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1.
Emerg Microbes Infect ; 10(1): 964-981, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33858301

RESUMO

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 Tratamento
2.
Vaccines (Basel) ; 9(2)2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33567792

RESUMO

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.

3.
JCI Insight ; 3(9)2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29720574

RESUMO

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 , Camundongos
4.
Emerg Microbes Infect ; 5(8): e92, 2016 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-27530750

RESUMO

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 , Vacinação
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