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1.
Molecules ; 26(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34361589

RESUMO

Virus-like particles are excellent inducers of the adaptive immune response of humans and are presently being used as scaffolds for the presentation of foreign peptides and antigens derived from infectious microorganisms for subunit vaccine development. The most common approaches for peptide and antigen presentation are translational fusions and chemical coupling, but some alternatives that seek to simplify the coupling process have been reported recently. In this work, an alternative platform for coupling full antigens to virus-like particles is presented. Heterodimerization motifs inserted in both Tobacco etch virus coat protein and green fluorescent protein directed the coupling process by simple mixing, and the obtained complexes were easily taken up by a macrophage cell line.


Assuntos
Apresentação do Antígeno/imunologia , Antígenos , Potyvirus , Vacinas de Partículas Semelhantes a Vírus , Animais , Antígenos/química , Antígenos/imunologia , Camundongos , Potyvirus/química , Potyvirus/imunologia , Células RAW 264.7 , Vacinas de Partículas Semelhantes a Vírus/química , Vacinas de Partículas Semelhantes a Vírus/imunologia
2.
Front Immunol ; 12: 636240, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34234771

RESUMO

CD8 positive, tissue resident memory T cells (TRM) are a specialized subset of CD8 memory T cells that surveil tissues and provide critical first-line protection against tumors and pathogen re-infection. Recently, much effort has been dedicated to understanding the function, phenotype and development of TRM. A myriad of signals is involved in the development and maintenance of resident memory T cells in tissue. Much of the initial research focused on the roles tissue-derived signals play in the development of TRM, including TGFß and IL-33 which are critical for the upregulation of CD69 and CD103. However, more recent data suggest further roles for antigenic and pro-inflammatory cytokines. This review will focus on the interplay of pro-inflammatory, tissue and antigenic signals in the establishment of resident memory T cells.


Assuntos
Antígenos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Memória Imunológica , Mediadores da Inflamação/metabolismo , Inflamação/metabolismo , Interleucinas/metabolismo , Animais , Antígenos/imunologia , Linfócitos T CD8-Positivos/imunologia , Humanos , Inflamação/imunologia , Mediadores da Inflamação/imunologia , Interleucina-33/imunologia , Interleucina-33/metabolismo , Interleucinas/imunologia , Fenótipo , Transdução de Sinais , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta/metabolismo
3.
Nat Methods ; 18(8): 881-892, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34282327

RESUMO

T cells express T cell receptors (TCRs) composed of somatically recombined TCRα and TCRß chains, which mediate recognition of major histocompatibility complex (MHC)-antigen complexes and drive the antigen-specific adaptive immune response to pathogens and cancer. The TCR repertoire in each individual is highly diverse, which allows for recognition of a wide array of foreign antigens, but also presents a challenge in analyzing this response using conventional methods. Recent studies have developed high-throughput sequencing technologies to identify TCR sequences, analyze their antigen specificities using experimental and computational tools, and pair TCRs with transcriptional and epigenetic cell state phenotypes in single cells. In this Review, we highlight these technological advances and describe how they have been applied to discover fundamental insights into T cell-mediated immunity.


Assuntos
Antígenos/imunologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Complexo Principal de Histocompatibilidade/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Análise de Célula Única/métodos , Linfócitos T/imunologia , Imunidade Adaptativa , Animais , Humanos
4.
Ann Allergy Asthma Immunol ; 127(3): 301-305, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34102303

RESUMO

OBJECTIVE: To review the literature and discuss a hypothesis as to why most people do not have allergy. This hypothesis is dependent on the following 3 main components: (1) airborne allergens (eg, from pollen or mites) are weak antigens that induce a B-cell response only in immunologically most reactive subjects (ie, with atopy); (2) a roadblock to production of immunoglobulin E (IgE) is the T helper 2/interleukin 4 requirement for class switch to IgE; (3) activated germinal centers prevent the formation of mature IgE-switched B-cells, creating a second roadblock to IgE production. DATA SOURCES: Transgenic reporter mice and a cross-sectional human cohort. STUDY SELECTIONS: From the mouse studies, we selected the data on histology and tissue-derived cell suspensions published by several groups in 2011 to 2014. From the human cohort, we selected our published microarray data on the levels of allergen-specific IgE and IgG in serum. RESULTS: The immune response to airborne atopic allergens entails both IgE and IgG antibodies rather than just an IgG or IgE response. However, as expected for an immune response without mature germinal centers, the specific IgG levels will be very low, typically in the ng/ml range. CONCLUSION: Control of IgE production is not just through the T helper 2/interleukin 4-mediated class switch. Recent studies suggest that mature germinal centers are likely to provide protection against the development of allergy to airborne allergens, as well. This may explain why allergen exposure does not induce allergen-specific IgE in everyone.


Assuntos
Centro Germinativo/imunologia , Hipersensibilidade/imunologia , Animais , Antígenos/imunologia , Linfócitos B/imunologia , Humanos , Imunoglobulina E/imunologia
5.
Int J Mol Sci ; 22(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069573

RESUMO

Antibody therapeutics are expanding with promising clinical outcomes, and diverse formats of antibodies are further developed and available for patients of the most challenging disease areas. Bispecific antibodies (BsAbs) have several significant advantages over monospecific antibodies by engaging two antigen targets. Due to the complicated mechanism of action, diverse structural variations, and dual-target binding, developing bioassays and other types of assays to characterize BsAbs is challenging. Developing bioassays for BsAbs requires a good understanding of the mechanism of action of the molecule, principles and applications of different bioanalytical methods, and phase-appropriate considerations per regulatory guidelines. Here, we review recent advances and case studies to provide strategies and insights for bioassay development for different types of bispecific molecules.


Assuntos
Anticorpos Biespecíficos/análise , Anticorpos Biespecíficos/imunologia , Anticorpos Biespecíficos/uso terapêutico , Animais , Antígenos/imunologia , Bioensaio/métodos , Humanos , Imunoterapia/métodos
6.
Front Immunol ; 12: 592731, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33968011

RESUMO

Childhood vaccination plays critical role in protecting infants from several dreaded diseases. Of the global 15 million preterm (PT) infants with compromised immune system born annually, India contributes to >3.5 million. Generation of adequate vaccine-induced immune response needs to be ensured of their protection. Immune response of Indian PT (n = 113) and full-term (FT, n = 80) infants to pentavalent vaccine administered as per the national recommendation was studied. Antibody titers against component antigens of pentavalent vaccine, immune cells profiling (T and B cells, monocytes and dendritic cells) and plasma cytokines were determined pre- and post-vaccination. Additionally, cell-mediated recall immune responses to pentavalent antigens were evaluated after short time antigenic exposure to infant PBMCs. Irrespective of gestational age (GA), all the infants developed adequate antibody response against tetanus, diphtheria, and protective but lower antibody levels for Haemophilus influenzae type-b and hepatitis B in preterm infants. Lower (~74%) protective antibody response to pertussis was independent of gestational age. PT-infants exhibited lower frequencies of CD4 T cells/dendritic cells/monocytes, increased plasma IL-10 levels and lower proliferation of central and effector memory T cells than in term-infants. Proliferative central memory response of FT-infants without anti-pertussis antibodies suggests protection from subsequent infection. Responder/non-responder PT-infants lacked immunological memory and could be infected with Bordetella. For hepatitis B, the recall response was gestational age-dependent and antibody status-independent. Humoral/cellular immune responses of PT-infants were dependent on the type of the immunogen. Preterm infants born before 32 weeks of gestation may need an extra dose of pentavalent vaccine for long lived robust immune response.


Assuntos
Antígenos/imunologia , Idade Gestacional , Imunidade , Recém-Nascido Prematuro/imunologia , Vacinas Combinadas/imunologia , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Biomarcadores , Citocinas/sangue , Feminino , Humanos , Memória Imunológica , Imunofenotipagem , Índia/epidemiologia , Lactente , Recém-Nascido , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Vigilância em Saúde Pública , Vacinação
7.
Chem Commun (Camb) ; 57(38): 4698-4701, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33977971

RESUMO

Despite the ease of production and improved safety profiles of recombinant vaccines, the inherently low immunogenicity of unadjuvanted proteins remains an impediment to their widespread adoption. The covalent tethering of TLR agonists to antigenic proteins offers a unique approach to co-deliver both constituents to the same cell-enhancing vaccine efficacy while minimizing reactogenicity. However, the paucity of simple and effective linker chemistries continues to hamper progress. Here, we present a modular, PEG-based linker system compatible with even extremely lipophilic and challenging TLR7/8 agonists. To advance the field and address previous obstacles, we offer the most straightforward and antigen-preserving linker system to date. These antigen-adjuvant conjugates enhance antigen-specific immune responses in mice, demonstrating the power of our approach within the context of modern vaccinology.


Assuntos
Antígenos/imunologia , Glicoproteínas de Membrana/imunologia , Receptor 7 Toll-Like/imunologia , Receptor 8 Toll-Like/imunologia , Adjuvantes Imunológicos , Animais , Camundongos
8.
Chem Biol Interact ; 344: 109497, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33991505

RESUMO

Extracellular vesicles like exosomes are important therapeutic tactics for treating COVID -19. By utilizing convalescent plasma derived exosomes (CPExo) from COVID-19 recovered persistence could accelerate the treatment strategies in the current state of affairs. Adequate literature has shown that administering the exosome to the in vivo system could be beneficial and could target the pathogens in an effective and precise manner. In this hypothesis we highlight the CPExo instead of convalescent plasma (CP), perhaps to dispense of exosomes are gratified and it's more effectively acquired immune response conferral through antibodies. COVID-19 convalescent plasma has billions of exosomes and it has aptitudes to carry molecular constituents like proteins, lipids, RNA and DNA, etc. Moreover, exosomes are capable of recognizing antigens with adequate sensitivity and specificity. Many of these derivatives could trigger an immune modulation into the cells and act as an epigenetic inheritor response to target pathogens through RNAs. COIVID-19 resistance activated plasma-derived exosomes are either responsible for the effects of plasma beyond the contained immune antibodies or could be inhibitory. The proposed hypothesis suggests that preselecting the plasma-derived antibodies and RNAs merged exosomes would be an optimized therapeutic tactic for COVID-19 patients. We suggest that, the CPExo has a multi-potential effect for treatment efficacy by acting as immunotherapeutic, drug carrier, and diagnostic target with noncoding genetic materials as a biomarker.


Assuntos
COVID-19/imunologia , COVID-19/terapia , Exossomos/imunologia , Plasma/imunologia , Imunidade Adaptativa/imunologia , Anticorpos/imunologia , Antígenos/imunologia , DNA/imunologia , Humanos , Imunização Passiva , RNA/imunologia , SARS-CoV-2/imunologia
9.
Nat Commun ; 12(1): 2782, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33986293

RESUMO

Chronic stimulation of CD8+ T cells triggers exhaustion, a distinct differentiation state with diminished effector function. Exhausted cells exist in multiple differentiation states, from stem-like progenitors that are the key mediators of the response to checkpoint blockade, through to terminally exhausted cells. Due to its clinical relevance, there is substantial interest in defining the pathways that control differentiation and maintenance of these subsets. Here, we show that chronic antigen induces the anergy-associated transcription factor EGR2 selectively within progenitor exhausted cells in both chronic LCMV and tumours. EGR2 enables terminal exhaustion and stabilizes the exhausted transcriptional state by both direct EGR2-dependent control of key exhaustion-associated genes, and indirect maintenance of the exhausted epigenetic state. We show that EGR2 is a regulator of exhaustion that epigenetically and transcriptionally maintains the differentiation competency of progenitor exhausted cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Anergia Clonal/imunologia , Proteína 2 de Resposta de Crescimento Precoce/metabolismo , Linfopoese/fisiologia , Animais , Antígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Proteína 2 de Resposta de Crescimento Precoce/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
10.
J Immunol ; 206(9): 2109-2121, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33858960

RESUMO

Ag-inexperienced memory-like T (AIMT) cells are functionally unique T cells, representing one of the two largest subsets of murine CD8+ T cells. However, differences between laboratory inbred strains, insufficient data from germ-free mice, a complete lack of data from feral mice, and an unclear relationship between AIMT cells formation during aging represent major barriers for better understanding of their biology. We performed a thorough characterization of AIMT cells from mice of different genetic background, age, and hygienic status by flow cytometry and multiomics approaches, including analyses of gene expression, TCR repertoire, and microbial colonization. Our data showed that AIMT cells are steadily present in mice, independent of their genetic background and hygienic status. Despite differences in their gene expression profiles, young and aged AIMT cells originate from identical clones. We identified that CD122 discriminates two major subsets of AIMT cells in a strain-independent manner. Whereas thymic CD122LOW AIMT cells (innate memory) prevail only in young animals with high thymic IL-4 production, peripheral CD122HIGH AIMT cells (virtual memory) dominate in aged mice. Cohousing with feral mice changed the bacterial colonization of laboratory strains but had only minimal effects on the CD8+ T cell compartment, including AIMT cells.


Assuntos
Envelhecimento/genética , Antígenos/genética , Memória Imunológica/genética , Linfócitos T/imunologia , Envelhecimento/imunologia , Animais , Antígenos/imunologia , Evolução Clonal , Instabilidade Genômica , Memória Imunológica/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo
11.
Mol Immunol ; 135: 165-169, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33901761

RESUMO

Antigen presentation is a key feature of classical dendritic cells (cDCs). Numerous studies have also reported in mouse that, upon inflammation, monocytes enter tissues and differentiate into monocyte-derived DCs (mo-DC) that have the ability to present antigens to T cells. However, a population of inflammatory cDCs sharing phenotypic features with mo-DC has been recently described, challenging the existence of in vivo-generated mo-DC. Here we review studies describing mouse mo-DC in the light of these findings, and evaluate the in vivo evidence for monocyte-derived antigen-presenting cells. We examine the strategies used to demonstrate the monocytic origin of these cells. Finally, we propose that mo-DC play a complementary role to cDCs, by presenting antigens to effector T cells locally in tissues.


Assuntos
Apresentação do Antígeno/imunologia , Células Dendríticas/citologia , Células Dendríticas/imunologia , Monócitos/imunologia , Linfócitos T/imunologia , Animais , Antígenos/imunologia , Diferenciação Celular/imunologia , Ativação Linfocitária/imunologia , Camundongos , Monócitos/citologia
12.
Angew Chem Int Ed Engl ; 60(26): 14679-14692, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-33852172

RESUMO

Streptococcus suis bacteria are one of the most serious health problems for pigs and an emerging zoonotic agent in humans working in the swine industry. S. suis bacteria express capsular polysaccharides (CPS) a major bacterial virulence factor that define the serotypes. Oligosaccharides resembling the CPS of S. suis serotypes 2, 3, 9, and 14 have been synthesized, glycans related to serotypes 2 and 9 were placed on glycan array surfaces to screen blood from infected pigs. Lead antigens for the development of semi-synthetic S. suis serotypes 2 and 9 glycoconjugate veterinary vaccines were identified in this way.


Assuntos
Antibacterianos/farmacologia , Antígenos/imunologia , Glicoconjugados/farmacologia , Polissacarídeos Bacterianos/imunologia , Streptococcus suis/efeitos dos fármacos , Vacinas Sintéticas/farmacologia , Antibacterianos/química , Antibacterianos/imunologia , Antígenos/química , Descoberta de Drogas , Glicoconjugados/química , Glicoconjugados/imunologia , Polissacarídeos Bacterianos/química , Vacinas Sintéticas/química , Vacinas Sintéticas/imunologia
13.
Immunity ; 54(5): 988-1001.e5, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33857421

RESUMO

Positive selection of high-affinity B cells within germinal centers (GCs) drives affinity maturation of antibody responses. Here, we examined the mechanism underlying the parallel transition from immunoglobulin M (IgM) to IgG. Early GCs contained mostly unswitched IgM+ B cells; IgG+ B cells subsequently increased in frequency, dominating GC responses 14-21 days after antigen challenge. Somatic hypermutation and generation of high-affinity clones occurred with equal efficiency among IgM+ and IgG+ GC B cells, and inactivation of Ig class-switch recombination did not prevent depletion of IgM+ GC B cells. Instead, high-affinity IgG+ GC B cells outcompeted high-affinity IgM+ GC B cells via a selective advantage associated with IgG antigen receptor structure but independent of the extended cytoplasmic tail. Thus, two parallel forms of GC B-cell-positive selection, based on antigen receptor variable and constant regions, respectively, operate in tandem to ensure high-affinity IgG antibodies predominate in mature serum antibody responses.


Assuntos
Linfócitos B/imunologia , Centro Germinativo/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Animais , Formação de Anticorpos/imunologia , Antígenos/imunologia , Feminino , Switching de Imunoglobulina/imunologia , Região Variável de Imunoglobulina/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ovinos/imunologia , Hipermutação Somática de Imunoglobulina/imunologia
14.
Nat Commun ; 12(1): 2403, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33893299

RESUMO

The ability to design functional sequences and predict effects of variation is central to protein engineering and biotherapeutics. State-of-art computational methods rely on models that leverage evolutionary information but are inadequate for important applications where multiple sequence alignments are not robust. Such applications include the prediction of variant effects of indels, disordered proteins, and the design of proteins such as antibodies due to the highly variable complementarity determining regions. We introduce a deep generative model adapted from natural language processing for prediction and design of diverse functional sequences without the need for alignments. The model performs state-of-art prediction of missense and indel effects and we successfully design and test a diverse 105-nanobody library that shows better expression than a 1000-fold larger synthetic library. Our results demonstrate the power of the alignment-free autoregressive model in generalizing to regions of sequence space traditionally considered beyond the reach of prediction and design.


Assuntos
Algoritmos , Biologia Computacional/métodos , Redes Neurais de Computação , Engenharia de Proteínas/métodos , Sequência de Aminoácidos , Anticorpos/genética , Anticorpos/imunologia , Anticorpos/metabolismo , Antígenos/imunologia , Genótipo , Humanos , Mutação , Fenótipo , Proteínas/genética , Proteínas/imunologia , Proteínas/metabolismo
15.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807663

RESUMO

T cells represent a critical arm of our immune defense against pathogens. Over the past two decades, considerable inroads have been made in understanding the fundamental principles underpinning the molecular presentation of peptide-based antigens by the Major Histocompatibility Complex molecules (MHC-I and II), and their molecular recognition by specialized subsets of T cells. However, some T cells can recognize lipid-based antigens presented by MHC-I-like molecules that belong to the Cluster of Differentiation 1 (CD1) family. Here, we will review the advances that have been made in the last five years to understand the molecular mechanisms orchestrating the presentation of novel endogenous and exogenous lipid-based antigens by the CD1 glycoproteins and their recognition by specific populations of CD1-reactive T cells.


Assuntos
Antígenos CD1/imunologia , Antígenos/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Lipídeos/imunologia , Ativação Linfocitária , Linfócitos T/imunologia , Humanos
16.
Nat Biomed Eng ; 5(6): 600-612, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33859386

RESUMO

The optimization of therapeutic antibodies is time-intensive and resource-demanding, largely because of the low-throughput screening of full-length antibodies (approximately 1 × 103 variants) expressed in mammalian cells, which typically results in few optimized leads. Here we show that optimized antibody variants can be identified by predicting antigen specificity via deep learning from a massively diverse space of antibody sequences. To produce data for training deep neural networks, we deep-sequenced libraries of the therapeutic antibody trastuzumab (about 1 × 104 variants), expressed in a mammalian cell line through site-directed mutagenesis via CRISPR-Cas9-mediated homology-directed repair, and screened the libraries for specificity to human epidermal growth factor receptor 2 (HER2). We then used the trained neural networks to screen a computational library of approximately 1 × 108 trastuzumab variants and predict the HER2-specific subset (approximately 1 × 106 variants), which can then be filtered for viscosity, clearance, solubility and immunogenicity to generate thousands of highly optimized lead candidates. Recombinant expression and experimental testing of 30 randomly selected variants from the unfiltered library showed that all 30 retained specificity for HER2. Deep learning may facilitate antibody engineering and optimization.


Assuntos
Antígenos/química , Aprendizado Profundo , Engenharia de Proteínas/métodos , Receptor ErbB-2/química , Trastuzumab/química , Sequência de Aminoácidos , Animais , Afinidade de Anticorpos , Especificidade de Anticorpos , Antígenos/genética , Antígenos/imunologia , Sistemas CRISPR-Cas , Humanos , Hibridomas/química , Hibridomas/imunologia , Mutagênese Sítio-Dirigida , Ligação Proteica , Receptor ErbB-2/genética , Receptor ErbB-2/imunologia , Reparo de DNA por Recombinação , Análise de Sequência de Proteína , Trastuzumab/genética , Trastuzumab/imunologia
17.
Front Immunol ; 12: 555095, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33746941

RESUMO

Hepatocytes compose up to 80% of the total liver and have been indicated as important players in the induction of immunologic tolerance in this organ. We show that hepatocytes possess the molecular machinery required for the cross-presentation of extracellular antigens. Using a derivative of the model antigen ovalbumin (OVA) covalently modified with a polymer containing multiple N-acetylgalactosamine residues (pGal-OVA) that enhance extracellular antigen uptake by mimicking the glycome of apoptotic debris, we show efficient hepatocyte-dependent induction of cross-tolerance of both adoptively transferred OT-I cells and endogenous OVA-specific CD8+ T lymphocytes, for example inducing tolerance to OVA-expressing skin transplants. Our study confirms that hepatocytes are capable of inducing peripheral tolerogenesis and provides proof of concept that they may be a valuable candidate for in vivo targeted tolerogenic treatments.


Assuntos
Acetilgalactosamina/imunologia , Antígenos/imunologia , Linfócitos T CD8-Positivos/imunologia , Apresentação Cruzada/imunologia , Hepatócitos/imunologia , Tolerância Imunológica/imunologia , Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/imunologia , Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/metabolismo , Transferência Adotiva/métodos , Animais , Apresentação do Antígeno/imunologia , Células Cultivadas , Hepatócitos/citologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Ovalbumina/imunologia , Transplante de Pele/métodos , Solubilidade , Proteínas de Transporte Vesicular/imunologia , Proteínas de Transporte Vesicular/metabolismo
18.
Biochemistry ; 60(11): 825-846, 2021 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-33705117

RESUMO

Structure-based antibody and antigen design has advanced greatly in recent years, due not only to the increasing availability of experimentally determined structures but also to improved computational methods for both prediction and design. Constant improvements in performance within the Rosetta software suite for biomolecular modeling have given rise to a greater breadth of structure prediction, including docking and design application cases for antibody and antigen modeling. Here, we present an overview of current protocols for antibody and antigen modeling using Rosetta and exemplify those by detailed tutorials originally developed for a Rosetta workshop at Vanderbilt University. These tutorials cover antibody structure prediction, docking, and design and antigen design strategies, including the addition of glycans in Rosetta. We expect that these materials will allow novice users to apply Rosetta in their own projects for modeling antibodies and antigens.


Assuntos
Anticorpos/imunologia , Antígenos/imunologia , Modelos Biológicos , Polissacarídeos/imunologia
19.
Ann Allergy Asthma Immunol ; 126(6): 630-638, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33716146

RESUMO

OBJECTIVE: Treatments with Food and Drug Administration-approved blocking antibodies targeting inhibitory cytotoxic T lymphocyte antigen 4 (CTLA4), programmed cell death protein 1 (PD-1) receptor, or programmed cell death ligand 1 (PD-L1), collectively named checkpoint inhibitors (CPIs), have been successful in producing long-lasting remissions, even in patients with advanced-stage cancers. However, these treatments are often accompanied by undesirable autoimmune and inflammatory side effects, sometimes bringing severe consequences for the patient. Rapid expansion of clinical applications necessitates a more nuanced understanding of CPI function in health and disease to develop new strategies for minimizing the negative side effects, while preserving the immunotherapeutic benefit. DATA SOURCES: This review summarizes a new paradigm-shifting approach to cancer immunotherapy with the focus on the mechanism of action of immune checkpoints (CTLA4, PD-1, and its ligands). STUDY SELECTIONS: We performed a literature search and identified relevant recent clinical reports, experimental research, and review articles. RESULTS: This review highlights our understanding of the CPI mechanism of action on cellular and molecular levels. The authors also discuss how reactivation of T cell responses through the inhibition of CTLA4, PD-1, and PD-L1 is used for tumor inhibition in cancer immunotherapy. CONCLUSION: Mechanisms of PD-1 and CTLA4 blockade and normal biological functions of these molecules are highly complex and require additional studies that will be critical for developing new approaches to dissociate the benefits of checkpoint blockade from off-target effects of the immune reactivation that leads to immune-related adverse events.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia , Neoplasias/terapia , Animais , Antígenos/imunologia , Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunoterapia/efeitos adversos , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
20.
Front Immunol ; 12: 614246, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33746958

RESUMO

Transplacental transfer of antibodies is essential for conferring protection in newborns against infectious diseases. We assessed the impact of different factors, including gestational age and maternal infections such as HIV and malaria, on the efficiency of cord blood levels and placental transfer of IgG subclasses. We measured total IgG and IgG subclasses by quantitative suspension array technology against 14 pathogens and vaccine antigens, including targets of maternal immunization, in 341 delivering HIV-uninfected and HIV-infected mother-infant pairs from southern Mozambique. We analyzed the association of maternal HIV infection, Plasmodium falciparum exposure, maternal variables and pregnancy outcomes on cord antibody levels and transplacental transfer. Our results show that maternal antibody levels were the main determinant of cord antibody levels. Univariable and multivariable analysis showed that HIV reduced the placental transfer and cord levels of IgG and IgG1 principally, but also IgG2 to half of the antigens tested. P. falciparum exposure and prematurity were negatively associated with cord antibody levels and placental transfer, but this was antigen-subclass dependent. Our findings suggest that lower maternally transferred antibodies may underlie increased susceptibility to infections of HIV-exposed infants. This could affect efficacy of maternal vaccination, especially in sub-Saharan Africa, where there is a high prevalence of HIV, malaria and unfavorable environmental factors.


Assuntos
Anticorpos/imunologia , Infecções por HIV/epidemiologia , Infecções por HIV/imunologia , Troca Materno-Fetal/imunologia , Placenta/imunologia , Adulto , Antígenos/imunologia , Terapia Antirretroviral de Alta Atividade , Feminino , Sangue Fetal/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Imunidade Materno-Adquirida , Imunoglobulina G/imunologia , Moçambique , Placenta/metabolismo , Gravidez , Transporte Proteico , Fatores Sexuais , Vacinas/imunologia , Adulto Jovem
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