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1.
Immunity ; 41(4): 592-604, 2014 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-25308333

RESUMO

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a pattern-recognition receptor for a variety of endogenous and exogenous ligands. However, LOX-1 function in the host immune response is not fully understood. Here, we report that LOX-1 expressed on dendritic cells (DCs) and B cells promotes humoral responses. On B cells LOX-1 signaling upregulated CCR7, promoting cellular migration toward lymphoid tissues. LOX-1 signaling on DCs licensed the cells to promote B cell differentiation into class-switched plasmablasts and led to downregulation of chemokine receptor CXCR5 and upregulation of chemokine receptor CCR10 on plasmablasts, enabling their exit from germinal centers and migration toward local mucosa and skin. Finally, we found that targeting influenza hemagglutinin 1 (HA1) subunit to LOX-1 elicited HA1-specific protective antibody responses in rhesus macaques. Thus, LOX-1 expressed on B cells and DC cells has complementary functions to promote humoral immune responses.


Assuntos
Linfócitos B/imunologia , Células Dendríticas/imunologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Switching de Imunoglobulina/imunologia , Receptores Depuradores Classe E/imunologia , Animais , Formação de Anticorpos/imunologia , Diferenciação Celular/imunologia , Movimento Celular/imunologia , Centro Germinativo/citologia , Humanos , Imunoglobulina A/biossíntese , Imunoglobulina G/biossíntese , Imunoglobulina M/biossíntese , Ativação Linfocitária/imunologia , Macaca mulatta , Masculino , Mucosa/citologia , Receptores CCR10/biossíntese , Receptores CCR7/biossíntese , Receptores CXCR5/biossíntese , Receptores Depuradores Classe E/biossíntese , Transdução de Sinais/imunologia , Pele/citologia
2.
Clin Immunol ; 232: 108874, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34740841

RESUMO

Female sex hormones affect the immune response in the lower female genital tract. To understand their mechanisms of action, it is essential to define cell types expressing estrogen receptor (ER) and/or progesterone receptor (PR) in the human vaginal mucosa (VM). Here, we report that none of the dendritic cell (DC) subsets in the human VM expressed ERα or PR in situ. However, they were capable of expressing ERα, but not PR, after in vitro culture of the whole VM tissues. Similarly, ERα and/or PR expression by T cells in the VM tissues was also inducible rather than constitutive. In contrast, ERα and/or PR were constitutively expressed in HLA-DR- non-immune cell types (vimentin+, desmin+, or CD10+). These new findings will help us understand the mechanisms of action of female sex hormones in the modulation of immune response in the human VM and lower female genital tract.


Assuntos
Mucosa/metabolismo , Receptores de Estrogênio/biossíntese , Receptores de Progesterona/biossíntese , Vagina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Dendríticas/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Linfócitos T/metabolismo
3.
Nat Immunol ; 9(5): 551-7, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18376401

RESUMO

Although plasmacytoid dendritic cells (pDCs) respond to virus replication in a nonspecific way by producing large amounts of type I interferon, a rapid, direct function for pDCs in activating antiviral lymphocytes is less apparent. Here we show that pDCs were able to rapidly initiate antigen-specific antiviral CD8+ T cell responses. After being exposed to virus, pDCs efficiently and rapidly internalized exogenous viral antigens and then presented those antigens on major histocompatibility complex (MHC) class I to CD8+ T cells. Processing of exogenous antigen occurred in endocytic organelles and did not require transit of antigen to the cytosol. Intracellular stores of MHC class I partially localized together with the transferrin receptor and internalized transferrin in endosomes, which suggested that such recycling endosomes are sites for loading peptide onto MHC class I or for peptide transit. Our data demonstrate that pDCs use 'ready-made' stores of MHC class I to rapidly present exogenous antigen to CD8+ T cells.


Assuntos
Células Dendríticas/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Apresentação de Antígeno , Antígenos Virais/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Cultivadas , Apresentação Cruzada , Endossomos/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Vírus da Influenza A/imunologia , Leucócitos Mononucleares , Ativação Linfocitária , Organelas/imunologia , Complexo de Endopeptidases do Proteassoma , Receptores da Transferrina/metabolismo
4.
Immunity ; 30(1): 120-9, 2009 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-19144318

RESUMO

Mucosal immunoglobulin A (IgA) secreted by local plasma cells (PCs) is a critical component of mucosal immunity. Although IgA class switching can occur at mucosal sites, high-affinity PCs are optimally generated in germinal centers (GCs) in a T cell-dependent fashion. However, how CD4(+) helper T cells induce mucosal-homing IgA-PCs remains unclear. Here, we show that transforming growth factor beta1 (TGFbeta1) and interleukin 21 (IL-21), produced by follicular helper T cells (Tfh), synergized to generate abundant IgA-plasmablasts (PBs). In the presence of IL-21, TGFbeta1 promoted naive B cell proliferation and differentiation and overrode IL-21-induced IgG class switching in favor of IgA. Furthermore, TGFbeta1 and IL-21 downregulated CXCR5 while upregulating CCR10 on plasmablasts, enabling their exit from GCs and migration toward local mucosa. This was supported by the presence of CCR10(+)IgA(+)PBs in tonsil GCs. These findings show that Tfh contribute to mucosal IgA. Thus, mucosal vaccines should aim to induce robust Tfh responses.


Assuntos
Quimiotaxia de Leucócito , Imunoglobulina A/metabolismo , Mucosa/imunologia , Plasmócitos/imunologia , Linfócitos T/imunologia , Linfócitos B/imunologia , Diferenciação Celular , Proliferação de Células , Criança , Regulação para Baixo , Ensaio de Imunoadsorção Enzimática , Humanos , Imunoglobulina A/classificação , Interleucina-2/genética , Interleucina-2/metabolismo , Interleucinas/fisiologia , Reação em Cadeia da Polimerase , Receptores CCR10/metabolismo , Receptores CXCR5/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Padrões de Referência , Fator de Crescimento Transformador beta1/fisiologia , Regulação para Cima
5.
J Immunol ; 195(4): 1723-31, 2015 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-26123355

RESUMO

Dendritic cells (DCs) can induce and control host immune responses. DC subset-dependent functional specialties and their ability to display functional plasticity, which is mainly driven by signals via pattern recognition receptors, identify DCs as immune orchestrators. A pattern recognition receptor, Dectin-1, is expressed on myeloid DCs and known to play important roles in Th17 induction and activation during fungal and certain bacterial infections. In this study, we first demonstrate that human plasmacytoid DCs express Dectin-1 in both mRNA and protein levels. More interestingly, Dectin-1-activated plasmacytoid DCs promote Th2-type T cell responses, whereas Dectin-1-activated myeloid DCs decrease Th2-type T cell responses. Such contrasting outcomes of Th2-type T cell responses by the two DC subsets are mainly due to their distinct abilities to control surface OX40L expression in response to ß-glucan. This study provides new insights for the regulation of host immune responses by Dectin-1 expressed on DCs.


Assuntos
Células Dendríticas/metabolismo , Expressão Gênica , Lectinas Tipo C/genética , Células Mieloides/metabolismo , Células Th2/metabolismo , Citocinas/biossíntese , Células Dendríticas/imunologia , Humanos , Memória Imunológica , Vírus da Influenza A/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lectinas Tipo C/química , Lectinas Tipo C/metabolismo , Dados de Sequência Molecular , Células Mieloides/imunologia , Ligante OX40/metabolismo , Tonsila Palatina/citologia , Tonsila Palatina/imunologia , Tonsila Palatina/metabolismo , Ligação Proteica , Proteínas Tirosina Quinases/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Baço/citologia , Baço/imunologia , Baço/metabolismo , Quinase Syk , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Células Th2/imunologia , beta-Glucanas/metabolismo
6.
J Immunol ; 192(12): 5776-88, 2014 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-24835401

RESUMO

Recent compelling evidence indicates that Th17 confer host immunity against a variety of microbes, including extracellular and intracellular pathogens. Therefore, understanding mechanisms for the induction and activation of Ag-specific Th17 is important for the rational design of vaccines against pathogens. To study this, we employed an in vitro system in which influenza hemagglutinin (HA) 1 was delivered to dendritic cells (DCs) via Dectin-1 using anti-human Dectin-1 (hDectin-1)-HA1 recombinant fusion proteins. We found that healthy individuals maintained broad ranges of HA1-specific memory Th17 that were efficiently activated by DCs targeted with anti-hDectin-1-HA1. Nonetheless, these DCs were not able to induce a significant level of HA1-specific Th17 responses even in the presence of the Th17-promoting cytokines IL-1ß and IL-6. We further found that the induction of surface IL-1R1 expression by signals via TCRs and common γ-chain receptors was essential for naive CD4(+) T cell differentiation into HA1-specific Th17. This process was dependent on MyD88, but not IL-1R-associated kinase 1/4. Thus, interruptions in STAT3 or MyD88 signaling led to substantially diminished HA1-specific Th17 induction. Taken together, the de novo generation of pathogen-specific human Th17 requires complex, but complementary, actions of multiple signals. Data from this study will help us design a new and effective vaccine strategy that can promote Th17-mediated immunity against microbial pathogens.


Assuntos
Antígenos Virais/imunologia , Células Dendríticas/imunologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Lectinas Tipo C/imunologia , Células Th17/imunologia , Células Dendríticas/citologia , Feminino , Humanos , Interleucina-1beta/imunologia , Interleucina-6/imunologia , Masculino , Fator 88 de Diferenciação Mieloide/imunologia , Células Th17/citologia
7.
Front Cell Dev Biol ; 12: 1442052, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39129784

RESUMO

PBX1 is a transcription factor that can promote the occurrence of various tumors and play a reg-ulatory role in tumor growth, metastasis, invasion, and drug resistance. Furthermore, a variant generated by fusion of E2A and PBX1, E2A-PBX1, has been found in 25% of patients with childhood acute lymphoblastic leukemia. Thus, PBX1 is a potential therapeutic target for many cancers. Here, we describe the structure of PBX1 and E2A-PBX1 as well as the molecular mecha-nisms whereby these proteins promote tumorigenesis to provide future research directions for developing new treatments. We show that PBX1 and E2A-PBX1 induce the development of highly malignant and difficult-to-treat solid and blood tumors. The development of specific drugs against their targets may be a good therapeutic strategy for PBX1-related cancers. Furthermore, we strongly recommend E2A-PBX1 as one of the genes for prenatal screening to reduce the incidence of childhood hematological malignancies.

8.
bioRxiv ; 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-39005456

RESUMO

The interaction between antigens and antibodies (B cell receptors, BCRs) is the key step underlying the function of the humoral immune system in various biological contexts. The capability to profile the landscape of antigen-binding affinity of a vast number of BCRs will provide a powerful tool to reveal novel insights at unprecedented levels and will yield powerful tools for translational development. However, current experimental approaches for profiling antibody-antigen interactions are costly and time-consuming, and can only achieve low-to-mid throughput. On the other hand, bioinformatics tools in the field of antibody informatics mostly focus on optimization of antibodies given known binding antigens, which is a very different research question and of limited scope. In this work, we developed an innovative Artificial Intelligence tool, Cmai, to address the prediction of the binding between antibodies and antigens that can be scaled to high-throughput sequencing data. Cmai achieved an AUROC of 0.91 in our validation cohort. We devised a biomarker metric based on the output from Cmai applied to high-throughput BCR sequencing data. We found that, during immune-related adverse events (irAEs) caused by immune-checkpoint inhibitor (ICI) treatment, the humoral immunity is preferentially responsive to intracellular antigens from the organs affected by the irAEs. In contrast, extracellular antigens on malignant tumor cells are inducing B cell infiltrations, and the infiltrating B cells have a greater tendency to co-localize with tumor cells expressing these antigens. We further found that the abundance of tumor antigen-targeting antibodies is predictive of ICI treatment response. Overall, Cmai and our biomarker approach filled in a gap that is not addressed by current antibody optimization works nor works such as AlphaFold3 that predict the structures of complexes of proteins that are known to bind.

9.
bioRxiv ; 2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-38105939

RESUMO

Profiling the binding of T cell receptors (TCRs) of T cells to antigenic peptides presented by MHC proteins is one of the most important unsolved problems in modern immunology. Experimental methods to probe TCR-antigen interactions are slow, labor-intensive, costly, and yield moderate throughput. To address this problem, we developed pMTnet-omni, an Artificial Intelligence (AI) system based on hybrid protein sequence and structure information, to predict the pairing of TCRs of αß T cells with peptide-MHC complexes (pMHCs). pMTnet-omni is capable of handling peptides presented by both class I and II pMHCs, and capable of handling both human and mouse TCR-pMHC pairs, through information sharing enabled this hybrid design. pMTnet-omni achieves a high overall Area Under the Curve of Receiver Operator Characteristics (AUROC) of 0.888, which surpasses competing tools by a large margin. We showed that pMTnet-omni can distinguish binding affinity of TCRs with similar sequences. Across a range of datasets from various biological contexts, pMTnet-omni characterized the longitudinal evolution and spatial heterogeneity of TCR-pMHC interactions and their functional impact. We successfully developed a biomarker based on pMTnet-omni for predicting immune-related adverse events of immune checkpoint inhibitor (ICI) treatment in a cohort of 57 ICI-treated patients. pMTnet-omni represents a major advance towards developing a clinically usable AI system for TCR-pMHC pairing prediction that can aid the design and implementation of TCR-based immunotherapeutics.

10.
Immunohorizons ; 3(3): 110-120, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-31240276

RESUMO

Graft-versus-host disease (GVHD) is one of the major obstacles for the success of allogeneic hematopoietic stem cell transplantation. Here, we report that the interaction between OX40L and OX40 is of critical importance for both induction and progression of acute GVHD (aGVHD) driven by human T cells. Anti-human OX40L monoclonal antibody (hOX40L) treatment could thus effectively reduce the disease severity in a xenogeneic-aGVHD (x-aGVHD) model in both preventative and therapeutic modes. Mechanistically, blocking OX40L-OX40 interaction with an anti-hOX40L antibody reduces infiltration of human T cells in target organs, including liver, gut, lung, and skin. It also decreases IL-21- and TNF-producing T cell responses, while promoting regulatory T cell (Treg) responses without compromising the cytolytic activity of CD8+ T cells. Single blockade of hOX40L was thus more effective than dual blockade of IL-21 and TNF in reducing the severity of aGVHD as well as mortality. Data from this study indicate that OX40L-OX40 interactions play a central role in the pathogenesis of aGVHD induced by human T cells. Therapeutic strategies that can efficiently interrupt OX40L-OX40 interaction in patients might have potential to provide patients with an improved clinical benefit.


Assuntos
Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/metabolismo , Ligante OX40/metabolismo , Receptores OX40/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Doença Aguda , Animais , Anticorpos Monoclonais/farmacologia , Citocinas/metabolismo , Citotoxicidade Imunológica/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Progressão da Doença , Etanercepte/farmacologia , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/patologia , Humanos , Interleucinas/antagonistas & inibidores , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Leucócitos/metabolismo , Camundongos , Ligante OX40/antagonistas & inibidores , Ligação Proteica , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
11.
Artigo em Inglês | MEDLINE | ID: mdl-29507584

RESUMO

BACKGROUND: T cells play a central role in chronic inflammation in asthma. However, the roles of individual subsets of T cells in the pathology of asthma in patients remain to be better understood. METHODS: We investigated the potential signatures of T cell subset phenotypes in asthma using fresh whole blood from adult atopic asthma patients (n = 43) and non-asthmatic control subjects (n = 22). We further assessed their potential clinical implications by correlating asthma severity. RESULTS: We report four major features of CD4+ T cells in the blood of atopic asthma patients. First, patients had a profound increase of CCR7+ memory CD4+ T cells, but not CCR7- memory CD4+ T cells. Second, an increase in CCR4+ CD4+ T cells in patients was mainly attributed to the increase of CCR7+ memory CD4+ T cells. Accordingly, the frequency of CCR4+CCR7+ memory CD4+ T cells correlated with asthma severity. Current common asthma therapeutics (including corticosteroids) were not able to affect the frequency of CCR4+CCR7+ memory CD4+ T cell subsets. Third, patients had an increase of Tregs, as assessed by measuring CD25, Foxp3, IL-10 and CTLA-4 expression. However, asthma severity was inversely correlated only with the frequency of CTLA-4+ CD4+ T cells. Lastly, patients and control subjects have similar frequencies of CD4+ T cells that express CCR5, CCR6, CXCR3, CXCR5, CD11a, or α4 integrin. However, the frequency of α4+ CD4+ T cells in patients correlated with asthma severity. CONCLUSIONS: CCR4+CCR7+ memory, but not CCR4+CCR7- memory, α4+, and CTLA4+ CD4+ T cells in patients show significant clinical implications in atopic asthma. Current common therapeutics cannot alter the frequency of such CD4+ T cell subsets in adult atopic asthma patients.

12.
EBioMedicine ; 5: 46-58, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27077111

RESUMO

Dendritic cells (DCs) are major antigen-presenting cells that can efficiently prime and cross-prime antigen-specific T cells. Delivering antigen to DCs via surface receptors is thus an appealing strategy to evoke cellular immunity. Nonetheless, which DC surface receptor to target to yield the optimal CD8(+) and CD4(+) T cell responses remains elusive. Herein, we report the superiority of CD40 over 9 different lectins and scavenger receptors at evoking antigen-specific CD8(+) T cell responses. However, lectins (e.g., LOX-1 and Dectin-1) were more efficient than CD40 at eliciting CD4(+) T cell responses. Common and distinct patterns of subcellular and intracellular localization of receptor-bound αCD40, αLOX-1 and αDectin-1 further support their functional specialization at enhancing antigen presentation to either CD8(+) or CD4(+) T cells. Lastly, we demonstrate that antigen targeting to CD40 can evoke potent antigen-specific CD8(+) T cell responses in human CD40 transgenic mice. This study provides fundamental information for the rational design of vaccines against cancers and viral infections.


Assuntos
Apresentação de Antígeno/imunologia , Ligante de CD40/imunologia , Células Dendríticas/imunologia , Imunoterapia Ativa , Ativação Linfocitária/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Humanos , Lectinas/imunologia , Lectinas Tipo C/imunologia , Camundongos , Camundongos Transgênicos , Proteínas Recombinantes de Fusão/imunologia , Receptores Depuradores Classe E/imunologia
13.
Cancer Immunol Res ; 4(10): 823-834, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27485136

RESUMO

Human papillomavirus (HPV), particularly HPV16 and HPV18, can cause cancers in diverse anatomical sites, including the anogenital and oropharyngeal (throat) regions. Therefore, development of safe and clinically effective therapeutic vaccines is an important goal. Herein, we show that a recombinant fusion protein of a humanized antibody to CD40 fused to HPV16.E6/7 (αCD40-HPV16.E6/7) can evoke HPV16.E6/7-specific CD8+ and CD4+ T-cell responses in head-and-neck cancer patients in vitro and in human CD40 transgenic (hCD40Tg) mice in vivo The combination of αCD40-HPV16.E6/7 and poly(I:C) efficiently primed HPV16.E6/7-specific T cells, particularly CD8+ T cells, in hCD40Tg mice. Inclusion of montanide enhanced HPV16.E6/7-specific CD4+, but not CD8+, T-cell responses. Poly(I:C) plus αCD40-HPV16.E6/7 was sufficient to mount both preventative and therapeutic immunity against TC-1 tumors in hCD40Tg mice, significantly increasing the frequency of HPV16-specific CD8+ CTLs in the tumors, but not in peripheral blood. In line with this, tumor volume inversely correlated with the frequency of HPV16.E6/7-specific CD8+ T cells in tumors, but not in blood. These data suggest that CD40-targeting vaccines for HPV-associated malignancies can provide a highly immunogenic platform with a strong likelihood of clinical benefit. Data from this study offer strong support for the development of CD40-targeting vaccines for other cancers in the future. Cancer Immunol Res; 4(10); 823-34. ©2016 AACR.


Assuntos
Antígenos CD40/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/imunologia , Neoplasias de Cabeça e Pescoço/imunologia , Vacinas contra Papillomavirus/imunologia , Animais , Antivirais/imunologia , Linfócitos T CD4-Positivos/imunologia , Feminino , Papillomavirus Humano 16/imunologia , Humanos , Imunidade Celular , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Poli I-C/imunologia , Proteínas Recombinantes de Fusão/imunologia , Células Tumorais Cultivadas , Neoplasias do Colo do Útero/prevenção & controle , Neoplasias do Colo do Útero/virologia , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Immunol Lett ; 168(1): 89-97, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26381186

RESUMO

Toll-like receptor 7 (TLR7) agonists are of interest as vaccine adjuvants and cancer therapeutics. Therefore, development of new TLR7 agonists that can efficiently promote host immune responses without evoking side effects is of great importance. Here, we describe two new compounds, J4 and F4, which elicit intracellular signaling exclusively via TLR7. Interestingly, both J4 and F4 induced less cytokine secretion (IL-1ß, IL-6, IL-10, IL-12p40, TNFα, and IL-12p70) from myeloid dendritic cells (mDCs) and monocytes than CL075 and R848; however, they all generated similar levels of phenotype maturation of antigen presenting cells (APCs), including plasmacytoid DCs. We further found that J4- and F4-induced APC activation was largely dependent on the activation of NF-κB and p38. Lastly, J4 and F4 could efficiently promote B cell proliferation and plasmablast differentiation as well as antigen-specific CD8(+) T cell responses in human in vitro. Therefore, these new TLR7 agonists could be employed to facilitate the development of new therapeutics and vaccine adjuvants against cancers and microbial infections.


Assuntos
Adenosina/análogos & derivados , Adjuvantes Imunológicos/farmacologia , Imunidade Celular/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Receptor 7 Toll-Like/agonistas , Adenosina/química , Adenosina/farmacologia , Adjuvantes Imunológicos/química , Células Apresentadoras de Antígenos/efeitos dos fármacos , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citocinas/imunologia , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Citometria de Fluxo , Células HEK293 , Humanos , Imunidade Celular/imunologia , Imunidade Humoral/imunologia , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Estrutura Molecular , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/metabolismo , NF-kappa B/imunologia , NF-kappa B/metabolismo , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/metabolismo
15.
In Vivo ; 16(6): 451-7, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12494889

RESUMO

A6 is an eight amino acid peptide derived from the non-receptor binding region of urokinase plasminogen activator (uPA), which interferes with the uPA/uPA receptor system. A6 has been synthesized as a potential anti-angiogenic, anti-cancer agent. The current study has investigated the potential therapeutic activity of A6 in the Lewis lung carcinoma (3LL) model of pulmonary metastasis. A6 was found to have direct anti-tumor activity against established 3LL pulmonary metastases at a low tumor burden (10-20 colonies per lung) and was therapeutic in combination with cyclophosphamide at high tumor burdens (> 100 colonies per lung). Mechanistic studies have revealed that A6 directly inhibits the invasion of 3LL cells through a Matrigel model basement membrane by 40-45%. Moreover, treatment with either A6 or doxorubicin resulted in thicker tubes in endothelial tube formation studies. Our results suggest that A6, by virtue of its anti-invasive and anti-angiogenic properties, might work additively or synergistically with chemotherapeutic agents and thereby contribute to enhanced therapy of established 3LL cancer metastases.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Fragmentos de Peptídeos/uso terapêutico , Ativador de Plasminogênio Tipo Uroquinase/uso terapêutico , Animais , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/secundário , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Sinergismo Farmacológico , Quimioterapia Combinada , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Humanos , Técnicas In Vitro , Camundongos , Invasividade Neoplásica/prevenção & controle , Transplante de Neoplasias , Neovascularização Patológica/prevenção & controle , RNA Mensageiro/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Receptores de Ativador de Plasminogênio Tipo Uroquinase , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Ativador de Plasminogênio Tipo Uroquinase/genética , Ativador de Plasminogênio Tipo Uroquinase/metabolismo
16.
Clin Vaccine Immunol ; 21(12): 1668-80, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25298110

RESUMO

Despite the availability of annually formulated vaccines, influenza virus infection remains a worldwide public health burden. Therefore, it is important to develop preclinical challenge models that enable the evaluation of vaccine candidates while elucidating mechanisms of protection. Here, we report that naive rhesus macaques challenged with 2009 pandemic H1N1 (pH1N1) influenza virus do not develop observable clinical symptoms of disease but develop a subclinical biphasic fever on days 1 and 5 to 6 postchallenge. Whole blood microarray analysis further revealed that interferon activity was associated with fever. We then tested whether type I interferon activity in the blood is a correlate of vaccine efficacy. The animals immunized with candidate vaccines carrying hemagglutinin (HA) or nucleoprotein (NP) exhibited significantly reduced interferon activity on days 5 to 6 postchallenge. Supported by cellular and serological data, we conclude that blood interferon activity is a prominent marker that provides a convenient metric of influenza virus vaccine efficacy in the subclinical rhesus macaque model.


Assuntos
Anticorpos Antivirais/sangue , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Animais , Humanos , Imunização , Macaca mulatta , Vacinação
17.
Nat Commun ; 5: 5283, 2014 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-25335753

RESUMO

The mechanisms by which microbial vaccines interact with human APCs remain elusive. Herein, we describe the transcriptional programs induced in human DCs by pathogens, innate receptor ligands and vaccines. Exposure of DCs to influenza, Salmonella enterica and Staphylococcus aureus allows us to build a modular framework containing 204 transcript clusters. We use this framework to characterize the responses of human monocytes, monocyte-derived DCs and blood DC subsets to 13 vaccines. Different vaccines induce distinct transcriptional programs based on pathogen type, adjuvant formulation and APC targeted. Fluzone, Pneumovax and Gardasil, respectively, activate monocyte-derived DCs, monocytes and CD1c+ blood DCs, highlighting APC specialization in response to vaccines. Finally, the blood signatures from individuals vaccinated with Fluzone or infected with influenza reveal a signature of adaptive immunity activation following vaccination and symptomatic infections, but not asymptomatic infections. These data, offered with a web interface, may guide the development of improved vaccines.


Assuntos
Células Dendríticas/citologia , Células Dendríticas/microbiologia , Transcrição Gênica , Vacinas/química , Algoritmos , Animais , Antígenos CD1/metabolismo , Antígenos de Superfície/metabolismo , Análise por Conglomerados , Citocinas/metabolismo , Células Dendríticas/metabolismo , Cães , Perfilação da Expressão Gênica , Glicoproteínas/metabolismo , Humanos , Vírus da Influenza A Subtipo H1N1 , Interleucina-4/metabolismo , Células Madin Darby de Rim Canino , Monócitos/citologia , Monócitos/metabolismo , Análise de Componente Principal , Salmonella enterica , Staphylococcus aureus , Trombomodulina , Transcriptoma
18.
AIDS ; 27(13): 2041-51, 2013 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-23615121

RESUMO

OBJECTIVE: Targeting HIV antigens directly to dendritic cells using monoclonal antibodies against cell-surface receptors has been shown to evoke potent cellular immunity in animal models. The objective of this study was to configure an anti-human CD40 antibody fused to a string of five highly conserved CD4 and CD8 T-cell epitope-rich regions of HIV-1 Gag, Nef and Pol (αCD40.HIV5pep), and then to demonstrate the capacity of this candidate therapeutic vaccine to target these HIV peptide antigens to human dendritic cells to expand functional HIV-specific T cells. METHODS: Antigen-specific cytokine production using intracellular flow cytometry and multiplex bead-based assay, and suppression of viral inhibition, were used to characterize the T cells expanded by αCD40.HIV5pep from HIV-infected patient peripheral blood mononuclear cell (PBMC) and dendritic cell/T-cell co-cultures. RESULTS: This candidate vaccine expands memory CD4 and CD8 T cells specific to multiple epitopes within all five peptide regions across a wide range of major histocompatibility complex (MHC) haplotypes from HIV-infected patient PBMC and dendritic cell/T-cell co-cultures. These in vitro expanded HIV antigen-specific CD4 and CD8 T cells produce multiple cytokines and chemokines. αCD40.HIV5pep-expanded CD8 T cells have characteristics of cytotoxic effector cells and are able to kill autologous target cells and suppress HIV-1 replication in vitro. CONCLUSION: Our data demonstrate the therapeutic potential of this CD40-targeting HIV candidate vaccine in inducing a broad repertoire of multifunctional T cells in patients.


Assuntos
Vacinas contra a AIDS/imunologia , Linfócitos T CD4-Positivos/imunologia , Antígenos CD40/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Antígenos HIV/imunologia , HIV-1/imunologia , Vacinas contra a AIDS/genética , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/metabolismo , Antígenos CD40/metabolismo , Proliferação de Células , Técnicas de Cocultura , Antígenos HIV/genética , Antígenos HIV/metabolismo , HIV-1/genética , Humanos , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/metabolismo
19.
J Exp Med ; 209(7): 1335-48, 2012 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-22689824

RESUMO

The development of autoantibodies is a hallmark of systemic lupus erythematosus (SLE). SLE serum can induce monocyte differentiation into dendritic cells (DCs) in a type I IFN-dependent manner. Such SLE-DCs activate T cells, but whether they promote B cell responses is not known. In this study, we demonstrate that SLE-DCs can efficiently stimulate naive and memory B cells to differentiate into IgG- and IgA-plasmablasts (PBs) resembling those found in the blood of SLE patients. SLE-DC-mediated IgG-PB differentiation is dependent on B cell-activating factor (BAFF) and IL-10, whereas IgA-PB differentiation is dependent on a proliferation-inducing ligand (APRIL). Importantly, SLE-DCs express CD138 and trans-present CD138-bound APRIL to B cells, leading to the induction of IgA switching and PB differentiation in an IFN-α-independent manner. We further found that this mechanism of providing B cell help is relevant in vivo, as CD138-bound APRIL is expressed on blood monocytes from active SLE patients. Collectively, our study suggests that a direct myeloid DC-B cell interplay might contribute to the pathogenesis of SLE.


Assuntos
Diferenciação Celular/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Monócitos/imunologia , Plasmócitos/imunologia , Adolescente , Autoanticorpos/imunologia , Autoanticorpos/farmacologia , Fator Ativador de Células B/imunologia , Fator Ativador de Células B/metabolismo , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Criança , Pré-Escolar , Técnicas de Cocultura , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Citometria de Fluxo , Humanos , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Lactente , Interleucina-10/imunologia , Interleucina-10/metabolismo , Lúpus Eritematoso Sistêmico/sangue , Masculino , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Plasmócitos/efeitos dos fármacos , Plasmócitos/metabolismo , Soro/imunologia , Sindecana-1/imunologia , Sindecana-1/metabolismo , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Adulto Jovem
20.
J Cell Biochem ; 88(3): 482-92, 2003 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-12532325

RESUMO

The proteasome is a multi-subunit protease complex that is involved in intracellular protein degradation in eukaryotes. Previously, we have reported that selective, synthetic chymotryptic proteasome inhibitors inhibit A-NK cell-mediated cytotoxicity by approximately 50%; however, the exact role of the proteasome in NK cell-mediated cytotoxicity remains unknown. Herein, we report that proteasome inhibitors, MG115 and MG132, decreased the proteasome chymotrypsin-like activity in the rat natural killer cell line RNK16 by 85% at a concentration of 5 microM. The viability of RNK16 cells was also reduced in the presence of these inhibitors. Both inhibitors induced the apoptosis of RNK16 cells, as shown by DNA fragmentation, caspase-3 activation and the appearance of sub-G-cell populations. An increase in the fraction of apoptotic cells was observed in a dose- and time-dependent manner in our studies. In addition, the activity of caspase-1, -2, -6, -7, -8, and -9, was increased following the treatment of RNK16 cells with these inhibitors. Further investigation revealed that the expression of Fas (CD95) protein on the RNK16 cell surface was increased after the treatment by MG115 or MG132, indicating that apoptosis induced by proteasome inhibitors in RNK16 cells might be mediated through the Fas (CD95)-mediated death pathway as well. Our studies indicate, for the first time, that proteasomal chymotryptic inhibitors can reduce natural killer cell viability and therefore indirectly inhibit cell-mediated cytotoxicity via the apoptosis-inducing properties of these agents.


Assuntos
Apoptose/fisiologia , Caspases/metabolismo , Células Matadoras Naturais/metabolismo , Complexos Multienzimáticos/antagonistas & inibidores , Receptor fas/metabolismo , Animais , Linhagem Celular , Cisteína Endopeptidases/metabolismo , Ativação Enzimática , Células Matadoras Naturais/citologia , Leupeptinas/metabolismo , Complexos Multienzimáticos/metabolismo , Inibidores de Proteases/metabolismo , Complexo de Endopeptidases do Proteassoma , Ratos
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