativa/imunologia , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/imunologia , Biomarcadores , Citocinas/imunologia , Citocinas/metabolismo , Diagnóstico Diferencial , Humanos , Esclerose Múltipla/diagnóstico , Neuromielite Óptica/diagnóstico , Células Th17/fisiologia
7.
Int J Mol Sci ; 22(15)2021 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-34360684

RESUMO

The outbreak of the coronavirus disease 2019 (COVID-19) began at the end of 2019. COVID-19 is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and patients with COVID-19 may exhibit poor clinical outcomes. Some patients with severe COVID-19 experience cytokine release syndrome (CRS) or a cytokine storm-elevated levels of hyperactivated immune cells-and circulating pro-inflammatory cytokines, including interleukin (IL)-1ß and IL-18. This severe inflammatory response can lead to organ damage/failure and even death. The inflammasome is an intracellular immune complex that is responsible for the secretion of IL-1ß and IL-18 in various human diseases. Recently, there has been a growing number of studies revealing a link between the inflammasome and COVID-19. Therefore, this article summarizes the current literature regarding the inflammasome complex and COVID-19.


Assuntos
COVID-19/imunologia , COVID-19/virologia , Inflamassomos/imunologia , Inflamassomos/metabolismo , SARS-CoV-2/imunologia , SARS-CoV-2/metabolismo , Imunidade Adaptativa/imunologia , Animais , COVID-19/complicações , COVID-19/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Humanos , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/imunologia
8.
mBio ; 12(4): e0159821, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34399617

RESUMO

The gut microbiota plays a critical role in the induction of adaptive immune responses to influenza virus infection. However, the role of nasal bacteria in the induction of the virus-specific adaptive immunity is less clear. Here, we found that disruption of nasal bacteria by intranasal application of antibiotics before influenza virus infection enhanced the virus-specific antibody response in a MyD88-dependent manner. Similarly, disruption of nasal bacteria by lysozyme enhanced antibody responses to intranasally administered influenza virus hemagglutinin (HA) vaccine in a MyD88-dependent manner, suggesting that intranasal application of antibiotics or lysozyme could release bacterial pathogen-associated molecular patterns (PAMPs) from disrupted nasal bacteria that act as mucosal adjuvants by activating the MyD88 signaling pathway. Since commensal bacteria in the nasal mucosal surface were significantly lower than those in the oral cavity, intranasal administration of HA vaccine alone was insufficient to induce the vaccine-specific antibody response. However, intranasal supplementation of cultured oral bacteria from a healthy human volunteer enhanced antibody responses to an intranasally administered HA vaccine. Finally, we demonstrated that oral bacteria combined with an intranasal vaccine protect from influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Our results reveal the role of nasal bacteria in the induction of the virus-specific adaptive immunity and provide clues for developing better intranasal vaccines. IMPORTANCE Intranasal vaccination induces the nasal IgA antibody which is protective against respiratory viruses, such as influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, understanding how mucosal immune responses are elicited following viral infection is important for developing better vaccines. Here, we focused on the role of nasal commensal bacteria in the induction of immune responses following influenza virus infection. To deplete nasal bacteria, we intranasally administered antibiotics to mice before influenza virus infection and found that antibiotic-induced disruption of nasal bacteria could release bacterial components which stimulate the virus-specific antibody responses. Since commensal bacteria in nasal mucosa were significantly lower than those in the oral cavity, intranasal administration of split virus vaccine alone was insufficient to induce the vaccine-specific antibody response. However, intranasal supplementation of cultured oral bacteria from a healthy human volunteer enhanced antibody responses to the intranasally administered vaccine. Therefore, both integrity and amounts of nasal bacteria may be critical for an effective intranasal vaccine.


Assuntos
Bactérias/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Vacinas contra Influenza/imunologia , Mucosa Nasal/microbiologia , Infecções por Orthomyxoviridae/prevenção & controle , Imunidade Adaptativa/imunologia , Adjuvantes Imunológicos , Administração Intranasal , Animais , Anticorpos Antivirais/imunologia , Linhagem Celular , Chlorocebus aethiops , Cães , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Imunidade nas Mucosas/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos BALB C , Fator 88 de Diferenciação Mieloide/metabolismo , Mucosa Nasal/imunologia , Padrões Moleculares Associados a Patógenos/imunologia , SARS-CoV-2/imunologia , Vacinação/métodos , Células Vero
9.
Sci Adv ; 7(34)2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34407944

RESUMO

The COVID-19 pandemic has spread worldwide, yet the role of antiviral T cell immunity during infection and the contribution of immune checkpoints remain unclear. By prospectively following a cohort of 292 patients with melanoma, half of which treated with immune checkpoint inhibitors (ICIs), we identified 15 patients with acute or convalescent COVID-19 and investigated their transcriptomic, proteomic, and cellular profiles. We found that ICI treatment was not associated with severe COVID-19 and did not alter the induction of inflammatory and type I interferon responses. In-depth phenotyping demonstrated expansion of CD8 effector memory T cells, enhanced T cell activation, and impaired plasmablast induction in ICI-treated COVID-19 patients. The evaluation of specific adaptive immunity in convalescent patients showed higher spike (S), nucleoprotein (N), and membrane (M) antigen-specific T cell responses and similar induction of spike-specific antibody responses. Our findings provide evidence that ICI during COVID-19 enhanced T cell immunity without exacerbating inflammation.


Assuntos
COVID-19/imunologia , Inibidores de Checkpoint Imunológico/imunologia , Melanoma/imunologia , SARS-CoV-2/imunologia , Linfócitos T/imunologia , Imunidade Adaptativa/efeitos dos fármacos , Imunidade Adaptativa/imunologia , Idoso , Anticorpos Antivirais/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , COVID-19/complicações , COVID-19/virologia , Feminino , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Memória Imunológica/efeitos dos fármacos , Memória Imunológica/imunologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Masculino , Melanoma/complicações , Melanoma/tratamento farmacológico , Pessoa de Meia-Idade , Estudos Prospectivos , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/virologia
10.
Front Immunol ; 12: 696816, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34305933

RESUMO

Early studies on vaccination of children with oncological diseases were only dedicated to the assessment of safety and immunogenicity of the drug. Mechanisms of the post-vaccination immune response were not investigated. This study involved 41 patients aged 7-15 years who were treated for solid tumors two or more years ago. Of these, 26 were vaccinated against diphtheria and tetanus with ADS-m toxoid. Fifteen children (i.e., controls) were not vaccinated. The vaccination tolerability and clinical characteristics of the underlying disease remission ware assessed. Lymphocyte subpopulations were investigated over time by flow cytometry at 1, 6, and 12 months. IgG anti-diphtheria and anti-tetanus toxoids levels were assessed by ELISA. Within the first day of the post-vaccination period, two (7.7%) children demonstrated moderate local reactions and increased body temperature (up to 38.0°C). Relapse and metastasis were not mentioned within a year after immunization. An increase in concentration of IgG antibodies, maintained for 12 months, were noted [2.1 (1.3-3.4) IU/ml against diphtheria (p <0.001), 6.4 (2.3-9.7) IU/ml against tetanus (p <0.001)]. In contrast to healthy children, those with a history of cancer demonstrated a decrease in the relative number of mature T lymphocytes, as well as in absolute number of cytotoxic T cells and B lymphocytes. In a month after the revaccination, a significant increase in absolute (p = 0.04) and relative (p = 0.007) numbers of T lymphocytes and T helpers was revealed. In a year, these values decreased to baseline levels. As for helpers, they decreased below baseline and control values (p = 0.004). In a year after the vaccination, there was a significant (p = 0.05) increase in lymphocyte level with a decrease in the number of NK cells and B cells as compared with controls. Revaccination against diphtheria and tetanus promoted proliferation of a total lymphocytic cell pool along with restoration of the T lymphocyte subpopulation in children with a history of solid tumors. The ADS-m toxoid has a certain nonspecific immunomodulatory effect. These findings are important, also in the midst of the coronavirus pandemic.


Assuntos
Imunidade Adaptativa/imunologia , Vacina contra Difteria e Tétano/imunologia , Neoplasias/imunologia , Vacinação , Adolescente , Anticorpos Antibacterianos/imunologia , Criança , Difteria/imunologia , Difteria/prevenção & controle , Vacina contra Difteria e Tétano/administração & dosagem , Humanos , Imunização Secundária , Subpopulações de Linfócitos/imunologia , Linfócitos/imunologia , Neoplasias/patologia , Federação Russa , Tétano/imunologia , Tétano/prevenção & controle
11.
Cytokine ; 146: 155637, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34242899

RESUMO

Interferons have prominent roles in various pathophysiological conditions, mostly related to inflammation. Interferon-gamma (IFNγ) was, initially discovered as a potent antiviral agent, over 50 years ago, and has recently garnered renewed interest as a promising factor involved in both innate and adaptive immunity. When new disease epidemics appear such as SARS-CoV (severe acute respiratory syndrome coronavirus), MERS-CoV (Middle East respiratory syndrome coronavirus), IAV (Influenza A virus), and in particular the current SARS-CoV-2 pandemic, it is especially timely to review the complexity of immune system responses to viral infections. Here we consider the controversial roles of effectors like IFNγ, discussing its actions in immunomodulation and immunotolerance. We explore the possibility that modulation of IFNγ could be used to influence the course of such infections. Importantly, not only could endogenous expression of IFNγ influence the outcome, there are existing IFNγ therapeutics that can readily be applied in the clinic. However, our understanding of the molecular mechanisms controlled by IFNγ suggests that the exact timing for application of IFNγ-based therapeutics could be crucial: it should be earlier to significantly reduce the viral load and thus decrease the overall severity of the disease.


Assuntos
Imunidade Adaptativa/imunologia , COVID-19/imunologia , Tolerância Imunológica/imunologia , Imunidade Inata/imunologia , Interferon gama/imunologia , Antivirais/imunologia , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/virologia , Humanos , Interferon gama/uso terapêutico , Receptores de Interferon/imunologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia , Transdução de Sinais/imunologia
12.
Curr Rheumatol Rep ; 23(8): 63, 2021 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-34216297

RESUMO

PURPOSE: Myositis as a rare manifestation of COVID-19 is only recently being reported. This review examines the current literature on COVID-19-induced myositis focusing on etiopathogenesis, clinical presentations, diagnostic practices, and therapeutic challenges with immunosuppression, and the difficulties experienced by rheumatologists in established myositis in the COVID-19 era. RECENT FINDINGS: COVID-19 is associated with a viral myositis attributable to direct myocyte invasion or induction of autoimmunity. COVID-19-induced myositis may be varied in presentation, from typical dermatomyositis to rhabdomyolysis, and a paraspinal affliction with back pain. It may or may not present with acute exponential elevations of enzyme markers such as creatine kinase (CK). Virus-mediated muscle inflammation is attributed to ACE2 (angiotensin-converting enzyme) receptor-mediated direct entry and affliction of muscle fibers, leading on to innate and adaptive immune activation. A greater recognition of the stark similarity between anti-MDA5-positive myositis with COVID-19 has thrown researchers into the alley of exploration - finding common etiopathogenic basis as well as therapeutic strategies. For patients with established myositis, chronic care was disrupted during the pandemic with several logistic challenges and treatment dilemmas leading to high flare rates. Teleconsultation bridged the gap while ushering in an era of patient-led care with the digital transition to tools of remote disease assessment. COVID-19 has brought along greater insight into unique manifestations of COVID-19-related myositis, ranging from direct virus-induced muscle disease to triggered autoimmunity and other etiopathogenic links to explore. A remarkable shift in the means of delivering chronic care has led patients and caregivers worldwide to embrace a virtual shift with teleconsultation and opened doorways to a new era of patient-led care.


Assuntos
COVID-19/fisiopatologia , Miosite/fisiopatologia , Rabdomiólise/fisiopatologia , Imunidade Adaptativa/imunologia , Enzima de Conversão de Angiotensina 2/metabolismo , Autoanticorpos/imunologia , Dor nas Costas/etiologia , COVID-19/complicações , COVID-19/imunologia , COVID-19/metabolismo , Creatina Quinase/metabolismo , Dermatomiosite/etiologia , Dermatomiosite/imunologia , Dermatomiosite/metabolismo , Dermatomiosite/fisiopatologia , Humanos , Imunidade Inata/imunologia , Helicase IFIH1 Induzida por Interferon/imunologia , Miastenia Gravis/etiologia , Miastenia Gravis/imunologia , Miastenia Gravis/metabolismo , Miastenia Gravis/fisiopatologia , Miosite/etiologia , Miosite/imunologia , Miosite/metabolismo , Músculos Paraespinais/fisiopatologia , Receptores de Coronavírus/metabolismo , Rabdomiólise/etiologia , Rabdomiólise/imunologia , Rabdomiólise/metabolismo , SARS-CoV-2
13.
Front Immunol ; 12: 650768, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248937

RESUMO

The role of adipose tissue (AT) inflammation in obesity and its multiple related-complications is a rapidly expanding area of scientific interest. Within the last 30 years, the role of the adipocyte as an endocrine and immunologic cell has been progressively established. Like the macrophage, the adipocyte is capable of linking the innate and adaptive immune system through the secretion of adipokines and cytokines; exosome release of lipids, hormones, and microRNAs; and contact interaction with other immune cells. Key innate immune cells in AT include adipocytes, macrophages, neutrophils, and innate lymphoid cells type 2 (ILC2s). The role of the innate immune system in promoting adipose tissue inflammation in obesity will be highlighted in this review. T cells and B cells also play important roles in contributing to AT inflammation and are discussed in this series in the chapter on adaptive immunity.


Assuntos
Imunidade Adaptativa/imunologia , Adipócitos/imunologia , Tecido Adiposo/imunologia , Imunidade Inata/imunologia , Obesidade/imunologia , Adipócitos/citologia , Adipócitos/metabolismo , Adipocinas/imunologia , Adipocinas/metabolismo , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo
14.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299236

RESUMO

Inflammatory bowel disease (IBD) is a heterogeneous state of chronic intestinal inflammation of unknown cause encompassing Crohn's disease (CD) and ulcerative colitis (UC). IBD has been linked to genetic and environmental factors, microbiota dysbiosis, exacerbated innate and adaptive immunity and epithelial intestinal barrier dysfunction. IBD is classically associated with gut accumulation of proinflammatory Th1 and Th17 cells accompanied by insufficient Treg numbers and Tr1 immune suppression. Inflammatory T cells guide innate cells to perpetuate a constant hypersensitivity to microbial antigens, tissue injury and chronic intestinal inflammation. Recent studies of intestinal mucosal homeostasis and IBD suggest involvement of innate lymphoid cells (ILCs). These lymphoid-origin cells are innate counterparts of T cells but lack the antigen receptors expressed on B and T cells. ILCs play important roles in the first line of antimicrobial defense and contribute to organ development, tissue protection and regeneration, and mucosal homeostasis by maintaining the balance between antipathogen immunity and commensal tolerance. Intestinal homeostasis requires strict regulation of the quantity and activity of local ILC subpopulations. Recent studies demonstrated that changes to ILCs during IBD contribute to disease development. A better understanding of ILC behavior in gastrointestinal homeostasis and inflammation will provide valuable insights into new approaches to IBD treatment. This review summarizes recent research into ILCs in intestinal homeostasis and the latest advances in the understanding of the role of ILCs in IBD, with particular emphasis on the interaction between microbiota and ILC populations and functions.


Assuntos
Imunidade Inata/imunologia , Mucosa Intestinal/metabolismo , Linfócitos/metabolismo , Imunidade Adaptativa/imunologia , Animais , Colite , Colite Ulcerativa , Doença de Crohn , Trato Gastrointestinal , Homeostase/fisiologia , Humanos , Tolerância Imunológica , Inflamação , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/fisiopatologia , Mucosa Intestinal/imunologia , Intestinos/imunologia , Linfócitos/imunologia , Microbiota , Células Th17
15.
Theranostics ; 11(14): 6936-6949, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093863

RESUMO

Substantial progress has been made with cancer immunotherapeutic strategies in recent years, most of which mainly rely on enhancing the T cell response. However, sufficient tumor antigen information often cannot be presented to T cells, resulting in a failed effector T cell response. The innate immune system can effectively recognize tumor antigens and then initiate an adaptive immune response. Here, we developed a spontaneous multifunctional hydrogel (NOCC-CpG/OX-M, Ncom Gel) vaccine to amplify the innate immune response and harness innate immunity to launch and maintain a powerful adaptive immune response. Methods: Ncom Gel was formed by a Schiff base reaction between CpG-modified carboxymethyl chitosan (NOCC-CpG) and partially oxidized mannan (OX-M). The effects of the Ncom Gel vaccine on DCs and macrophages in vitro and antigen-specific humoral immunity and cellular immunity in vivo were studied. Furthermore, the antitumor immune response of the Ncom Gel vaccine and its effect on the tumor microenvironment were evaluated. Results: The Ncom Gel vaccine enhanced antigen presentation to T cells by facilitating DC uptake and maturation and inducing macrophages to a proinflammatory subtype, further leading to a T cell-mediated adaptive immune response. Moreover, the innate immune response could be amplified via the promotion of antigen-specific antibody production. The Ncom Gel vaccine reversed the tumor immune microenvironment to an inflamed phenotype and showed a significant antitumor response in a melanoma model. Conclusions: Our research implies the potential application of injectable hydrogels as a platform for tumor immunotherapy. The strategy also opens up a new avenue for multilayered cancer immunotherapy.


Assuntos
Imunidade Adaptativa/efeitos dos fármacos , Vacinas Anticâncer/imunologia , Hidrogéis/química , Hidrogéis/farmacologia , Imunidade Inata/efeitos dos fármacos , Imunoterapia/métodos , Melanoma/imunologia , Microambiente Tumoral/efeitos dos fármacos , Imunidade Adaptativa/imunologia , Animais , Linhagem Celular Tumoral , Quitosana/química , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Feminino , Hidrogéis/síntese química , Inflamação/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Mananas/química , Melanoma/terapia , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Varredura , Ovalbumina/imunologia , Reologia , Bases de Schiff/química , Linfócitos T/imunologia , Microambiente Tumoral/imunologia
16.
Int J Mol Sci ; 22(10)2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067536

RESUMO

Several virus-induced models were used to study the underlying mechanisms of multiple sclerosis (MS). The infection of susceptible mice with Theiler's murine encephalomyelitis virus (TMEV) establishes persistent viral infections and induces chronic inflammatory demyelinating disease. In this review, the innate and adaptive immune responses to TMEV are discussed to better understand the pathogenic mechanisms of viral infections. Professional (dendritic cells (DCs), macrophages, and B cells) and non-professional (microglia, astrocytes, and oligodendrocytes) antigen-presenting cells (APCs) are the major cell populations permissive to viral infection and involved in cytokine production. The levels of viral loads and cytokine production in the APCs correspond to the degrees of susceptibility of the mice to the TMEV-induced demyelinating diseases. TMEV infection leads to the activation of cytokine production via TLRs and MDA-5 coupled with NF-κB activation, which is required for TMEV replication. These activation signals further amplify the cytokine production and viral loads, promote the differentiation of pathogenic Th17 responses, and prevent cellular apoptosis, enabling viral persistence. Among the many chemokines and cytokines induced after viral infection, IFN α/ß plays an essential role in the downstream expression of costimulatory molecules in APCs. The excessive levels of cytokine production after viral infection facilitate the pathogenesis of TMEV-induced demyelinating disease. In particular, IL-6 and IL-1ß play critical roles in the development of pathogenic Th17 responses to viral antigens and autoantigens. These cytokines, together with TLR2, may preferentially generate deficient FoxP3+CD25- regulatory cells converting to Th17. These cytokines also inhibit the apoptosis of TMEV-infected cells and cytolytic function of CD8+ T lymphocytes (CTLs) and prolong the survival of B cells reactive to viral and self-antigens, which preferentially stimulate Th17 responses.


Assuntos
Doenças Desmielinizantes/imunologia , Esclerose Múltipla/imunologia , Theilovirus/fisiologia , Imunidade Adaptativa/imunologia , Animais , Células Apresentadoras de Antígenos/metabolismo , Astrócitos/metabolismo , Infecções por Cardiovirus/imunologia , Infecções por Cardiovirus/metabolismo , Infecções por Cardiovirus/virologia , Citocinas , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Humanos , Imunidade Inata/imunologia , Camundongos , Microglia/metabolismo , Esclerose Múltipla/metabolismo , Oligodendroglia/metabolismo , Transdução de Sinais/imunologia , Theilovirus/patogenicidade
17.
Clin Pharmacol Ther ; 110(3): 607-615, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34143437

RESUMO

The human leukocyte antigen (HLA) system is the most polymorphic in the human genome that has been associated with protection and predisposition to a broad array of infectious, autoimmune, and malignant diseases. More recently over the last two decades, HLA class I alleles have been strongly associated with T-cell-mediated drug hypersensitivity reactions. In the case of abacavir hypersensitivity and HLA-B*57:01, the 100% negative predictive value and low number needed to test to prevent a single case has led to a durable and effective global preprescription screening strategy. However, HLA associations are still undefined for most drugs clinically associated with different delayed drug hypersensitivity phenotypes, and an HLA association relevant to one population is not generalizable across ethnicities. Furthermore, while a specific risk HLA allele is necessary for drug-induced T-cell activation, it is not sufficient. The low and incomplete positive predictive value has hindered efforts at clinical implementation for many drugs but has provided the impetus to understand the mechanisms of HLA class I restricted T-cell-mediated drug hypersensitivity reactions. Current research has focused on defining the contribution of additional elements of the adaptive immune response and other genetic and ecologic risk factors that contribute to drug hypersensitivity risk. In this review we focus on new insights into immunological, pharmacological, and genetic mechanisms underpinning HLA-associated drug reactions and the implications for future translation into clinical care.


Assuntos
Hipersensibilidade a Drogas/genética , Antígenos HLA/genética , Imunidade Adaptativa/genética , Imunidade Adaptativa/imunologia , Alelos , Animais , Hipersensibilidade a Drogas/imunologia , Antígenos HLA/imunologia , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Humanos , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Farmacogenética/métodos , Linfócitos T/imunologia
18.
Biomed Res Int ; 2021: 8845826, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34095312

RESUMO

Immunotherapy, a treatment based on host immune system activation, has been shown to provide a substitute for marginally effective conventional chemotherapy in controlling visceral leishmaniasis (VL), the deadliest form of leishmaniasis. As the majority of endemic inhabitants exhibit either subclinical or asymptomatic infection which often develops into the active disease state, therapeutic intervention seems to be an important avenue for combating infections by stimulating the natural defense system of infected individuals. With this perspective, the present study focuses on two immunodominant Leishmania (L.) donovani antigens (triosephosphate isomerase and enolase) previously proved to be potent prophylactic VL vaccine candidates, for generating a recombinant chimeric antigen. This is based on the premise that in a heterogeneous population, a multivalent antigen vaccine would be required for an effective response against leishmaniasis (a complex parasitic disease). The resulting molecule rLdT-E chimeric protein was evaluated for its immunogenicity and immunotherapeutic efficacy. A Th1 stimulating adjuvant BCG was employed with the protein which showed a remarkable 70% inhibition of splenic parasitic multiplication positively correlated with boosted Th1 dominant immune response against lethal L. donovani challenge in hamsters as evidenced by high IFN-γ and TNF-α and low IL-10. In addition, immunological analysis of antibody subclass presented IgG2-based humoral response besides considerable delayed-type hypersensitivity and lymphocyte proliferative responses in rLdT-E/BCG-treated animals. Our observations indicate the potential of the chimera towards its candidature for an effective vaccine against Leishmania donovani infection.


Assuntos
Leishmania donovani/genética , Leishmaniose Visceral/terapia , Células Th1/imunologia , Imunidade Adaptativa/imunologia , Animais , Antígenos de Protozoários/imunologia , Quimera , Cricetinae , Citocinas/metabolismo , Feminino , Fatores Imunológicos/metabolismo , Imunoterapia/métodos , Leishmania donovani/imunologia , Leishmania donovani/patogenicidade , Leishmaniose Visceral/imunologia , Leishmaniose Visceral/metabolismo , Leucócitos Mononucleares/metabolismo , Ativação Linfocitária/imunologia , Linfócitos/metabolismo , Fosfopiruvato Hidratase/imunologia , Proteínas de Protozoários/metabolismo , Proteínas Recombinantes/metabolismo , Triose-Fosfato Isomerase/imunologia , Vacinas/farmacologia
19.
Mol Immunol ; 136: 138-149, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34146759

RESUMO

Gamma-delta (γδ) T cells are a heterogeneous population of immune cells, which constitute <5% of total T cells in mice lymphoid tissue and human peripheral blood. However, they comprise a higher proportion of T cells in the epithelial and mucosal barrier, where they perform immune functions, help in tissue repair, and maintaining homeostasis. These tissues resident γδ T cells possess properties of innate and adaptive immune cells which enables them to perform a variety of functions during homeostasis and disease. Emerging data suggest the involvement of γδ T cells during transplant rejection and survival. Interestingly, several functions of γδ T cells can be modulated through their interaction with other immune cells. This review provides an overview of development, differentiation plasticity into regulatory and effector phenotypes of γδ T cells during homeostasis and various diseases.


Assuntos
Rejeição de Enxerto/imunologia , Tolerância Imunológica/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Linfócitos T/imunologia , Imunidade Adaptativa/imunologia , Animais , Plasticidade Celular/imunologia , Humanos , Imunidade Inata/imunologia , Camundongos , Linfócitos T/citologia
20.
AIDS Rev ; 23(3): 153-163, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34082440

RESUMO

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly infectious RNA coronavirus responsible for the pandemic of the coronavirus disease 2019 (COVID-19). Recent advances in virology, epidemiology, diagnosis, and clinical management of COVID-19 have contributed to the control and prevention of this disease, but re-positivity of SARS-CoV-2 in recovered COVID-19 patients has brought a new challenge for this worldwide anti-viral battle. Reverse transcription polymerase chain reaction (RT-PCR) tests of the SARS-CoV-2 pathogen is widely used in clinical diagnosis, but a positive RT-PCR result may be multifactorial, including false positive, SARS-CoV-2 RNA fragment shedding, reinfection of SARS-CoV-2, or re-activation of COVID-19. Re-infection of SARS-CoV-2 or re-activation of COVID-19 is an indicator of live viral carriers and isolation/treatment is needed, but SARS-CoV-2 RNA fragment shedding is not. SARS-CoV-2 RNA is recently reported to integrate into the host genome, but the far-reaching outcome is currently unclear. Therefore, it is critical for appropriate manipulation and prevention of COVID-19 to distinguish these causal factors of SARS-CoV-2 re-positivity. In this review article, we updated the current knowledge of SARS-CoV-2 re-positivity in discharged COVID-19 patients with a focus on re-infection and re-activation. We proposed a hypothetical flowchart for handling of the SARS-CoV-2 re-positive cases.


Assuntos
COVID-19/patologia , RNA Viral/análise , Reinfecção/virologia , SARS-CoV-2/genética , Ativação Viral/genética , Imunidade Adaptativa/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/sangue , COVID-19/diagnóstico , Criança , Pré-Escolar , Reações Falso-Positivas , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto Jovem
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