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1.
Cell ; 151(1): 153-66, 2012 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-23021222

RESUMO

Regulatory T (Treg) cells, whose identity and function are defined by the transcription factor Foxp3, are indispensable for immune homeostasis. It is unclear whether Foxp3 exerts its Treg lineage specification function through active modification of the chromatin landscape and establishment of new enhancers or by exploiting a pre-existing enhancer landscape. Analysis of the chromatin accessibility of Foxp3-bound enhancers in Treg and Foxp3-negative T cells showed that Foxp3 was bound overwhelmingly to preaccessible enhancers occupied by its cofactors in precursor cells or a structurally related predecessor. Furthermore, the bulk of Foxp3-bound Treg cell enhancers lacking in Foxp3(-) CD4(+) cells became accessible upon T cell receptor activation prior to Foxp3 expression, and only a small subset associated with several functionally important genes were exclusively Treg cell specific. Thus, in a late cellular differentiation process, Foxp3 defines Treg cell functionality in an "opportunistic" manner by largely exploiting the preformed enhancer network instead of establishing a new enhancer landscape.


Assuntos
Fatores de Transcrição Forkhead/metabolismo , Linfócitos T Reguladores/citologia , Animais , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular , Cromatina/metabolismo , Elementos Facilitadores Genéticos , Feminino , Proteína Forkhead Box O1 , Ativação Linfocitária , Camundongos , Organismos Livres de Patógenos Específicos , Linfócitos T Reguladores/metabolismo
2.
Immunity ; 44(3): 609-621, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26944201

RESUMO

Targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) can induce regression of tumors bearing activating mutations in the Ras pathway but rarely leads to tumor eradication. Although combining MEK inhibition with T-cell-directed immunotherapy might lead to more durable efficacy, T cell responses are themselves at least partially dependent on MEK activity. We show here that MEK inhibition did profoundly block naive CD8(+) T cell priming in tumor-bearing mice, but actually increased the number of effector-phenotype antigen-specific CD8(+) T cells within the tumor. MEK inhibition protected tumor-infiltrating CD8(+) T cells from death driven by chronic TCR stimulation while sparing cytotoxic activity. Combining MEK inhibition with anti-programmed death-ligand 1 (PD-L1) resulted in synergistic and durable tumor regression even where either agent alone was only modestly effective. Thus, despite the central importance of the MAP kinase pathway in some aspects of T cell function, MEK-targeted agents can be compatible with T-cell-dependent immunotherapy.


Assuntos
Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma/terapia , Neoplasias do Colo/terapia , Imunoterapia , Animais , Anticorpos Monoclonais/administração & dosagem , Apoptose , Azetidinas/administração & dosagem , Azetidinas/farmacologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Carcinoma/imunologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias do Colo/imunologia , Sinergismo Farmacológico , Tratamento Farmacológico , Quimioterapia Combinada , MAP Quinases Reguladas por Sinal Extracelular , Humanos , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Terapia de Alvo Molecular , Transplante de Neoplasias , Piperidinas/administração & dosagem , Piperidinas/farmacologia
3.
J Immunol ; 199(4): 1238-1249, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28696253

RESUMO

Ox40 ligand (Ox40L) locus genetic variants are associated with the risk for systemic lupus erythematosus (SLE); however, it is unclear how Ox40L contributes to SLE pathogenesis. In this study, we evaluated the contribution of Ox40L and its cognate receptor, Ox40, using in vivo agonist and antagonist approaches in the NZB × NZW (NZB/W) F1 mouse model of SLE. Ox40 was highly expressed on several CD4 Th cell subsets in the spleen and kidney of diseased mice, and expression correlated with disease severity. Treatment of aged NZB/W F1 mice with agonist anti-Ox40 mAbs potently exacerbated renal disease, which was accompanied by activation of kidney-infiltrating T cells and cytokine production. The agonist mAbs also induced activation and inflammatory gene expression in splenic CD4 T cells, including IFN-regulated genes, increased the number of follicular helper T cells and plasmablasts in the spleen, and led to elevated levels of serum IgM and enhanced renal glomerular IgM deposition. In a type I IFN-accelerated lupus model, treatment with an antagonist Ox40:Fc fusion protein significantly delayed the onset of severe proteinuria and improved survival. These data support the hypothesis that the Ox40/Ox40L pathway drives cellular and humoral autoimmune responses during lupus nephritis in NZB/W F1 mice and emphasize the potential clinical value of targeting this pathway in human lupus.


Assuntos
Nefrite Lúpica/imunologia , Glicoproteínas de Membrana/metabolismo , Plasmócitos/imunologia , Receptores OX40/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Fatores de Necrose Tumoral/metabolismo , Animais , Anticorpos Antinucleares/imunologia , Anticorpos Monoclonais/imunologia , Autoimunidade , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Rim/imunologia , Rim/patologia , Glomérulos Renais/imunologia , Glomérulos Renais/patologia , Nefrite Lúpica/fisiopatologia , Camundongos , Camundongos Endogâmicos NZB , Ligante OX40 , Proteinúria/imunologia , Transdução de Sinais , Linfócitos T Auxiliares-Indutores/metabolismo
4.
Nature ; 458(7236): 351-6, 2009 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-19182775

RESUMO

In the course of infection or autoimmunity, particular transcription factors orchestrate the differentiation of T(H)1, T(H)2 or T(H)17 effector cells, the responses of which are limited by a distinct lineage of suppressive regulatory T cells (T(reg)). T(reg) cell differentiation and function are guided by the transcription factor Foxp3, and their deficiency due to mutations in Foxp3 results in aggressive fatal autoimmune disease associated with sharply augmented T(H)1 and T(H)2 cytokine production. Recent studies suggested that Foxp3 regulates the bulk of the Foxp3-dependent transcriptional program indirectly through a set of transcriptional regulators serving as direct Foxp3 targets. Here we show that in mouse T(reg) cells, high amounts of interferon regulatory factor-4 (IRF4), a transcription factor essential for T(H)2 effector cell differentiation, is dependent on Foxp3 expression. We proposed that IRF4 expression endows T(reg) cells with the ability to suppress T(H)2 responses. Indeed, ablation of a conditional Irf4 allele in T(reg) cells resulted in selective dysregulation of T(H)2 responses, IL4-dependent immunoglobulin isotype production, and tissue lesions with pronounced plasma cell infiltration, in contrast to the mononuclear-cell-dominated pathology typical of mice lacking T(reg) cells. Our results indicate that T(reg) cells use components of the transcriptional machinery, promoting a particular type of effector CD4(+) T cell differentiation, to efficiently restrain the corresponding type of the immune response.


Assuntos
Fatores Reguladores de Interferon/metabolismo , Linfócitos T Reguladores/imunologia , Células Th2/imunologia , Animais , Doenças Autoimunes/patologia , Contagem de Linfócito CD4 , Diferenciação Celular , Fatores de Transcrição Forkhead/deficiência , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Fatores Reguladores de Interferon/deficiência , Fatores Reguladores de Interferon/genética , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Células Th2/citologia , Células Th2/metabolismo , Timo/citologia
5.
Cancer Immunol Immunother ; 61(7): 1055-64, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22159473

RESUMO

Based on the specificity of antigen recognition and the ability to generate long-lived memory responses, cancer immunotherapies primarily target tumor-associated T cells. Systemic administration of anti-IL-10R1 antibody in combination with local CpG administration has been shown to induce tumor regression in a T-cell-dependent manner. Here, we confirmed the anti-tumor efficacy of anti-IL-10R1 and CpG therapy in the highly aggressive B16F10 melanoma model. However, T cells were not required for tumor growth inhibition. Through cellular depletions and genetic models of leukocyte deficiency, we demonstrated that T, B, and NK cells, and neutrophils are not essential for anti-tumor efficacy. Nevertheless, hematopoietic cells as a whole are required for anti-IL-10R1- and CpG-induced tumor growth inhibition, suggesting that the collective action of multiple subsets of hematopoietic-derived cells is required for anti-tumor efficacy.


Assuntos
Anticorpos Monoclonais/farmacologia , Fosfatos de Dinucleosídeos/imunologia , Fosfatos de Dinucleosídeos/farmacologia , Células-Tronco Hematopoéticas/imunologia , Subunidade alfa de Receptor de Interleucina-10/imunologia , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Animais , Anticorpos Monoclonais/imunologia , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Humanos , Imuno-Histoquímica , Interleucina-10/imunologia , Subpopulações de Linfócitos/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Metástase Neoplásica
6.
Cancer Immunol Res ; 8(6): 806-818, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32238381

RESUMO

Antiangiogenic therapies that target the VEGF pathway have been used clinically to combat cancer for over a decade. Beyond having a direct impact on blood vessel development and tumor perfusion, accumulating evidence indicates that these agents also affect antitumor immune responses. Numerous clinical trials combining antiangiogenic drugs with immunotherapies for the treatment of cancer are ongoing, but a mechanistic understanding of how disruption of tumor angiogenesis may impact immunity is not fully discerned. Here, we reveal that blockade of VEGF-A with a mAb to VEGF augments activation of CD8+ T cells within tumors and potentiates their capacity to produce cytokines. We demonstrate that this phenomenon relies on the disruption of VEGFR2 signaling in the tumor microenvironment but does not affect CD8+ T cells directly. Instead, the augmented functional capacity of CD8+ T cells stems from increased tumor hypoxia that initiates a hypoxia-inducible factor-1α program within CD8+ T cells that directly enhances cytokine production. Finally, combinatorial administration of anti-VEGF with an immunotherapeutic antibody, anti-OX40, improved antitumor activity over single-agent treatments. Our findings illustrate that anti-VEGF treatment enhances CD8+ T-cell effector function and provides a mechanistic rationale for combining antiangiogenic and immunotherapeutic drugs for cancer treatment.


Assuntos
Bevacizumab/farmacologia , Linfócitos T CD8-Positivos/imunologia , Neoplasias do Colo/terapia , Hipóxia/patologia , Ativação Linfocitária/imunologia , Melanoma Experimental/terapia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/farmacologia , Animais , Apoptose , Linfócitos T CD8-Positivos/efeitos dos fármacos , Proliferação de Células , Neoplasias do Colo/imunologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Citotoxicidade Imunológica/imunologia , Feminino , Humanos , Hipóxia/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Imunoterapia , Ativação Linfocitária/efeitos dos fármacos , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Células Tumorais Cultivadas , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Nat Cancer ; 1(7): 681-691, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-35122038

RESUMO

Inhibiting the programmed death-1 (PD-1) pathway is one of the most effective approaches to cancer immunotherapy, but its mechanistic basis remains incompletely understood. Binding of PD-1 to its ligand PD-L1 suppresses T-cell function in part by inhibiting CD28 signaling. Tumor cells and infiltrating myeloid cells can express PD-L1, with myeloid cells being of particular interest as they also express B7-1, a ligand for CD28 and PD-L1. Here we demonstrate that dendritic cells (DCs) represent a critical source of PD-L1, despite being vastly outnumbered by PD-L1+ macrophages. Deletion of PD-L1 in DCs, but not macrophages, greatly restricted tumor growth and led to enhanced antitumor CD8+ T-cell responses. Our data identify a unique role for DCs in the PD-L1-PD-1 regulatory axis and have implications for understanding the therapeutic mechanism of checkpoint blockade, which has long been assumed to reflect the reversal of T-cell exhaustion induced by PD-L1+ tumor cells.


Assuntos
Antígeno B7-H1 , Neoplasias , Antígeno B7-H1/genética , Antígenos CD28/metabolismo , Células Dendríticas , Humanos , Ligantes , Neoplasias/genética , Receptor de Morte Celular Programada 1/genética
8.
J Immunother Cancer ; 7(1): 207, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31387641

RESUMO

BACKGROUND: One of the mechanisms by which tumors evade immune surveillance is through shedding of the major histocompatibility complex (MHC) class I chain-related protein A and B (MICA/B) from their cell surface. MICA/B are ligands for the activating receptor NKG2D on NK and CD8 T cells. This shedding reduces cell surface levels of MICA/B and impairs NKG2D recognition. Shed MICA/B can also mask NKG2D receptor and is thought to induce NKG2D internalization, further compromising immune surveillance by NK cells. METHODS: We isolated human primary NK cells from normal donors and tested the suppressive activity of soluble recombinant MICA in vitro. Utilizing a panel of novel anti-MICA antibodies, we further examined the stimulatory activities of anti-MICA antibodies that reversed the suppressive effects of soluble MICA. RESULTS: We show that suppressive effects of soluble MICA (sMICA) on NK cell cytolytic activity was not due to the down-regulation of cell surface NKG2D. In the presence of an α3 domain-specific MICA antibody, which did not obstruct NKG2D binding, sMICA-mediated NK cell suppression was completely reversed. Reversal of NK cell inhibition by sMICA was mediated by immune complex formation that agonized NKG2D signaling. Furthermore, this restorative activity was dependent on antibody Fc effector function as the introduction of Fc mutations to abrogate Fc receptor binding failed to reverse sMICA-mediated NK cell suppression. Furthermore, MICA immune complexes preformed with an α3 domain-specific antibody (containing a wild-type Fc) induced IFN-γ and TNF-α secretion by NK cells in the absence of cancer cells, whereas MICA immune complexes preformed with the Fc effectorless antibody failed to induce IFN-γ and TNF-α secretion. Finally, we demonstrated that MICA immune complexes formed with the α3 domain-specific antibody activates NKG2D on NK cells leading to the release of IFN-γ. CONCLUSIONS: Our results demonstrate that an α3 domain-specific MICA antibody can circumvent sMICA-mediated suppression of NK cell cytolytic activity. Moreover, our data suggest that MICA immune complexes formed with α3-specific antibodies can activate NKG2D receptor and restore NK cell function in a Fc-dependent manner. The clinical utility of α3 domain-specific MICA/B antibodies may hold great promise as a new strategy for cancer immunotherapy.


Assuntos
Complexo Antígeno-Anticorpo/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Imunoterapia/métodos , Células Matadoras Naturais/imunologia , Linhagem Celular , Humanos , Transfecção
9.
MAbs ; 11(6): 996-1011, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31156033

RESUMO

Agonism of members of the tumor necrosis factor receptor superfamily (TNFRSF) with monoclonal antibodies is of high therapeutic interest due to their role in immune regulation and cell proliferation. A major hurdle for pharmacologic activation of this receptor class is the requirement for high-order clustering, a mechanism that imposes a reliance in vivo on Fc receptor-mediated crosslinking. This extrinsic dependence represents a potential limitation of virtually the entire pipeline of agonist TNFRSF antibody drugs, of which none have thus far been approved or reached late-stage clinical trials. We show that tetravalent biepitopic targeting enables robust intrinsic antibody agonism for two members of this family, OX40 and DR5, that is superior to extrinsically crosslinked native parental antibodies. Tetravalent biepitopic anti-OX40 engagement co-stimulated OX40low cells, obviated the requirement for CD28 co-signal for T cell activation, and enabled superior pharmacodynamic activity relative to native IgG in a murine vaccination model. This work establishes a proof of concept for an engineering approach that addresses a major gap for the therapeutic activation of this important receptor class.


Assuntos
Anticorpos Monoclonais/imunologia , Capeamento Imunológico , Ligante OX40/agonistas , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/agonistas , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Animais , Antígenos CD28/imunologia , Células CHO , Cricetulus , Humanos , Células Jurkat , Camundongos , Camundongos SCID , Camundongos Transgênicos , Ligante OX40/imunologia , Receptores Fc/imunologia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/imunologia , Linfócitos T/citologia
10.
PLoS One ; 13(1): e0190158, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29320521

RESUMO

The prevalence of cytotoxic tumor infiltrating lymphocytes (TILs) has demonstrated prognostic value in multiple tumor types. In particular, CD8 counts (in combination with CD3 and CD45RO) have been shown to be superior to traditional UICC staging in colon cancer patients and higher total CD8 counts have been associated with better survival in breast cancer patients. However, immune infiltrate heterogeneity can lead to potentially significant misrepresentations of marker prevalence in routine histologic sections. We examined step sections of breast and colorectal cancer samples for CD8+ T cell prevalence by standard chromogenic immunohistochemistry to determine marker variability and inform practice of T cell biomarker assessment in formalin-fixed, paraffin-embedded (FFPE) tissue samples. Stained sections were digitally imaged and CD8+ lymphocytes within defined regions of interest (ROI) including the tumor and surrounding stroma were enumerated. Statistical analyses of CD8+ cell count variability using a linear model/ANOVA framework between patients as well as between levels within a patient sample were performed. Our results show that CD8+ T-cell distribution is highly homogeneous within a standard tissue sample in both colorectal and breast carcinomas. As such, cytotoxic T cell prevalence by immunohistochemistry on a single level or even from a subsample of biopsy fragments taken from that level can be considered representative of cytotoxic T cell infiltration for the entire tumor section within the block. These findings support the technical validity of biomarker strategies relying on CD8 immunohistochemistry.


Assuntos
Neoplasias da Mama/imunologia , Linfócitos T CD8-Positivos/patologia , Carcinoma/imunologia , Neoplasias Colorretais/imunologia , Linfócitos do Interstício Tumoral/patologia , Subpopulações de Linfócitos T/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia/métodos , Neoplasias da Mama/patologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma/patologia , Neoplasias Colorretais/patologia , Simulação por Computador , Citotoxicidade Imunológica , Feminino , Técnicas Histológicas , Humanos , Processamento de Imagem Assistida por Computador , Contagem de Linfócitos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Subpopulações de Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/patologia , Microambiente Tumoral
11.
Cell Rep ; 25(1): 80-94, 2018 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-30282040

RESUMO

We examined hematopoietic protein kinase 1 (HPK1), whose reliance on scaffold versus kinase functions for negative immune cell regulation is poorly understood and critical to its assessment as a viable drug target. We identify kinase-dependent roles for HPK1 in CD8 T cells that restrict their anti-viral and anti-tumor responses by using HPK1 kinase-dead (HPK1.kd) knockin mice. Loss of HPK1 kinase function enhanced T cell receptor signaling and cytokine secretion in a T-cell-intrinsic manner. In response to chronic lymphocytic choriomeningitis virus (LCMV) infection or tumor challenge, viral clearance and tumor growth inhibition were enhanced in HPK1.kd mice, accompanied by an increase in effector CD8 T cell function. Co-blockade of PD-L1 further enhanced T effector cell function, resulting in superior anti-viral and anti-tumor immunity over single target blockade. These results identify the importance of HPK1 kinase activity in the negative regulation of CD8 effector functions, implicating its potential as a cancer immunotherapy target.


Assuntos
Proteínas Serina-Treonina Quinases/metabolismo , Linfócitos T/enzimologia , Linfócitos T/imunologia , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/enzimologia , Linfócitos T CD8-Positivos/imunologia , Neoplasias do Colo/imunologia , Neoplasias do Colo/terapia , Feminino , Glioma/imunologia , Glioma/terapia , Imunoterapia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/imunologia , Distribuição Aleatória , Transdução de Sinais
12.
Science ; 355(6332): 1428-1433, 2017 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-28280247

RESUMO

Programmed cell death-1 (PD-1) is a coinhibitory receptor that suppresses T cell activation and is an important cancer immunotherapy target. Upon activation by its ligand PD-L1, PD-1 is thought to suppress signaling through the T cell receptor (TCR). By titrating PD-1 signaling in a biochemical reconstitution system, we demonstrate that the co-receptor CD28 is strongly preferred over the TCR as a target for dephosphorylation by PD-1-recruited Shp2 phosphatase. We also show that CD28, but not the TCR, is preferentially dephosphorylated in response to PD-1 activation by PD-L1 in an intact cell system. These results reveal that PD-1 suppresses T cell function primarily by inactivating CD28 signaling, suggesting that costimulatory pathways play key roles in regulating effector T cell function and responses to anti-PD-L1/PD-1 therapy.


Assuntos
Antígeno B7-H1/metabolismo , Antígenos CD28/metabolismo , Neoplasias/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T/imunologia , Animais , Antígenos CD28/genética , Humanos , Imunoterapia , Células Jurkat , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação
13.
Nat Commun ; 8: 14572, 2017 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-28220772

RESUMO

Expression of PD-L1, the ligand for T-cell inhibitory receptor PD-1, is one key immunosuppressive mechanism by which cancer avoids eradication by the immune system. Therapeutic use of blocking antibodies to PD-L1 or its receptor PD-1 has produced unparalleled, durable clinical responses, with highest likelihood of response seen in patients whose tumour or immune cells express PD-L1 before therapy. The significance of PD-L1 expression in each cell type has emerged as a central and controversial unknown in the clinical development of immunotherapeutics. Using genetic deletion in preclinical mouse models, here we show that PD-L1 from disparate cellular sources, including tumour cells, myeloid or other immune cells can similarly modulate the degree of cytotoxic T-cell function and activity in the tumour microenvironment. PD-L1 expression in both the host and tumour compartment contribute to immune suppression in a non-redundant fashion, suggesting that both sources could be predictive of sensitivity to therapeutic agents targeting the PD-L1/PD-1 axis.


Assuntos
Anticorpos Bloqueadores/farmacologia , Antígeno B7-H1/imunologia , Neoplasias/imunologia , Microambiente Tumoral/imunologia , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Linhagem Celular Tumoral , Humanos , Camundongos Knockout , Neoplasias/tratamento farmacológico , Neoplasias/genética , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética
14.
Minerva Anestesiol ; 82(6): 649-56, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26576858

RESUMO

BACKGROUND: Patients undergoing laparoscopic gynecological surgery are at high risk of postoperative nausea and vomiting (PONV). We compared the antiemetic efficacy of ondansetron plus betahistine with that of ondansetron alone in this patient population. METHODS: In this randomized, double-blinded study, 168 patients were randomly allocated to receive placebo (O group) or betahistine 18 mg (OB group) orally 3 hours before surgery and 24 hours thereafter. In both groups, ondansetron 4 mg was administered at the end of surgery and 8 mg were added to an intravenous patient-controlled analgesia (IV-PCA) fentanyl solution. The primary outcome was complete response (no PONV and no rescue antiemetics) during the first 48 hours after surgery. The severity of nausea, pain score, and adverse events were assessed. RESULTS: The incidence of complete response was significantly higher in OB group than in O group (69% vs. 46%, P=0.004). The severity of nausea was lower in OB group than in O group during 30 minutes to 6 hours and 6 to 24 hours after surgery (P=0.001 and P<0.001). Pain score was similar between the groups. The incidence of dizziness was lower in OB group than in O group (13% vs. 40%, P < 0.001). Six patients (7%) in OB group and 15 patients (18%) in O group required early IV-PCA discontinuation, primarily because of PONV and/or dizziness (P=0.038). CONCLUSIONS: Compared to ondansetron alone, ondansetron plus betahistine was more effective to prevent PONV and dizziness in high-risk patients undergoing laparoscopic gynecological surgery.


Assuntos
Antieméticos/uso terapêutico , beta-Histina/uso terapêutico , Laparoscopia/efeitos adversos , Ondansetron/uso terapêutico , Náusea e Vômito Pós-Operatórios/tratamento farmacológico , Adulto , Idoso , Antieméticos/efeitos adversos , beta-Histina/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada/métodos , Feminino , Procedimentos Cirúrgicos em Ginecologia , Humanos , Pessoa de Meia-Idade , Ondansetron/efeitos adversos , Medição da Dor , Estudos Prospectivos , Índice de Gravidade de Doença , Adulto Jovem
15.
Laryngoscope ; 125(1): 111-7, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25291409

RESUMO

OBJECTIVES/HYPOTHESIS: To evaluate the effect of oral prednisolone on recovery from tonsillectomy. STUDY DESIGN: Prospective, randomized, controlled trial of 198 consecutive patients, aged 4 years and older, with no previous or known contraindications to steroid therapy. METHODS: All 198 patients scheduled for elective tonsillectomy with or without adenoidectomy from April 2013 to April 2014 were included. The participants were then randomly assigned to receive a postoperative course of prednisolone 0.25 mg/kg/d or no prednisolone over 7 days. During the first postoperative day, pain, type of diet (none, fluid, soft, normal), type of activity (none, bed rest, quiet, restricted, normal), presence of nausea and vomiting, postoperative bleeding rate, and sleep disturbance were assessed using questionnaires. All patients were followed up on days 7 and 14 by endoscopic photographic examination of both tonsillar fossa and by completion of questionnaires. RESULTS: No statistically significant differences in pain, diet, activity, rate of minor bleeding, nausea/vomiting, fever, or sleep disturbance were observed between the groups on day 1. On day 7, however, in pediatric patients, differences in pain (P = .001), diet (P = .001), activity (P = .004), mean area of re-epithelialization (P = .000), fever (P = .04), and sleep disturbance (P = .04) were observed. On day 14, differences in the mean area of re-epithelialization (P = .000, .001) remained in both pediatric and adult patients. CONCLUSIONS: Oral prednisolone may be beneficial during recovery from tonsillectomy without causing any serious complications.


Assuntos
Cuidados Pós-Operatórios , Prednisolona/administração & dosagem , Tonsilectomia , Adenoidectomia , Administração Oral , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Endoscopia , Feminino , Humanos , Masculino , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/prevenção & controle , Readmissão do Paciente , Satisfação do Paciente , Hemorragia Pós-Operatória/etiologia , Hemorragia Pós-Operatória/prevenção & controle , Estudos Prospectivos , Inquéritos e Questionários , Cicatrização/efeitos dos fármacos , Adulto Jovem
17.
J Exp Med ; 210(9): 1647-51, 2013 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-23980122

RESUMO

Antibodies have important roles in controlling cellular immunity through interaction with activating or inhibitory Fcγ receptors (FcγRs). FcγR engagement can facilitate receptor cross-linking on target cells, or induce retrograde FcγR signals to stimulate or suppress antibody-dependent, cell-mediated depletion of antigen-bearing target cells. Recent studies uncover unexpectedly important roles for FcγRs in the anticancer action of antibodies designed to trigger tumor cell apoptosis or enhance antitumor immunity. Here, we outline a conceptual framework for understanding these findings and discuss their mechanistic and translational implications.


Assuntos
Anticorpos/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Receptores de IgG/metabolismo , Animais , Humanos , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo
18.
Prog Mol Biol Transl Sci ; 92: 279-314, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20800825

RESUMO

The requirement for regulatory T cells (Treg) to maintain tolerance to self-tissues is evidenced by fatal autoimmune disease that results from genetic deficiencies in Treg cell development or Treg cell depletion in vivo. These observations revealed that a normal T cell repertoire harbors self-reactive T cells that are kept dormant by Treg cells. In order to prevent auto-reactive T cell activation, Treg cells disarm antigen-presenting cells (APC) through multiple suppressive mechanisms including B7 signaling and sequestration, ATP catabolism, cytolysis, and immunosuppressive cytokine secretion. In addition to APCs, multiple leukocyte subsets are subjected to Treg cell mediated suppression. The acquisition of suppressive activity occurs concomitantly with Treg cell lineage commitment. The identification of molecular cues that guide differentiation of Treg cells versus auto-reactive cells or other CD4(+) T cell subsets have been aided by the differential expression of the transcription factor Foxp3 by Treg cells. Foxp3 is the most faithful marker for Treg cells and in its absence, Treg cell development is abrogated. Utilizing Foxp3 expression as a surrogate for Treg cell commitment, factors that promote Foxp3 transcription have provided new insights to Treg cell development at a molecular level.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Diferenciação Celular , Tolerância Imunológica/imunologia , Linfócitos T Reguladores/imunologia , Animais , Fatores de Transcrição Forkhead/metabolismo , Humanos , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo
19.
Nat Immunol ; 8(2): 191-7, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17136045

RESUMO

Mice lacking the transcription factor Foxp3 (Foxp3(-)) lack regulatory T (T(reg)) cells and develop fatal autoimmune pathology. In Foxp3(-) mice, many activated effector T cells express self-reactive T cell receptors that are expressed in T(reg) cells in wild-type mice. Thus, in wild-type mice, most self-reactive thymocytes escaping negative selection are diverted into the T(reg) lineage, and whether T(reg) cells are critical in self-tolerance in wild-type mice remains unknown. Here, acute in vivo ablation of T(reg) cells demonstrated a vital function for T(reg) cells in neonatal and adult mice. We suggest that self-reactive T cells are continuously suppressed by T(reg) cells and that when suppression is relieved, self-reactive T cells become activated and facilitate accelerated maturation of dendritic cells.


Assuntos
Envelhecimento/imunologia , Autoimunidade/imunologia , Linfócitos T Reguladores/imunologia , Animais , Animais Recém-Nascidos , Células Dendríticas/imunologia , Fatores de Transcrição Forkhead/metabolismo , Cinética , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Tolerância a Antígenos Próprios/imunologia , Linfócitos T Reguladores/metabolismo
20.
Immunol Rev ; 212: 86-98, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16903908

RESUMO

Early studies of mice subjected to neonatal thymectomy and analyses of adoptive T-cell transfer into lymphopenic hosts led to the identification of a specialized subset of regulatory CD4+ T cells capable of suppressing various manifestations of autoimmunity. Recently, a combination of genetic, molecular, and traditional cellular approaches provided novel powerful means to investigate the biology of these cells. Here, we review earlier and current work from our laboratory, establishing a dedicated function for the transcription factor Foxp3 in the process of regulatory T-cell lineage commitment and a role for TCR- and cytokine-mediated signals in regulation of Foxp3 expression.


Assuntos
Fatores de Transcrição Forkhead/fisiologia , Linfócitos T Reguladores/imunologia , Animais , Diferenciação Celular/genética , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Camundongos , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/efeitos dos fármacos , Timo/citologia , Fator de Crescimento Transformador beta/farmacologia
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