Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.499
Filtrar
1.
Adv Exp Med Biol ; 1223: 155-165, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32030689

RESUMO

Tumor-associated inflammation and immune responses are key components in the tumor microenvironment (TME) which regulate tumor growth, progression, and metastasis. Tumor-associated myeloid cells (TAMCs) are a group of cells that play multiple key roles including induction of tumor-associated inflammation/angiogenesis and regulation of tumor-specific T-cell responses. Thus, identification and characterization of key pathways that can regulate TAMCs are of critical importance for developing cancer immunotherapy. Recent studies suggest that CD200-CD200 receptor (CD200R) interaction may be important in regulating the TME via affecting TAMCs. In this chapter, we will give a brief overview of the CD200-CD200R axis, including the biology behind CD200-CD200R interaction and the role(s) it plays in tumor microenvironment and tumor growth, and activation/effector functions of T cells. We will also discuss CD200-CD200R's role as potential checkpoint molecules for cancer immunotherapy. Further investigation of the CD200-CD200R pathway will not only advance our understanding of tumor pathogenesis and immunity but also provide the rationale for CD200-CD200R-targeted immunotherapy of human cancer.


Assuntos
Antígenos CD/metabolismo , Imunoterapia , Neoplasias/terapia , Receptores de Orexina/metabolismo , Microambiente Tumoral/imunologia , Antígenos CD/imunologia , Humanos , Células Mieloides/imunologia , Células Mieloides/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Receptores de Orexina/imunologia
2.
J Exp Med ; 217(4)2020 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-31985756

RESUMO

In a forward genetic screen of N-ethyl-N-nitrosourea (ENU)-induced mutant mice for aberrant immune function, we identified mice with a syndromic disorder marked by growth retardation, diabetes, premature death, and severe lymphoid and myeloid hypoplasia together with diminished T cell-independent (TI) antibody responses. The causative mutation was in Pdia6, an essential gene encoding protein disulfide isomerase A6 (PDIA6), an oxidoreductase that functions in nascent protein folding in the endoplasmic reticulum. The immune deficiency caused by the Pdia6 mutation was, with the exception of a residual T cell developmental defect, completely rescued in irradiated wild-type recipients of PDIA6-deficient bone marrow cells, both in the absence or presence of competition. The viable hypomorphic allele uncovered in these studies reveals an essential role for PDIA6 in hematopoiesis, but one extrinsic to cells of the hematopoietic lineage. We show evidence that this role is in the proper folding of Wnt3a, BAFF, IL-7, and perhaps other factors produced by the extra-hematopoietic compartment that contribute to the development and lineage commitment of hematopoietic cells.


Assuntos
Linfócitos/imunologia , Células Mieloides/imunologia , Isomerases de Dissulfetos de Proteínas/imunologia , Animais , Fator Ativador de Células B/imunologia , Linhagem Celular , Feminino , Células HEK293 , Hematopoese/imunologia , Humanos , Interleucina-7/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T/imunologia , Proteína Wnt3A/imunologia
3.
Nat Commun ; 11(1): 581, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996683

RESUMO

Cancer cells are poorly immunogenic and have a wide range of mutations, which makes them unsuitable for use in vaccination treatment. Here, we show that elimination of CD47, a ligand for the myeloid cell inhibitory receptor SIRPα, from tumor cells by genetic deletion or antibody blocking, significantly improves the effectiveness of the immune response to tumour cells. In both solid and hematopoietic mouse tumor models, vaccination with tumor cells or tumor antigen-expressing cells, that lack CD47 or were pre-coated with anti-CD47 antibodies, achieved an antitumor immune response. The efficacy of this approach was synergistically enhanced when used in combination with anti-PD-1 antibodies. The induction of antitumor responses depends on SIRPα+CD11c+ DCs, which exhibit rapid expansion following introduction of CD47-deficient tumor cells. Our results indicate that CD47-deficient whole tumor cells can induce antitumor responses.


Assuntos
Anticorpos Antineoplásicos/efeitos dos fármacos , Antineoplásicos/imunologia , Antineoplásicos/farmacologia , Antígeno CD47/genética , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Vacinação , Animais , Anticorpos Bloqueadores/farmacologia , Anticorpos Antineoplásicos/imunologia , Antígenos de Diferenciação/imunologia , Antígenos de Neoplasias , Antígeno CD11c , Antígeno CD47/imunologia , Feminino , Transplante de Células-Tronco Hematopoéticas , Imunoterapia/métodos , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Células Mieloides/imunologia
4.
Immunology ; 159(1): 121-129, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31606895

RESUMO

The transcription factor hypoxia-inducible factor-1 alpha (HIF-1α) is a key regulator of the response and function of myeloid cells in hypoxic and inflammatory microenvironments. To define the role of HIF-1α in tuberculosis, the progression of aerosol Mycobacterium tuberculosis infection was analysed in mice deficient in HIF-1α in the myeloid lineage (mHIF-1α-/- ). We show that myeloid HIF-1α is not required for the containment of the infection, as both wild-type (WT) and mHIF-1α-/- mice mounted normal Th1 responses and maintained control of bacterial growth throughout infection. However, during chronic infection mHIF-1α-/- mice developed extensive lymphocytic inflammatory involvement of the interstitial lung tissue and died earlier than WT mice. These data support the hypothesis that HIF-1α activity coordinates the response of myeloid cells during M. tuberculosis infection to prevent excessive leucocyte recruitment and immunopathological consequences to the host.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pulmão/metabolismo , Mycobacterium tuberculosis/crescimento & desenvolvimento , Células Mieloides/metabolismo , Pneumonia/metabolismo , Tuberculose Pulmonar/metabolismo , Animais , Carga Bacteriana , Células Cultivadas , Modelos Animais de Doenças , Progressão da Doença , Interações Hospedeiro-Patógeno , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Pulmão/imunologia , Pulmão/microbiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mycobacterium tuberculosis/imunologia , Células Mieloides/imunologia , Células Mieloides/microbiologia , Pneumonia/genética , Pneumonia/imunologia , Pneumonia/microbiologia , Transdução de Sinais , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia
5.
Helicobacter ; 24 Suppl 1: e12644, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31486236

RESUMO

Chronic inflammation induced by Helicobacter pylori infection is a critical factor in the development of peptic ulcer disease and gastric cancer. Central to this inflammation is the initiation of pro-inflammatory signaling cascades within epithelial cells, in particular those mediated by two sensors of bacterial cell wall components, nucleotide-binding oligomerization domain-containing protein 1 (NOD1) and alpha-protein kinase 1 (ALPK1). H pylori is, however, also highly adept at mitigating inflammation in the host, thereby restricting tissue damage and favoring bacterial persistence. H pylori modulates host immune responses by altering cytokine signaling in epithelial and myeloid cells, which results in increased proliferation of regulatory T cells and downregulation of effector T-cell responses. H pylori vacuolating cytotoxin A (VacA) has been shown to play an important role in the dampening of immune responses and induction of immune tolerance capable of protecting against asthma. It is also possible to generate protective immune responses by immunization with various H pylori antigens or their epitopes, in combination with an adjuvant, though this for now has only been shown in mouse models. Novel non-toxic adjuvants, consisting of modified bacterial enterotoxins or nanoparticles, have recently been developed that may not only enhance vaccine efficacy, but also help translate candidate vaccines to the clinic. This review will summarize the main discoveries in the past year regarding host immune responses to H pylori infection, as well as the design of new vaccine approaches against this infection.


Assuntos
Vacinas Bacterianas/imunologia , Infecções por Helicobacter/imunologia , Infecções por Helicobacter/patologia , Helicobacter pylori/imunologia , Helicobacter pylori/patogenicidade , Interações Hospedeiro-Patógeno , Vacinas Bacterianas/isolamento & purificação , Pesquisa Biomédica/tendências , Células Epiteliais/imunologia , Células Epiteliais/microbiologia , Infecções por Helicobacter/prevenção & controle , Humanos , Tolerância Imunológica , Inflamação/imunologia , Inflamação/patologia , Inflamação/prevenção & controle , Células Mieloides/imunologia , Células Mieloides/microbiologia , Linfócitos T Reguladores/imunologia
6.
Nat Cell Biol ; 21(9): 1113-1126, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31451770

RESUMO

Cancer-induced immune responses affect tumour progression and therapeutic response. In multiple murine models and clinical datasets, we identified large variations of neutrophils and macrophages that define 'immune subtypes' of triple-negative breast cancer (TNBC), including neutrophil-enriched (NES) and macrophage-enriched subtypes (MES). Different tumour-intrinsic pathways and mutual regulation between macrophages (or monocytes) and neutrophils contribute to the development of a dichotomous myeloid compartment. MES contains predominantly macrophages that are CCR2-dependent and exhibit variable responses to immune checkpoint blockade (ICB). NES exhibits systemic and local accumulation of immunosuppressive neutrophils (or granulocytic myeloid-derived suppressor cells), is resistant to ICB, and contains a minority of macrophages that seem to be unaffected by CCR2 knockout. A MES-to-NES conversion mediated acquired ICB resistance of initially sensitive MES models. Our results demonstrate diverse myeloid cell frequencies, functionality and potential roles in immunotherapies, and highlight the need to better understand the inter-patient heterogeneity of the myeloid compartment.


Assuntos
Imunoterapia , Células Mieloides/imunologia , Neoplasias de Mama Triplo Negativas/terapia , Microambiente Tumoral/imunologia , Animais , Modelos Animais de Doenças , Feminino , Granulócitos/imunologia , Imunoterapia/métodos , Macrófagos/imunologia , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/imunologia , Neutrófilos/imunologia , Neutrófilos/patologia , Neoplasias de Mama Triplo Negativas/patologia
7.
Mol Immunol ; 114: 216-225, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31386978

RESUMO

C-type lectin-like domain containing proteins (CTLDcps) mainly bind carbohydrate-based ligands, but also other ligands. CTLDcps are involved in several biological processes including cell adhesion, cell-cell interactions, and pathogen recognition. Pathogen recognition by myeloid cells, e.g. dendritic cells (DCs), can be facilitated through cell surface expressed CTLDcps. Cell surface expressed CTLDcps have been exploited in vaccine designs for specific targeting of human and mouse DCs using antibodies. In recent years, however, DC targeting using carbohydrate-based vaccines has gained interest due to low production cost, limited immunogenicity, and possibility of multivalent adjustment. In chicken, however, only a few CTLDcps have been identified. Identifying and annotating additional chicken CTLDcps (chCTLDcps) is needed to exploit carbohydrate-mediated DC targeting in chicken. Therefore, we searched the chicken GRCg6a assembly for novel chCTLDcps. We identified 28 chCTLDcps of which 10 had previously been described and also experimentally validated. RNA-seq and RT-qPCR confirmed mRNA expression of the remaining 18 identified chCTLDcps. A group of highly related chCTLDcps, moreover, was shown to be avian-specific and comprise novel members mapped to the proposed chicken natural killer gene complex. Two chCTLDcps, chCLEC17AL-A and chCLEC17AL-B, were found to share a recent common ancestor with CLEC17A. Putative mannose or fucose-binding sequence motifs, EPN and WND, were found in the CTLD of chCLEC17AL-A. Both contained intracellular internalisation and signalling sequence motifs. In conclusion, several chCTLDcps were identified and their expression confirmed. Both chCLEC17AL-A and -B showed promise as potential targets in carbohydrate-based chicken vaccine strategies. Determination of DC-specific expression of chCLEC17AL-A and -B, thus, might prove useful in chicken vaccinology.


Assuntos
Carboidratos/imunologia , Lectinas Tipo C/imunologia , Lectinas Tipo C/metabolismo , Vacinas/imunologia , Sequência de Aminoácidos , Animais , Galinhas , Células Dendríticas/imunologia , Feminino , Humanos , Ligantes , Camundongos , Células Mieloides/imunologia
8.
J Neuroinflammation ; 16(1): 151, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31325968

RESUMO

BACKGROUND: Microglia are essential to the development of the CNS and its homeostasis. Our prior findings suggested a niche model to describe the behaviors of retinal microglia. Here, we ask whether new myeloid cells recruited to the retina are constrained to resemble endogenous microglia morphologically and functionally. METHODS: Use of CD11cDTR/GFP transgenic mouse allowed identification of two niches of retinal microglia distinguished by being GFPlo or GFPhi. We also used transgenic mice in which CX3CR1+ cells expressed YFP and were depletable following tamoxifen-induced expression of diphtheria toxin subunit A. We employed several ablation and injury stimulation protocols to examine the origin and fate of myeloid cells repopulating the retina. Analysis of retinal myeloid cells was done by microscopy, flow cytometry, and qRT-PCR. RESULTS: We found that the origin of new GFPhi and GFPlo myeloid cells in the retina of CD11cDTR/GFP mice, whether recruited or local, depended on the ablation and stimulation protocols. Regardless of origin, new GFPlo and GFPhi retinal myeloid cells were CD45medCD11b+Ly6G-Ly6CloIba1+F4/80+, similar to endogenous microglia. Following tamoxifen-induced diphtheria toxin ablation, myeloid cell repopulation differed in the retina compared to the brain and optic nerve. Stimulation of replacement GFPhi cells was substantially attenuated in repopulating retinas after tamoxifen-induced diphtheria toxin ablation compared to control or radiation-ablated mice. In radiation bone marrow chimeric mice, replacement GFPhi myeloid cells from the circulation were slow to repopulate the retina unless stimulated by an optic nerve crush injury. However, once stimulated, recruited GFPhi cells were found to concentrate on injured retinal ganglion cells and were morphologically similar to GFPhi cells in non-ablated control CD11cDTR/GFP mice. CONCLUSIONS: The results support the idea that GFPhi cells in the CD11cDTR/GFP mouse, whether recruited or from resident microglia, mark a unique niche of activated retinal myeloid cells. We conclude that the retinal environment has a potent influence on the function, morphology, and proliferative capacity of new myeloid cells regardless of their origin, compelling them to be equivalent to the endogenous microglia.


Assuntos
Microglia/citologia , Células Mieloides/citologia , Retina/citologia , Retina/imunologia , Animais , Diferenciação Celular/imunologia , Microambiente Celular/imunologia , Camundongos , Camundongos Transgênicos , Microglia/imunologia , Células Mieloides/imunologia
9.
PLoS Pathog ; 15(7): e1007883, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31260499

RESUMO

Chronic infection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) affects an estimated 35 million and 75 million individuals worldwide, respectively. These viruses induce persistent inflammation which often drives the development or progression of organ-specific diseases and even cancer including Hepatocellular Carcinoma (HCC). In this study, we sought to examine inflammatory responses following HIV or HCV stimulation of macrophages or Kupffer cells (KCs), that may contribute to virus mediated inflammation and subsequent liver disease. KCs are liver-resident macrophages and reports have provided evidence that HIV can stimulate and infect them. In order to characterize HIV-intrinsic innate immune responses that may occur in the liver, we performed microarray analyses on KCs following HIV stimulation. Our data demonstrate that KCs upregulate several innate immune signaling pathways involved in inflammation, myeloid cell maturation, stellate cell activation, and Triggering Receptor Expressed on Myeloid cells 1 (TREM1) signaling. TREM1 is a member of the immunoglobulin superfamily of receptors and it is reported to be involved in systemic inflammatory responses due to its ability to amplify activation of host defense signaling pathways. Our data demonstrate that stimulation of KCs with HIV or HCV induces the upregulation of TREM1. Additionally, HIV viral proteins can upregulate expression of TREM1 mRNA through NF-кB signaling. Furthermore, activation of the TREM1 signaling pathway, with a targeted agonist, increased HIV or HCV-mediated inflammatory responses in macrophages due to enhanced activation of the ERK1/2 signaling cascade. Silencing TREM1 dampened inflammatory immune responses elicited by HIV or HCV stimulation. Finally, HIV and HCV infected patients exhibit higher expression and frequency of TREM1 and CD68 positive cells. Taken together, TREM1 induction by HIV contributes to chronic inflammation in the liver and targeting TREM1 signaling may be a therapeutic option to minimize HIV induced chronic inflammation.


Assuntos
Infecções por HIV/imunologia , Hepatite C Crônica/imunologia , Receptor Gatilho 1 Expresso em Células Mieloides/imunologia , Estudos de Casos e Controles , Linhagem Celular , Quimiocinas/biossíntese , Citocinas/biossíntese , Infecções por HIV/complicações , Infecções por HIV/genética , Hepatite C Crônica/complicações , Hepatite C Crônica/genética , Humanos , Imunidade Inata/genética , Inflamação/etiologia , Inflamação/genética , Inflamação/imunologia , Macrófagos do Fígado/imunologia , Sistema de Sinalização das MAP Quinases/imunologia , Células Mieloides/imunologia , Transdução de Sinais/imunologia , Receptor Gatilho 1 Expresso em Células Mieloides/genética
10.
Nat Commun ; 10(1): 3371, 2019 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-31358760

RESUMO

TNF-like ligand 1 A (TL1A) and death receptor 3 (DR3) are a ligand-receptor pair involved in the pathogenesis of inflammatory bowel disease. Group 3 innate lymphoid cells (ILC3s) regulate intestinal immunity and highly express DR3. Here, we report that activation of DR3 signaling by an agonistic anti-DR3 antibody increases GM-CSF production from ILC3s through the p38 MAPK pathway. GM-CSF causes accumulation of eosinophils, neutrophils and CD11b+CD11c+ myeloid cells, resulting in loss of ILC3s from the intestine in an IL-23-dependent manner and exacerbating colitis. Blockade of GM-CSF or IL-23 reverses anti-DR3 antibody-driven ILC3 loss, whereas overexpression of IL-23 induces loss of ILC3s in the absence of GM-CSF. Neutralization of TL1A by soluble DR3 ameliorates both DSS and anti-CD40 antibody-induced colitis. Moreover, ILC3s are required for the deleterious effect of anti-DR3 antibodies on innate colitis. These findings clarify the process and consequences of DR3 signaling-induced intestinal inflammation through regulation of ILC3s.


Assuntos
Colite/imunologia , Doenças Inflamatórias Intestinais/imunologia , Linfócitos/imunologia , Membro 25 de Receptores de Fatores de Necrose Tumoral/imunologia , Transdução de Sinais/imunologia , Animais , Anticorpos/imunologia , Anticorpos/farmacologia , Células Cultivadas , Colite/genética , Colite/metabolismo , Eosinófilos/citologia , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Interleucina-23/farmacologia , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Células Mieloides/citologia , Células Mieloides/efeitos dos fármacos , Células Mieloides/imunologia , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Membro 25 de Receptores de Fatores de Necrose Tumoral/genética , Membro 25 de Receptores de Fatores de Necrose Tumoral/metabolismo , Transdução de Sinais/genética
11.
Nat Commun ; 10(1): 2450, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164648

RESUMO

Tumor-associated myeloid cells regulate tumor growth and metastasis, and their accumulation is a negative prognostic factor for breast cancer. Here we find calcium/calmodulin-dependent kinase kinase (CaMKK2) to be highly expressed within intratumoral myeloid cells in mouse models of breast cancer, and demonstrate that its inhibition within myeloid cells suppresses tumor growth by increasing intratumoral accumulation of effector CD8+ T cells and immune-stimulatory myeloid subsets. Tumor-associated macrophages (TAMs) isolated from Camkk2-/- mice expressed higher levels of chemokines involved in the recruitment of effector T cells compared to WT. Similarly, in vitro generated Camkk2-/- macrophages recruit more T cells, and have a reduced capability to suppress T cell proliferation, compared to WT. Treatment with CaMKK2 inhibitors blocks tumor growth in a CD8+ T cell-dependent manner, and facilitates a favorable reprogramming of the immune cell microenvironment. These data, credential CaMKK2 as a myeloid-selective checkpoint, the inhibition of which may have utility in the immunotherapy of breast cancer.


Assuntos
Neoplasias da Mama/imunologia , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/imunologia , Carcinoma/imunologia , Neoplasias Mamárias Animais/imunologia , Células Mieloides/imunologia , Evasão Tumoral/imunologia , Microambiente Tumoral/imunologia , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linfócitos T CD8-Positivos/imunologia , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/genética , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Carcinoma/genética , Carcinoma/metabolismo , Proliferação de Células , Quimiocinas/imunologia , Feminino , Humanos , Imuno-Histoquímica , Técnicas In Vitro , Macrófagos/imunologia , Macrófagos/metabolismo , Neoplasias Mamárias Animais/genética , Neoplasias Mamárias Animais/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Células Mieloides/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/metabolismo , Evasão Tumoral/genética
12.
Nat Commun ; 10(1): 2410, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160587

RESUMO

Medulloblastoma, which is the most common malignant paediatric brain tumour, has a 70% survival rate, but standard treatments often lead to devastating life-long side effects and recurrence is fatal. One of the emerging strategies in the search for treatments is to determine the roles of tumour microenvironment cells in the growth and maintenance of tumours. The most attractive target is tumour-associated macrophages (TAMs), which are abundantly present in the Sonic Hedgehog (SHH) subgroup of medulloblastoma. Here, we report an unexpected beneficial role of TAMs in SHH medulloblastoma. In human patients, decreased macrophage number is correlated with significantly poorer outcome. We confirm macrophage anti-tumoural behaviour in both ex vivo and in vivo murine models of SHH medulloblastoma. Taken together, our findings suggest that macrophages play a positive role by impairing tumour growth in medulloblastoma, in contrast to the pro-tumoural role played by TAMs in glioblastoma, another common brain tumour.


Assuntos
Neoplasias Cerebelares/imunologia , Macrófagos/imunologia , Meduloblastoma/imunologia , Microambiente Tumoral/imunologia , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/metabolismo , Antígeno CD11b/genética , Antígeno CD11b/metabolismo , Proteínas de Ligação ao Cálcio , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/metabolismo , Quimiocina CCL2/imunologia , Quimiocina CCL2/metabolismo , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Proteínas Hedgehog/metabolismo , Humanos , Macrófagos/metabolismo , Meduloblastoma/genética , Meduloblastoma/metabolismo , Camundongos , Proteínas dos Microfilamentos , Microglia/imunologia , Células Mieloides/imunologia , Receptores CCR2/genética , Regulação para Cima
13.
PLoS Genet ; 15(6): e1008178, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31199784

RESUMO

Type 1 diabetes (T1D) is a chronic multi-factorial disorder characterized by the immune-mediated destruction of insulin-producing pancreatic beta cells. Variations at a large number of genes influence susceptibility to spontaneous autoimmune T1D in non-obese diabetic (NOD) mice, one of the most frequently studied animal models for human disease. The genetic analysis of these mice allowed the identification of many insulin-dependent diabetes (Idd) loci and candidate genes, one of them being Cd101. CD101 is a heavily glycosylated transmembrane molecule which exhibits negative-costimulatory functions and promotes regulatory T (Treg) function. It is abundantly expressed on subsets of lymphoid and myeloid cells, particularly within the gastrointestinal tract. We have recently reported that the genotype-dependent expression of CD101 correlates with a decreased susceptibility to T1D in NOD.B6 Idd10 congenic mice compared to parental NOD controls. Here we show that the knockout of CD101 within the introgressed B6-derived Idd10 region increased T1D frequency to that of the NOD strain. This loss of protection from T1D was paralleled by decreased Gr1-expressing myeloid cells and FoxP3+ Tregs and an enhanced accumulation of CD4-positive over CD8-positive T lymphocytes in pancreatic tissues. As compared to CD101+/+ NOD.B6 Idd10 donors, adoptive T cell transfers from CD101-/- NOD.B6 Idd10 mice increased T1D frequency in lymphopenic NOD scid and NOD.B6 Idd10 scid recipients. Increased T1D frequency correlated with a more rapid expansion of the transferred CD101-/- T cells and a lower proportion of recipient Gr1-expressing myeloid cells in the pancreatic lymph nodes. Fewer of the Gr1+ cells in the recipients receiving CD101-/- T cells expressed CD101 and the cells had lower levels of IL-10 and TGF-ß mRNA. Thus, our results connect the Cd101 haplotype-dependent protection from T1D to an anti-diabetogenic function of CD101-expressing Tregs and Gr1-positive myeloid cells and confirm the identity of Cd101 as Idd10.


Assuntos
Antígenos CD/genética , Antígenos Ly/genética , Diabetes Mellitus Tipo 1/genética , Pâncreas/metabolismo , Animais , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Diabetes Mellitus Tipo 1/patologia , Regulação da Expressão Gênica/genética , Predisposição Genética para Doença , Haplótipos/genética , Humanos , Linfonodos/metabolismo , Linfonodos/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Células Mieloides/imunologia , Células Mieloides/metabolismo , Pâncreas/patologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
14.
Cell Mol Life Sci ; 76(20): 3917-3937, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31250035

RESUMO

The gastrointestinal tract is the site of nutrient digestion and absorption and is also colonized by diverse, highly mutualistic microbes. The intestinal microbiota has diverse effects on the development and function of the gut-specific immune system, and provides some protection from infectious pathogens. However, interactions between intestinal immunity and microorganisms are very complex, and recent studies have revealed that this intimate crosstalk may depend on the production and sensing abilities of multiple bioactive small molecule metabolites originating from direct produced by the gut microbiota or by the metabolism of dietary components. Here, we review the interplay between the host immune system and the microbiota, how commensal bacteria regulate the production of metabolites, and how these microbiota-derived products influence the function of several major innate and adaptive immune cells involved in modulating host immune homeostasis.


Assuntos
Imunidade Adaptativa , Disbiose/metabolismo , Microbioma Gastrointestinal/imunologia , Imunidade Inata , Mucosa Intestinal/metabolismo , Metaboloma/imunologia , Aminoácidos/imunologia , Aminoácidos/metabolismo , Animais , Ácidos e Sais Biliares/imunologia , Ácidos e Sais Biliares/metabolismo , Disbiose/imunologia , Disbiose/microbiologia , Disbiose/terapia , Ácidos Graxos/imunologia , Ácidos Graxos/metabolismo , Transplante de Microbiota Fecal , Vida Livre de Germes/imunologia , Homeostase/imunologia , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Linfócitos/imunologia , Linfócitos/metabolismo , Linfócitos/microbiologia , Células Mieloides/imunologia , Células Mieloides/metabolismo , Células Mieloides/microbiologia , Simbiose/imunologia
15.
Nat Immunol ; 20(7): 902-914, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209404

RESUMO

Lupus nephritis is a potentially fatal autoimmune disease for which the current treatment is ineffective and often toxic. To develop mechanistic hypotheses of disease, we analyzed kidney samples from patients with lupus nephritis and from healthy control subjects using single-cell RNA sequencing. Our analysis revealed 21 subsets of leukocytes active in disease, including multiple populations of myeloid cells, T cells, natural killer cells and B cells that demonstrated both pro-inflammatory responses and inflammation-resolving responses. We found evidence of local activation of B cells correlated with an age-associated B-cell signature and evidence of progressive stages of monocyte differentiation within the kidney. A clear interferon response was observed in most cells. Two chemokine receptors, CXCR4 and CX3CR1, were broadly expressed, implying a potentially central role in cell trafficking. Gene expression of immune cells in urine and kidney was highly correlated, which would suggest that urine might serve as a surrogate for kidney biopsies.


Assuntos
Rim/imunologia , Nefrite Lúpica/imunologia , Biomarcadores , Biópsia , Análise por Conglomerados , Biologia Computacional/métodos , Células Epiteliais/metabolismo , Citometria de Fluxo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Imunofenotipagem , Interferons/metabolismo , Rim/metabolismo , Rim/patologia , Leucócitos/imunologia , Leucócitos/metabolismo , Nefrite Lúpica/genética , Nefrite Lúpica/metabolismo , Nefrite Lúpica/patologia , Linfócitos/imunologia , Linfócitos/metabolismo , Anotação de Sequência Molecular , Células Mieloides/imunologia , Células Mieloides/metabolismo , Análise de Célula Única , Transcriptoma
16.
J Immunol Res ; 2019: 4260987, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31211147

RESUMO

Bone metastases are prevalent in many common cancers such as breast, prostate, and lung cancers, and novel therapies for treating bone metastases are needed. Human immune system-engrafted models are used in immuno-oncology (IO) studies for subcutaneous cancer cell or patient-derived xenograft implantations that mimic primary tumor growth. Novel efficacy models for IO compounds on bone metastases need to be established. The study was performed using CIEA NOG (NOG) mice engrafted with human CD34+ hematopoietic stem cells (huNOG) and age-matched immunodeficient NOG mice. Bone phenotyping was performed to evaluate baseline differences. BT-474 human breast cancer cells were inoculated into the tibia bone marrow, and cancer-induced bone changes were monitored by X-ray imaging. Bone content and volume were analyzed by dual X-ray absorptiometry and microcomputed tomography. Tumor-infiltrating lymphocytes (TILs) and the expression of immune checkpoint markers were analyzed by immunohistochemistry. Bone phenotyping showed no differences in bone architecture or volume of the healthy bones in huNOG and NOG mice, but the bone marrow fat was absent in huNOG mice. Fibrotic areas were observed in the bone marrow of some huNOG mice. BT-474 tumors induced osteoblastic bone growth. Bone lesions appeared earlier and were larger, and bone mineral density was higher in huNOG mice. huNOG mice had a high number of human CD3-, CD4-, and CD8-positive T cells and CD20-positive B cells in immune-related organs. A low number of TILs and PD-1-positive cells and low PD-L1 expression were observed in the BT-474 tumors at the endpoint. This study reports characterization of the first breast cancer bone growth model in huNOG mice. BT-474 tumors represent a "cold" tumor with a low number of TILs. This model can be used for evaluating the efficacy of combination treatments of IO therapies with immune-stimulatory compounds or therapeutic approaches on bone metastatic breast cancer.


Assuntos
Desenvolvimento Ósseo , Osso e Ossos/imunologia , Osso e Ossos/metabolismo , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Osteoblastos/metabolismo , Animais , Biomarcadores , Desenvolvimento Ósseo/imunologia , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Linfócitos/imunologia , Linfócitos/metabolismo , Camundongos , Células Mieloides/imunologia , Células Mieloides/metabolismo , Microtomografia por Raio-X
17.
Molecules ; 24(11)2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31212694

RESUMO

Recent evidence suggests that PPARγ agonists may promote anti-tumor immunity. We show that immunogenic PDV cutaneous squamous cell carcinoma (CSCC) tumors are rejected when injected intradermally at a low cell number (1 × 106) into immune competent syngeneic hosts, but not immune deficient mice. At higher cell numbers (5 × 106 PDV cells), progressively growing tumors were established in 14 of 15 vehicle treated mice while treatment of mice with the PPARγ agonist rosiglitazone resulted in increased tumor rejection (5 of 14 tumors), a significant decrease in PDV tumor size, and a significant decrease in tumor cell Ki67 labeling. Rosiglitazone treatment had no effect on tumor rejection, tumor volume or PDV tumor cell proliferation in immune deficient NOD.CB17-PrkdcSCID/J mice. Rosiglitazone treatment also promoted an increase in tumor infiltrating CD3+ T-cells at both early and late time points. In contrast, rosiglitazone treatment had no significant effect on myeloid cells expressing either CD11b or Gr-1 but suppressed a late accumulation of myeloid cells expressing both CD11b and Gr-1, suggesting a potential role for CD11b+Gr-1+ myeloid cells in the late anti-tumor immune response. Overall, our data provides evidence that the PPARγ agonist rosiglitazone promotes immune-mediated anti-neoplastic activity against tumors derived from this immunogenic CSCC cell line.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/metabolismo , Hipoglicemiantes/farmacologia , Imunomodulação/efeitos dos fármacos , PPAR gama/agonistas , Rosiglitazona/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células Mieloides/efeitos dos fármacos , Células Mieloides/imunologia , Células Mieloides/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transplante Isogênico , Carga Tumoral/efeitos dos fármacos
18.
Immunol Invest ; 48(7): 704-718, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31044626

RESUMO

Immunoglobulin-like transcript (ILT) 4 is an inhibitory immune receptor of the immunoglobulin superfamily, which could deliver inhibitory signals and induce immunosuppression. The significance of the expression of ILT4 in mDCs subsets in patients with hepatocellular carcinoma (HCC) remains unclear. In this study, the frequency of mDCs subsets in the peripheral blood of 121 patients with HCC and 103 normal controls, and in the tumor and tumor free liver tissues (TFL) of 43 HCC patients was analyzed by flow cytometry. Then, the expressions of ILT4 in mDCs subsets in the microenvironment of liver cancer were also analyzed. Results showed that the percentage of CD1c+ subset was dramatically decreased in peripheral blood mononuclear cells (PBMCs) of HCC patients compared with normal controls, and also significantly decreased in tumor tissue compared with the TFL. The decreased of CD1c+ subset in blood could be a diagnostic factor for HCC with the area under the receiver operating characteristic curve 0.975 (P < 0.01). The percentage of ILT4+CD1c+ subset was dramatically increased in tumor than that of TFL and blood. There were significant correlations between the percentage of ILT4+ in CD1c+ subset in tumor and that of in blood. The percentage of ILT4+CD1c+ subset in tumor tissue was strongly associated with the Edmondson-Steiner stage in HCC (P = 0.03). Furthermore, the capacity of ILT4+CD1c+ subset producing IFN-γ was lower than ILT4- CD1c subset in PBMC of HCC patients following Poly I:C stimulation. Taken together, the increased ILT4+CD1c+ subset in tumor tissue might play an important role in immune suppression for patients with HCC.


Assuntos
Carcinoma Hepatocelular/imunologia , Células Dendríticas/imunologia , Neoplasias Hepáticas/imunologia , Glicoproteínas de Membrana/imunologia , Células Mieloides/imunologia , Receptores Imunológicos/imunologia , Antígenos CD1/imunologia , Biomarcadores Tumorais/imunologia , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/patologia , Células Dendríticas/patologia , Feminino , Glicoproteínas/imunologia , Humanos , Interferon gama/metabolismo , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Células Mieloides/patologia , Poli I-C/farmacologia , Curva ROC , Microambiente Tumoral
19.
Am Soc Clin Oncol Educ Book ; 39: 165-174, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31099649

RESUMO

Emerging immunotherapeutic approaches have revolutionized the treatment of multiple malignancies. Immune checkpoint blockers (ICBs) have enabled never-before-seen success rates in durable tumor control and enhanced survival benefit in patients with advanced cancers. However, this effect is not universal, resulting in responder and nonresponder populations not only between, but also within solid tumor types. Although ICBs are thought to be most effective against tumors with more genetic mutations and higher antigen loads, this is not always the case for all cancers or for all patients within a cancer subtype. Furthermore, debilitating and sometimes deadly immune-related adverse events (irAEs) have resulted from aberrant activation of T-cell responses following immunotherapy. Thus, we must identify new ways to overcome resistance to ICB-based immunotherapies and limit irAEs. In fact, preclinical and clinical data have identified abnormalities in the tumor microenvironment (TME) that can thwart the efficacy of immunotherapies such as ICBs. Here, we will discuss how reprogramming various facets of the TME (blood vessels, myeloid cells, and regulatory T cells [Tregs]) may overcome TME-instigated resistance mechanisms to immunotherapy. We will discuss clinical applications of this strategic approach, including the recent successful phase III trial combining bevacizumab with atezolizumab and chemotherapy for metastatic nonsquamous non-small cell lung cancer that led to rapid approval by the U.S. Food and Drug Administration of this regimen for first-line treatment. Given the accelerated testing and approval of ICBs combined with various targeted therapies in larger numbers of patients with cancer, we will discuss how these concepts and approaches can be incorporated into clinical practice to improve immunotherapy outcomes.


Assuntos
Reprogramação Celular/genética , Reprogramação Celular/imunologia , Neoplasias/etiologia , Neoplasias/patologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Animais , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais , Terapia Combinada , Progressão da Doença , Humanos , Imunomodulação , Imunoterapia , Terapia de Alvo Molecular , Células Mieloides/imunologia , Células Mieloides/metabolismo , Neoplasias/terapia , Neovascularização Patológica/genética , Neovascularização Patológica/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Resultado do Tratamento
20.
EBioMedicine ; 44: 60-70, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31130476

RESUMO

BACKGROUND: Mature myeloid cells play a crucial role in Crohn's disease (CD) but the molecular players that regulate their functions in CD are not fully characterized. We and others have shown that TRIM33 is involved in the innate immune response and in the inflammatory response but TRIM33 role in intestinal inflammation is not known. In this study, we investigated the role of TRIM33 in myeloid cells during dextran sulfate sodium (DSS)-induced colitis. METHODS: We study the role of TRIM33 during DSS-induced colitis which mimics intestinal inflammation using mice deleted for Trim33 only in mature myeloid cells (Trim33-/- mice) FINDINGS: We first show that Trim33 mRNA level is decreased in CD patient's blood monocytes suggesting a role of TRIM33 in CD. Using Trim33-/- mice, we show that these mice display an impaired resolution of colonic inflammation with an increased number of blood and colon monocytes and a decreased number of colonic macrophages. Trim33-/- monocytes are less competent for recruitment and macrophage differentiation. Finally, during resolution of inflammation, Trim33-/- colonic macrophages display an impaired M1/M2 switch and express a low level of membrane-bound TNF that is associated with an increased number of colonic neutrophils. INTERPRETATION: Our study shows an important role of TRIM33 in monocytes/macrophages during DSS-induced colitis and suggests that the decreased expression of TRIM33 in CD patient's blood monocytes might not be a consequence but might be involved in CD progression. FUND: La Ligue contre le Cancer (équipe labelisée), INSERM, CEA, Université Paris-Diderot, Université Paris-Sud.


Assuntos
Colite/etiologia , Macrófagos/metabolismo , Monócitos/metabolismo , Fatores de Transcrição/deficiência , Animais , Biomarcadores , Colite/metabolismo , Colite/patologia , Doença de Crohn/etiologia , Doença de Crohn/metabolismo , Doença de Crohn/patologia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Camundongos , Camundongos Knockout , Monócitos/imunologia , Células Mieloides/imunologia , Células Mieloides/metabolismo , RNA Mensageiro
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA