RESUMO
The activation of the complement system is a key initiating step in the protective innate immune-inflammatory response against injury, although it may also cause harm if left unchecked. The structurally related soluble complement inhibitors C4b-binding protein (C4BP) and factor H (FH) exert a tight regulation of the classical/lectin and alternative pathways of complement activation, respectively, attenuating the activity of the C3/C5 convertases and, consequently, avoiding serious damage to host tissues. We recently reported that the acute-phase C4BP isoform C4BP lacking the ß-chain plays a pivotal role in the modulation of the adaptive immune responses. In this study, we demonstrate that FH acts in the early stages of monocyte to dendritic cell (DC) differentiation and is able to promote a distinctive tolerogenic and anti-inflammatory profile on monocyte-derived DCs (MoDCs) challenged by a proinflammatory stimulus. Accordingly, FH-treated and LPS-matured MoDCs are characterized by altered cytoarchitecture, resembling immature MoDCs, lower expression of the maturation marker CD83 and the costimulatory molecules CD40, CD80, and CD86, decreased production of key proinflammatory Th1-cytokines (IL-12, TNF-α, IFN-γ, IL-6, and IL-8), and preferential production of immunomodulatory mediators (IL-10 and TGF-ß). Moreover, FH-treated MoDCs show low Ag uptake and, when challenged with LPS, display reduced CCR7 expression and chemotactic migration, impaired CD4(+) T cell alloproliferation, inhibition of IFN-γ secretion by the allostimulated T cells, and, conversely, induction of CD4(+)CD127(low/negative)CD25(high)Foxp3(+) regulatory T cells. Thus, this novel noncanonical role of FH as an immunological brake able to directly affect the function of MoDCs in an inflammatory environment may exhibit therapeutic potential in hypersensitivity, transplantation, and autoimmunity.
Assuntos
Células Dendríticas/imunologia , Tolerância Imunológica , Inflamação/imunologia , Monócitos/imunologia , Antígenos CD/metabolismo , Diferenciação Celular , Células Cultivadas , Quimiotaxia , Proteína de Ligação ao Complemento C4b/imunologia , Fator H do Complemento/imunologia , Citocinas/imunologia , Endocitose , Humanos , Linfócitos T Reguladores/imunologiaRESUMO
APOBEC3G (apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3G; A3G) is an innate defense protein showing activity against retroviruses and retrotransposons. Activated CD4(+) T cells are highly permissive for HIV-1 replication, whereas resting CD4(+) T cells are refractory. Dendritic cells (DCs), especially mature DCs, are also refractory. We investigated whether these differences could be related to a differential A3G expression and/or subcellular distribution. We found that A3G mRNA and protein expression is very low in resting CD4(+) T cells and immature DCs, but increases strongly following T-cell activation and DC maturation. The Apo-7 anti-A3G monoclonal antibody (mAb), which was specifically developed, confirmed these differences at the protein level and disclosed that A3G is mainly cytoplasmic in resting CD4(+) T cells and immature DCs. Nevertheless, A3G translocates to the nucleus in activated-proliferating CD4(+) T cells, yet remaining cytoplasmic in matured DCs, a finding confirmed by immunoblotting analysis of cytoplasmic and nuclear fractions. Apo-7 mAb was able to immunoprecipitate endogenous A3G allowing to detect complexes with numerous proteins in activated-proliferating but not in resting CD4(+) T cells. The results show for the first time the nuclear translocation of A3G in activated-proliferating CD4(+) T cells.
Assuntos
Desaminase APOBEC-3G/metabolismo , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular , Células Dendríticas/citologia , Ativação Linfocitária/imunologia , Desaminase APOBEC-3G/genética , Desaminase APOBEC-3G/imunologia , Animais , Anticorpos Monoclonais/metabolismo , Linhagem Celular , Núcleo Celular/metabolismo , Humanos , Imunoprecipitação , Camundongos Endogâmicos BALB C , Peso Molecular , Monócitos/citologia , Ligação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Frações Subcelulares/enzimologia , Regulação para Cima/genéticaRESUMO
The classical pathway complement regulator C4b-binding protein (C4BP) is composed of two polypeptides (α- and ß-chains), which form three plasma oligomers with different subunit compositions (α7ß1, α7ß0, and α6ß1). We show in this article that the C4BP α7ß0 isoform (hereafter called C4BP[ß(-)] [C4BP lacking the ß-chain]), overexpressed under acute-phase conditions, induces a semimature, tolerogenic state on human monocyte-derived dendritic cells (DCs) activated by a proinflammatory stimulus. C4BP isoforms containing ß-chain (α7ß1 and α6ß1; C4BP[ß(+)]) neither interfered with the normal maturation of DCs nor competed with C4BP(ß(-)) activity on these cells. Immature DCs (iDCs) treated with C4BP(ß(-)) retained high endocytic activity, but, upon LPS treatment, they did not upregulate surface expression of CD83, CD80, and CD86. Transcriptional profiling of these semimature DCs revealed that treatment with C4BP(ß(-)) prevented the induction of IDO and BIC-1, whereas TGF-ß1 expression was maintained to the level of iDCs. C4BP(ß(-))-treated DCs were also unable to release proinflammatory Th1 cytokines (IL-12, TNF-α, IFN-γ, IL-6, IL-8) and, conversely, increased IL-10 secretion. They prevented surface CCR7 overexpression and, accordingly, displayed reduced chemotaxis, being morphologically indistinguishable from iDCs. Moreover, C4BP(ß(-))-treated DCs failed to enhance allogeneic T cell proliferation, impairing IFN-γ production in these cells and, conversely, promoting CD4(+)CD127(low/neg)CD25(high)Foxp3(+) T cells. Deletion mutant analysis revealed that the complement control protein-6 domain of the α-chain is necessary for the tolerogenic activity of C4BP(ß(-)). Our data demonstrate a novel anti-inflammatory and immunomodulatory function of the complement regulator C4BP, suggesting a relevant role of the acute-phase C4BP(ß(-)) isoform in a number of pathophysiological conditions and potential applications in autoimmunity and transplantation.
Assuntos
Anti-Inflamatórios não Esteroides/química , Diferenciação Celular/imunologia , Proteína de Ligação ao Complemento C4b/fisiologia , Células Dendríticas/química , Células Dendríticas/imunologia , Antígenos de Histocompatibilidade/fisiologia , Diferenciação Celular/genética , Proteína de Ligação ao Complemento C4b/química , Proteína de Ligação ao Complemento C4b/genética , Células Dendríticas/patologia , Células HEK293 , Antígenos de Histocompatibilidade/química , Antígenos de Histocompatibilidade/genética , Humanos , Tolerância Imunológica/genética , Inflamação/genética , Inflamação/imunologia , Inflamação/prevenção & controle , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiologiaRESUMO
Introduction: Granulocytes are innate immune cells that play a key role in pathogen elimination. Recent studies revealed the diversity of granulocytes in terms of phenotype and function. In particular, a subset of granulocytes identified as low-density granulocytes (LDG) has been described in physiological conditions and with increased frequencies in several pathological contexts. However, the properties of LDG are still controversial as they vary according to the pathophysiological environment. Here we investigated the heterogeneity of granulocyte populations and the potential differences in phenotype and immunomodulatory capacity between LDG and normal density granulocytes (NDG) in people living with HIV-1 (PLWH). Methods: To this end, we developed an optimized method to purify LDG and NDG from a single blood sample, and performed in-depth, comparative phenotypic characterization of both granulocyte subtypes. We also assessed the impact of purification steps on the expression of cell surface markers on LDG by immunophenotyping them at different stages of isolation. Results: We identified 9 cell surface markers (CD16, CD32, CD89, CD62L, CD177, CD31, CD10, CXCR4 and CD172α) differentially expressed between LDG and NDG. Noteworthy, markers that distinguish the two subsets include receptors for the Fc part of IgG (CD16, CD32) and IgA (CD89). Importantly, we also highlighted that the purification procedure affects the expression of several cell surface markers (i.e.CD63, CD66b, ) which must be taken into account when characterizing LDG. Our work sheds new light on the properties of LDG in PLWH and provides an extensive characterization of this granulocyte subset in which Fc receptors are key discriminatory markers.
Assuntos
HIV-1 , Receptores Fc , Humanos , Receptores Fc/metabolismo , Granulócitos , Biomarcadores/metabolismo , FenótipoRESUMO
Multiple sclerosis (MS) is a chronic demyelinating autoimmune disease of the central nervous system. Current therapies decrease the frequency of relapses and limit, to some extent, but do not prevent disease progression. Hence, new therapeutic approaches that modify the natural course of MSneed to be identified. Tolerance induction to self-antigens using monocyte-derived dendritic cells (MDDCs) is a promising therapeutic strategy in autoimmunity. In this work, we sought to generate and characterize tolerogenic MDDCs (tolDCs) from relapsing-remitting (RR) MSpatients, loaded with myelin peptides as specific antigen, with the aim of developing immunotherapeutics for MS. MDDCs were generated from both healthy-blood donors and RR-MSpatients, and MDDCmaturation was induced with a proinflammatory cytokine cocktail in the absence or presence of 1α,25-dihydroxyvitamin-D(3) , a tolerogenicity-inducing agent. tolDCs were generated from monocytes of RR-MSpatients as efficiently as from monocytes of healthy subjects. The RR-MStolDCs expressed a stable semimature phenotype and an antiinflammatory profile as compared with untreated MDDCs. Importantly, myelin peptide-loaded tolDCs induced stable antigen-specific hyporesponsiveness in myelin-reactive T cells from RR-MS patients. These results suggest that myelin peptide-loaded tolDCs may be a powerful tool for inducing myelin-specific tolerance in RR-MS patients.
Assuntos
Células Dendríticas/imunologia , Imunoterapia Adotiva/métodos , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/terapia , Proteína Básica da Mielina/imunologia , Linfócitos T/imunologia , Adulto , Estudos de Casos e Controles , Diferenciação Celular/imunologia , Citocinas/imunologia , Células Dendríticas/citologia , Ensaio de Imunoadsorção Enzimática , Epitopos de Linfócito T/imunologia , Feminino , Citometria de Fluxo , Humanos , Tolerância Imunológica/imunologia , Masculino , Pessoa de Meia-Idade , Proteína Básica da Mielina/uso terapêutico , Projetos Piloto , Estatísticas não ParamétricasRESUMO
Notch signaling is involved in multiple cellular processes. Recent data also support the prominent role of Notch signaling in the regulation of the immune response. In this study, we analyzed the expression and function of Notch receptors and ligands on both human blood conventional dendritic cells (cDCs) and plasmacytoid DCs (pDCs). The expression and modulation upon TLR activation of Notch molecules partially differed between cDCs and pDCs, but functional involvement of the Notch pathway in both cell types was clearly revealed by specific inhibition using DAPT. Beyond the induction of Notch target genes and modulation of maturation markers, Notch pathway was also involved in a differential secretion of some specific cytokines/chemokines by DC subsets. Whereas Notch ligation induced IL-10 and CCL19 secretion in cDCs, Notch inhibition resulted in a diminished production of these proteins. With regard to pDCs, Notch activation induced TNF-α whereas Notch inhibition significantly abrogated the secretion of CCL19, CXCL9, CXCL10, and TNF-α. Additionally, Notch modulation of DC subsets differentially affected Th polarization of allostimulated T cells. Our results suggest that the Notch pathway may function as an additional mechanism controlling human DC responses, with differential activity on cDCs and pDCs. This control mechanism may ultimately contribute to define the local milieu promoted by these cells under the particular conditions of the immune response.
Assuntos
Citocinas/metabolismo , Células Dendríticas/imunologia , Receptores Notch/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Células Sanguíneas , Quimiocinas/metabolismo , Células Dendríticas/classificação , Células Epiteliais , Humanos , Receptores Notch/metabolismo , Transdução de Sinais/imunologiaRESUMO
PURPOSE OF REVIEW: This review summarizes recent studies reporting the induction of vaccinal effects by human immunodeficiency virus (HIV-1) antibody therapy. It also puts into perspective preclinical studies that have identified mechanisms involved in the immunomodulatory properties of antiviral antibodies. Finally, it discusses potential therapeutic interventions to enhance host adaptive immune responses in people living with HIV (PLWH) treated with broadly neutralizing antibodies (bNAbs). RECENT FINDINGS: Recent studies in promising clinical trials have shown that, in addition to controlling viremia, anti-HIV-1 bNAbs are able to enhance the host's humoral and cellular immune response. Such vaccinal effects, in particular the induction of HIV-1-specific CD8 + T-cell responses, have been observed upon treatment with two potent bNAbs (3BNC117 and 10-1074) alone or in combination with latency-reversing agents (LRA). While these studies reinforce the idea that bNAbs can induce protective immunity, the induction of vaccinal effects is not systematic and might depend on both the virological status of the patient as well as the therapeutic strategy chosen. SUMMARY: HIV-1 bNAbs can enhance adaptive host immune responses in PLWH. The challenge now is to exploit these immunomodulatory properties to design optimized therapeutic interventions to promote and enhance the induction of protective immunity against HIV-1 infection during bNAbs therapy.
Assuntos
Infecções por HIV , HIV-1 , Humanos , Infecções por HIV/tratamento farmacológico , Anticorpos Amplamente Neutralizantes , Anticorpos Neutralizantes , Anticorpos Anti-HIVRESUMO
Exosomes are secreted cellular vesicles that can induce specific CD4(+) T cell responses in vivo when they interact with competent antigen-presenting cells like mature dendritic cells (mDCs). The Trojan exosome hypothesis proposes that retroviruses can take advantage of the cell-encoded intercellular vesicle traffic and exosome exchange pathway, moving between cells in the absence of fusion events in search of adequate target cells. Here, we discuss recent data supporting this hypothesis, which further explains how DCs can capture and internalize retroviruses like HIV-1 in the absence of fusion events, leading to the productive infection of interacting CD4(+) T cells and contributing to viral spread through a mechanism known as trans-infection. We suggest that HIV-1 can exploit an exosome antigen-dissemination pathway intrinsic to mDCs, allowing viral internalization and final trans-infection of CD4(+) T cells. In contrast to previous reports that focus on the ability of immature DCs to capture HIV in the mucosa, this review emphasizes the outstanding role that mature DCs could have promoting trans-infection in the lymph node, underscoring a new potential viral dissemination pathway.
Assuntos
Células Dendríticas/imunologia , Células Dendríticas/virologia , Exossomos/imunologia , Infecções por HIV/imunologia , HIV/crescimento & desenvolvimento , Apresentação de Antígeno/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , HIV/imunologia , Humanos , Linfonodos/imunologia , Linfonodos/virologiaRESUMO
BACKGROUND: Low levels of plasma 25-hydroxyvitaminD (25(OH)D) are associated with a higher incidence of multiple sclerosis (MS) due to the immune suppressive properties of vitamin D.The aim of this study was to determine the correlation between plasma 25(OH)D concentrations and clinical and immunological variables in a cohort of multiple sclerosis patients. METHODS: Plasma 25(OH)D concentrations were evaluated in summer and winter in 15 primary progressive MS (PPMS) patients, 40 relapsing- remitting MS (RRMS) patients and 40 controls (HC). Protocol variables included demographic and clinical data, radiological findings and immunological variables (oligoclonal bands, HLADR15 and T-lymphocyte proliferation to a definite mix of 7 myelin peptides). RESULTS: During the winter, plasma concentrations were significantly lower in RRMS patients compared to HC, whereas no differences were found in summer. No relationships were found between plasma 25(OH)D concentrations and clinical or radiological variables. RRMS patients with a positive T-cell proliferation to a mix of myelin peptides (n = 31) had lower 25(OH)D concentrations. CONCLUSIONS: 25(OH)D is an immunomodulatory molecule that might have a regulatory role in T-cell proliferation to myelin peptides in RRMS patients.
Assuntos
Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Proteínas da Mielina/sangue , Estações do Ano , Linfócitos T/metabolismo , Vitamina D/sangue , Adulto , Feminino , Humanos , MasculinoRESUMO
The multiple mechanisms of action of antiviral monoclonal antibodies (mAbs) have made these molecules a potential therapeutic alternative for treating severe viral infections. In addition to their direct effect on viral propagation, several studies have shown that mAbs are able to enhance the host's adaptive immune response and generate long-lasting protective immunity. Such immunomodulatory effects occur in an Fc-dependent manner and rely on Fc-FcγR interactions. It is noteworthy that several FcγR-expressing cells have been shown to play a key role in enhancing humoral and cellular immune responses (so-called "vaccinal effects") in different experimental settings. This review recalls recent findings concerning the vaccinal effects induced by antiviral mAbs, both in several preclinical animal models and in patients treated with mAbs. It summarizes the main cellular and molecular mechanisms involved in these immunomodulatory properties of antiviral mAbs identified in different pathological contexts. It also describes potential therapeutic interventions to enhance host immune responses that could guide the design of improved mAb-based immunotherapies.
RESUMO
Exosomes are secreted cellular vesicles that can be internalized by dendritic cells (DCs), contributing to antigen-specific naive CD4(+) T-cell activation. Here, we demonstrate that human immunodeficiency virus type 1 (HIV-1) can exploit this exosome antigen-dissemination pathway intrinsic to mature DCs (mDCs) for mediating trans-infection of T lymphocytes. Capture of HIV-1, HIV-1 Gag-enhanced green fluorescent protein (eGFP) viral-like particles (VLPs), and exosomes by DCs was up-regulated upon maturation, resulting in localization within a CD81(+) compartment. Uptake of VLPs or exosomes could be inhibited by a challenge with either particle, suggesting that the expression of common determinant(s) on VLP or exosome surface is necessary for internalization by mDCs. Capture by mDCs was insensitive to proteolysis but blocked when virus, VLPs, or exosomes were produced from cells treated with sphingolipid biosynthesis inhibitors that modulate the lipid composition of the budding particles. Finally, VLPs and exosomes captured by mDCs were transmitted to T lymphocytes in an envelope glycoprotein-independent manner, underscoring a new potential viral dissemination pathway.
Assuntos
Células Dendríticas/virologia , Endocitose/fisiologia , Exossomos/fisiologia , HIV-1/fisiologia , Interações Hospedeiro-Patógeno/fisiologia , Microdomínios da Membrana/fisiologia , Internalização do Vírus , Apresentação de Antígeno , Antígenos CD/análise , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/virologia , Ceramidas/biossíntese , Ceramidas/fisiologia , Células Dendríticas/imunologia , Endocitose/efeitos dos fármacos , Exocitose/fisiologia , Exossomos/química , Fumonisinas/farmacologia , Proteínas de Fluorescência Verde/análise , Humanos , Células Jurkat/efeitos dos fármacos , Células Jurkat/virologia , Rim , Lipídeos de Membrana/análise , Lipídeos de Membrana/fisiologia , Microdomínios da Membrana/química , Pronase/farmacologia , Tetraspanina 28 , Produtos do Gene gag do Vírus da Imunodeficiência Humana/análiseRESUMO
Antiviral monoclonal antibodies (mAbs) can generate protective immunity through Fc-FcγRs interactions. We previously showed a role for immune complexes (ICs) in the enhancement of antiviral T-cell responses through FcγR-mediated activation of dendritic cells (DCs). Here we addressed how mAb therapy in retrovirus-infected mice affects the activation of neutrophils and inflammatory monocytes, two FcγR-expressing innate effector cells rapidly recruited to sites of infection. We found that both cell-types activated in vitro by viral ICs secreted chemokines able to recruit monocytes and neutrophils themselves. Moreover, inflammatory cytokines potentiated chemokines and cytokines release by IC-activated cells and induced FcγRIV upregulation. Similarly, infection and mAb-treatment upregulated FcγRIV on neutrophils and inflammatory monocytes and enhanced their cytokines/chemokines secretion. Notably, upon antibody therapy neutrophils and inflammatory monocytes displayed distinct functional activation states and sequentially modulated the antiviral immune response by secreting Th1-type polarizing cytokines and chemokines, which occurred in a FcγRIV-dependent manner. Consistently, FcγRIV- blocking in mAb-treated, infected mice led to reduced immune protection. Our work provides new findings on the immunomodulatory role of neutrophils and monocytes in the enhancement of immune responses upon antiviral mAb therapy.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Monócitos/imunologia , Neutrófilos/imunologia , Infecções por Retroviridae/tratamento farmacológico , Animais , Anticorpos Monoclonais/imunologia , Complexo Antígeno-Anticorpo/metabolismo , Antígenos Ly/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Camundongos , Receptores de IgG/metabolismo , Infecções por Retroviridae/imunologia , Resultado do TratamentoRESUMO
Monoclonal antibodies (mAbs) are now considered as a therapeutic approach to prevent and treat severe viral infections. Using a mouse retroviral model, we showed that mAbs induce protective immunity (vaccinal effects). Here, we investigated the role of natural killer (NK) cells on this effect. NK cells are effector cells that are crucial to control viral propagation upon mAb treatment. However, their immunomodulatory activity during antiviral mAb immunotherapies has been little studied. Our data reveal that the mAb treatment of infected mice preserves the functional activation of NK cells. Importantly, functional NK cells play an essential role in preventing immune dysfunction and inducing antiviral protective immunity upon mAb therapy. Thus, NK cell depletion in mAb-treated, viral-infected mice leads to the upregulation of molecules involved in immunosuppressive pathways (i.e., PD-1, PD-L1 and CD39) on dendritic cells and T cells. NK cell depletion also abrogates the vaccinal effects induced by mAb therapy. Our data also reveal a role for IFNγ-producing NK cells in the enhancement of the B-cell responses through the potentiation of the B-cell helper properties of neutrophils. These findings suggest that preserved NK cell functions and counts might be required for achieving mAb-induced protective immunity. They open new prospects for improving antiviral immunotherapies.
RESUMO
Human milk is a significant source of different CD133+ and/or CD34+ stem/progenitor-like cell subsets in healthy women but their cell distribution and percentages in this compartment of HIV-positive women have not been explored. To date, a decrease of CD34+ hematopoietic stem and progenitor cell frequencies in peripheral blood and bone marrow of HIV-positive patients has been reported. Herein, human milk and peripheral blood samples were collected between day 2-15 post-partum from HIV-positive and HIV-negative women, and cells were stained with stem cell markers and analyzed by flow cytometry. We report that the median percentage of CD45+/highCD34-CD133+ cell subset from milk and blood was significantly higher in HIV-positive than in HIV-negative women. The percentage of CD45dimCD34-CD133+ cell subset from blood was significantly higher in HIV-positive than HIV-negative women. Moreover, percentages of CD45dimCD34+, CD45dimCD34+CD133-, and CD45+highCD34+CD133- cell subsets from blood were significantly lower in HIV-positive than HIV-negative women. The CD133+ stem/progenitor-like cell subsets are increased in early human milk and blood of HIV-positive women and are differentially distributed to CD34+ cell subset frequencies which are decreased in blood.
Assuntos
Infecções por HIV , Leite Humano , Antígeno AC133 , Feminino , Sangue Fetal , Citometria de Fluxo , HumanosRESUMO
PURPOSE OF REVIEW: The review recalls recent findings regarding the induction of vaccinal effects by HIV-1 broadly neutralizing antibodies (bNAbs) and highlights potential therapeutic strategies to exploit such immunomodulatory properties. RECENT FINDINGS: Studies in different animal models have shown that mAbs can generate long-lasting protective immunity. Induction of this vaccinal effect by HIV-1 bNAbs has also been more recently reported in animal models of HIV-1 infection. Notably, bNAbs treatment of macaques infected with the chimeric simian-human immunodeficiency virus (SHIV) improved both humoral and cellular adaptive immune responses that contributed to disease control. Importantly, this concept has been extended to HIV-1-infected patients as enhancement of humoral responses was recently reported in HIV-1 patients treated with bNAbs. Studies aiming at elucidating the mechanisms underlying these immunomodulatory properties of bNAbs have identified a role for immune complexes in shaping immune responses against HIV-1. They also highlight different Fc (fragment crystallizable) region effector functions that might be required for the enhancement of HIV-1 immune responses upon bNAbs treatment. SUMMARY: HIV-1 bNAbs can elicit protective adaptive immune responses through mechanisms involving multiple cellular and molecular actors of the immune system. Harnessing these mechanisms will be crucial to achieve protective immunity against HIV-1 infection by bNAbs.
Assuntos
Anticorpos Amplamente Neutralizantes/administração & dosagem , Anticorpos Anti-HIV/administração & dosagem , Infecções por HIV/terapia , HIV-1/imunologia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Anticorpos Amplamente Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/genética , HumanosRESUMO
Using a mouse retroviral model, we have shown that mAb-based immunotherapy can induce life-long endogenous protective immunity (vaccine-like effects). This observation has potentially important consequences for treating life-threatening human viral infections. Here, we investigated the role of neutrophils in this effect. Neutrophils are innate immunity effector cells with well-established microbe-killing activities that are rapidly mobilized upon infection. They are also emerging as orchestrators of innate and adaptive immunities. However, their immunomodulatory activity during antiviral mAb immunotherapies has never been studied. Our data reveal that neutrophils have an essential role in immunotherapy-induced immune protection of infected mice. Unexpectedly, neutrophils have a limited effect in controlling viral propagation upon passive immunotherapy administration, which is mostly mediated by NK cells. Instead, neutrophils operate as essential inducers of a potent host humoral antiviral response. Thus, neutrophils play an unexpected key role in protective immunity induction by antiviral mAbs. Our work opens approaches to improve antiviral immunotherapies, as it suggests that preserving neutrophil functions and counts might be required for achieving mAb-induced protective immunity.
Assuntos
Anticorpos Monoclonais/imunologia , Células Matadoras Naturais/imunologia , Vírus da Leucemia Murina , Leucemia Experimental/imunologia , Neutrófilos/imunologia , Infecções por Retroviridae/imunologia , Infecções Tumorais por Vírus/imunologia , Replicação Viral , Animais , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Imunidade Humoral , Imunidade Inata , Imunoterapia , Leucemia Eritroblástica Aguda/imunologia , CamundongosRESUMO
Tolerogenic dendritic cell (tolDC)-based therapies have become a promising approach for the treatment of autoimmune diseases by their potential ability to restore immune tolerance in an antigen-specific manner. However, the broad variety of protocols used to generate tolDC in vitro and their functional and phenotypical heterogeneity are evidencing the need to find robust biomarkers as a key point towards their translation into the clinic, as well as better understanding the mechanisms involved in the induction of immune tolerance. With that aim, in this study we have compared the transcriptomic profile of tolDC induced with either vitamin D3 (vitD3-tolDC), dexamethasone (dexa-tolDC) or rapamycin (rapa-tolDC) through a microarray analysis in 5 healthy donors. The results evidenced that common differentially expressed genes could not be found for the three different tolDC protocols. However, individually, CYP24A1, MUCL1 and MAP7 for vitD3-tolDC; CD163, CCL18, C1QB and C1QC for dexa-tolDC; and CNGA1 and CYP7B1 for rapa-tolDC, constituted good candidate biomarkers for each respective cellular product. In addition, a further gene set enrichment analysis of the data revealed that dexa-tolDC and vitD3-tolDC share several immune regulatory and anti-inflammatory pathways, while rapa-tolDC seem to be playing a totally different role towards tolerance induction through a strong immunosuppression of their cellular processes.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Colecalciferol/farmacologia , Células Dendríticas/imunologia , Dexametasona/farmacologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Tolerância Imunológica/efeitos dos fármacos , Sirolimo/farmacologia , Diferenciação Celular/imunologia , Células Dendríticas/citologia , Feminino , Regulação da Expressão Gênica/imunologia , Humanos , MasculinoRESUMO
Dendritic cells (DC) play essential functions in both innate and adaptive immune responses. Peripheral blood DCs are divided into two major subsets, named conventional DC (cDC) and plasmacytoid DC (pDC), which play specific functions in the immune response. The absolute numbers of DCs (and their subsets) in peripheral blood may suffer variations due to physiological or pathological reasons, and therefore the enumeration of DC subsets in blood samples may be of clinical interest. However, to date this enumeration has produced controversial rather than consistent results. Here, using a two-tube platform approach, peripheral blood DCs have been enumerated in samples from healthy blood donors aged 18-65 years old. The results obtained showed a significant age-related decrease in pDC numbers, whilst cDC numbers remained unaltered. The different protocols used to define and enumerate DC subsets from blood samples may account for the controversial results reported before, thus emphasizing the importance of a general consensus to enumerate DCs. Reduced pDC numbers may be related to the higher susceptibility to infection and deficient response to vaccination often observed in aged individuals.
Assuntos
Envelhecimento/imunologia , Doadores de Sangue , Células Dendríticas/fisiologia , Adolescente , Adulto , Idoso , Contagem de Células , Células Dendríticas/imunologia , Feminino , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-IdadeRESUMO
Monoclonal antibodies (mAbs), which currently constitute the main class of biotherapeutics, are now recognized as major medical tools that are increasingly being considered to fight severe viral infections. Indeed, the number of antiviral mAbs developed in recent years has grown exponentially. Although their direct effects on viral blunting have been studied in detail, their potential immunomodulatory actions have been overlooked until recently. The ability of antiviral mAbs to modulate antiviral immune responses in infected organisms has recently been revealed. More specifically, upon recognition of their cognate antigens, mAbs form immune complexes (ICs) that can be recognized by the Fc receptors expressed on different immune cells of infected individuals. This binding may be followed by the modulation of the host immune responses. Harnessing this immunomodulatory property may facilitate improvements in the therapeutic potential of antiviral mAbs. This review focuses on the role of ICs formed with different viral determinants and mAbs in the induction of antiviral immune responses in the context of both passive immunotherapies and vaccination strategies. Potential deleterious effects of ICs on the host immune response are also discussed.
Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Complexo Antígeno-Anticorpo/imunologia , Imunização Passiva , Imunoterapia Ativa , Viroses/imunologia , Viroses/terapia , Animais , Anticorpos Antivirais/imunologia , Antígenos Virais/imunologia , Antivirais/imunologia , Antivirais/uso terapêutico , Modelos Animais de Doenças , Humanos , Fragmentos Fc das Imunoglobulinas/imunologia , Fatores Imunológicos/uso terapêutico , Imunomodulação , VacinaçãoRESUMO
Monoclonal antibodies (mAbs) are increasingly being considered as agents to fight severe viral diseases. So far, they have essentially been selected and used on the basis of their virus-neutralizing activity and/or cell-killing activity to blunt viral propagation via direct mechanisms. There is, however, accumulating evidence that they can also induce long-lasting protective antiviral immunity by recruiting the endogenous immune system of infected individuals during the period of immunotherapy. Exploiting this property may revolutionize antiviral mAb-based immunotherapies, with benefits for both patients and healthcare systems.