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1.
Nat Immunol ; 22(10): 1231-1244, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34556887

RESUMO

The generation of lymphoid tissues during embryogenesis relies on group 3 innate lymphoid cells (ILC3) displaying lymphoid tissue inducer (LTi) activity and expressing the master transcription factor RORγt. Accordingly, RORγt-deficient mice lack ILC3 and lymphoid structures, including lymph nodes (LN). Whereas T-bet affects differentiation and functions of ILC3 postnatally, the role of T-bet in regulating fetal ILC3 and LN formation remains completely unknown. Using multiple mouse models and single-cell analyses of fetal ILCs and ILC progenitors (ILCP), here we identify a key role for T-bet during embryogenesis and show that its deficiency rescues LN formation in RORγt-deficient mice. Mechanistically, T-bet deletion skews the differentiation fate of fetal ILCs and promotes the accumulation of PLZFhi ILCP expressing central LTi molecules in a RORα-dependent fashion. Our data unveil an unexpected role for T-bet and RORα during embryonic ILC function and highlight that RORγt is crucial in counteracting the suppressive effects of T-bet.


Assuntos
Diferenciação Celular/imunologia , Imunidade Inata/imunologia , Linfonodos/imunologia , Linfócitos/imunologia , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Proteínas com Domínio T/imunologia , Animais , Linhagem da Célula/imunologia , Feminino , Tecido Linfoide/imunologia , Camundongos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Linfócitos T Auxiliares-Indutores/imunologia
2.
Nat Immunol ; 22(10): 1245-1255, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34556884

RESUMO

Innate lymphoid cells (ILCs) are guardians of mucosal immunity, yet the transcriptional networks that support their function remain poorly understood. We used inducible combinatorial deletion of key transcription factors (TFs) required for ILC development (RORγt, RORα and T-bet) to determine their necessity in maintaining ILC3 identity and function. Both RORγt and RORα were required to preserve optimum effector functions; however, RORα was sufficient to support robust interleukin-22 production among the lymphoid tissue inducer (LTi)-like ILC3 subset, but not natural cytotoxicity receptor (NCR)+ ILC3s. Lymphoid tissue inducer-like ILC3s persisted with only selective loss of phenotype and effector functions even after the loss of both TFs. In contrast, continued RORγt expression was essential to restrain transcriptional networks associated with type 1 immunity within NCR+ ILC3s, which coexpress T-bet. Full differentiation to an ILC1-like population required the additional loss of RORα. Together, these data demonstrate how TF networks integrate within mature ILCs after development to sustain effector functions, imprint phenotype and restrict alternative differentiation programs.


Assuntos
Imunidade Inata/imunologia , Linfócitos/imunologia , Animais , Diferenciação Celular/imunologia , Linhagem da Célula/imunologia , Células Cultivadas , Feminino , Regulação da Expressão Gênica/imunologia , Imunidade nas Mucosas/imunologia , Tecido Linfoide/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Proteínas com Domínio T/imunologia , Fatores de Transcrição/imunologia
3.
Invest Ophthalmol Vis Sci ; 62(10): 27, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34427624

RESUMO

Purpose: We aimed to evaluate activation of conjunctiva-associated lymphoid tissue (CALT) in patients with keratitis using in vivo confocal microscopy (IVCM) and conjunctival impression cytology (CIC). Methods: In addition to anterior segment photography and corneal fluorescein staining, IVCM revealed the palpebral conjunctiva in all subjects, and CIC and immunofluorescence staining were performed. Results: Diffuse lymphoid tissue cell density in the eyes of patients with keratitis was significantly greater compared with healthy volunteers (P < 0.001). Similar trends were found in perifollicular lymphocyte density (P < 0.001), follicular density (P = 0.029), follicular center reflection intensity (P = 0.011), and follicular area (P < 0.001). Immunofluorescence staining showed that the proportions of CD4+ (61.7% ± 8.0% vs. 17.3% ± 10.2%, respectively, P < 0.001) and CD8+ (46.9% ± 10.0% vs. 19.6% ± 11.5%, respectively, P < 0.001) cells in patients with keratitis was greater compared with healthy volunteers. Interestingly, we also observed changes in the contralateral eye in subjects with keratitis. Conclusions: Our research suggests that CALT, as an ocular immune structure, is activated and plays an important role in the pathogenesis of keratitis. This has been overlooked previously. CALT is also active in the contralateral eye of subjects with keratitis.


Assuntos
Túnica Conjuntiva/patologia , Córnea/patologia , Infecções Oculares Bacterianas/patologia , Imunidade Celular , Ceratite/patologia , Tecido Linfoide/patologia , Adulto , Túnica Conjuntiva/imunologia , Córnea/metabolismo , Infecções Oculares Bacterianas/imunologia , Infecções Oculares Bacterianas/metabolismo , Feminino , Humanos , Ceratite/imunologia , Ceratite/metabolismo , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Masculino , Microscopia Confocal , Pessoa de Meia-Idade , Estudos Retrospectivos
4.
Aging (Albany NY) ; 13(15): 19920-19941, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34382946

RESUMO

Immunosenescence is a multi-faceted phenomenon at the root of age-associated immune dysfunction. It can lead to an array of pathological conditions, including but not limited to a decreased capability to surveil and clear senescent cells (SnCs) and cancerous cells, an increased autoimmune responses leading to tissue damage, a reduced ability to tackle pathogens, and a decreased competence to illicit a robust response to vaccination. Cellular senescence is a phenomenon by which oncogene-activated, stressed or damaged cells undergo a stable cell cycle arrest. Failure to efficiently clear SnCs results in their accumulation in an organism as it ages. SnCs actively secrete a myriad of molecules, collectively called senescence-associated secretory phenotype (SASP), which are factors that cause dysfunction in the neighboring tissue. Though both cellular senescence and immunosenescence have been studied extensively and implicated in various pathologies, their relationship has not been greatly explored. In the wake of an ongoing pandemic (COVID-19) that disproportionately affects the elderly, immunosenescence as a function of age has become a topic of great importance. The goal of this review is to explore the role of cellular senescence in age-associated lymphoid organ dysfunction and immunosenescence, and provide a framework to explore therapies to rejuvenate the aged immune system.


Assuntos
Envelhecimento/imunologia , Senescência Celular/imunologia , Imunossenescência , Tecido Linfoide/imunologia , COVID-19/imunologia , Humanos
5.
Sci Rep ; 11(1): 16394, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34385480

RESUMO

The spleen, a secondary lymphoid tissue (SLT), has an important role in generation of adaptive immune responses. Although splenectomy remains a common procedure, recent studies reported poor prognosis and increased risk of haematological malignancies in asplenic patients. The high baseline trafficking of T lymphocytes to splenic tissue suggests splenectomy may lead to loss of blood-borne malignant immunosurveillance that is not compensated for by the remaining SLT. To date, no quantitative analysis of the impact of splenectomy on the human T cell trafficking dynamics and tissue localisation has been reported. We developed a quantitative computational model that describes organ distribution and trafficking of human lymphocytes to explore the likely impact of splenectomy on immune cell distributions. In silico splenectomy resulted in an average reduction of T cell numbers in SLT by 35% (95%CI 0.12-0.97) and a comparatively lower, 9% (95%CI 0.17-1.43), mean decrease of T cell concentration in SLT. These results suggest that the surveillance capacity of the remaining SLT insufficiently compensates for the absence of the spleen. This may, in part, explain haematological malignancy risk in asplenic patients and raises the question of whether splenectomy has a clinically meaningful impact on patient responses to immunotherapy.


Assuntos
Neoplasias Hematológicas/imunologia , Tecido Linfoide/imunologia , Esplenopatias/imunologia , Linfócitos T/imunologia , Humanos , Linfócitos/imunologia , Baço/imunologia , Esplenectomia/métodos
6.
J Clin Invest ; 131(16)2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34396986

RESUMO

Therapeutic vaccines that augment T cell responses to tumor antigens have been limited by poor potency in clinical trials. In contrast, the transfer of T cells modified with foreign transgenes frequently induces potent endogenous T cell responses to epitopes in the transgene product, and these responses are undesirable, because they lead to rejection of the transferred T cells. We sought to harness gene-modified T cells as a vaccine platform and developed cancer vaccines composed of autologous T cells modified with tumor antigens and additional adjuvant signals (Tvax). T cells expressing model antigens and a broad range of tumor neoantigens induced robust and durable T cell responses through cross-presentation of antigens by host DCs. Providing Tvax with signals such as CD80, CD137L, IFN-ß, IL-12, GM-CSF, and FLT3L enhanced T cell priming. Coexpression of IL-12 and GM-CSF induced the strongest CD4+ and CD8+ T cell responses through complimentary effects on the recruitment and activation of DCs, mediated by autocrine IL-12 receptor signaling in the Tvax. Therapeutic vaccination with Tvax and adjuvants showed antitumor activity in subcutaneous and metastatic preclinical mouse models. Human T cells modified with neoantigens readily activated specific T cells derived from patients, providing a path for clinical translation of this therapeutic platform in cancer.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/uso terapêutico , Adjuvantes Imunológicos/administração & dosagem , Aloenxertos , Animais , Apresentação do Antígeno , Antígenos de Neoplasias/administração & dosagem , Autoenxertos , Linfócitos T CD8-Positivos/transplante , Vacinas Anticâncer/imunologia , Reações Cruzadas/imunologia , Células Dendríticas/imunologia , Feminino , Humanos , Memória Imunológica , Imunoterapia Adotiva , Interleucina-12/imunologia , Tecido Linfoide/imunologia , Masculino , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pesquisa Médica Translacional
7.
Int J Mol Sci ; 22(13)2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34206847

RESUMO

Recently, we clarified the function of mediastinal fat-associated lymphoid clusters (MFALCs) in the progression of several respiratory diseases. However, their role has not yet been identified in the lung asthmatic condition. Hence, we compared the immune cells in lung and MFALCs of C57BL/6N mice on days 3 and 7 following intranasal instillation of either papain (papain group "PG") or phosphate buffer saline (PBS) (vehicle group "VG"). The PG showed significantly prominent MFALCs, numerous goblet cells (GCs), and higher index ratios of different immune cells (macrophages, natural helper cells (NHC), B- and T-lymphocytes) within the MFALCs and lung than in the VG on both days 3 and 7. Interestingly, a tendency of decreased size of MFALCs and a significant reduction in the number of GCs and immune cells were observed within the MFALCs and lung in the PG on day 7 than on day 3. Furthermore, the quantitative parameters of these immune cells in MFALCs were significantly and positively correlated with the size of MFALCs and immune cells in the lung. This suggested that the possible crosstalk between immune cells within MFALCs and the lung could play a critical role in the progression and recovery of the acute inflammatory lung asthma.


Assuntos
Asma/imunologia , Pulmão/imunologia , Tecido Linfoide/imunologia , Macrófagos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Tecido Adiposo/imunologia , Animais , Células Cultivadas , Células Caliciformes/imunologia , Imunidade Inata , Masculino , Mediastino , Camundongos , Camundongos Endogâmicos C57BL
8.
J Clin Invest ; 131(18)2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34314390

RESUMO

NK cell suppression of T cells is a key determinant of viral pathogenesis and vaccine efficacy. This process involves perforin-dependent elimination of activated CD4+ T cells during the first 3 days of infection. Although this mechanism requires cell-cell contact, NK cells and T cells typically reside in different compartments of lymphoid tissues at steady state. Here, we showed that NK cell suppression of T cells is associated with transient accumulation of NK cells within T cell-rich sites of the spleen during lymphocytic choriomeningitis virus infection. The chemokine receptor CXCR3 was required for this relocation and suppression of antiviral T cells. Accordingly, NK cell migration was mediated by type I IFN-dependent promotion of CXCR3 ligand expression. In contrast, adenoviral vectors that weakly induced type I IFN and did not stimulate NK cell inhibition of T cells also did not promote measurable redistribution of NK cells to T cell zones. Exogenous IFN rescued NK cell migration during adenoviral vector immunization. Thus, type I IFN and CXCR3 were critical for properly positioning NK cells to constrain antiviral T cell responses. Development of strategies to curtail migration of NK cells between lymphoid compartments may enhance vaccine-elicited immune responses.


Assuntos
Células Matadoras Naturais/imunologia , Tecido Linfoide/imunologia , Receptores CXCR3/metabolismo , Animais , Movimento Celular/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Tolerância Imunológica , Imunidade Inata , Ativação Linfocitária , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T/imunologia
9.
Aging (Albany NY) ; 13(11): 14590-14603, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083496

RESUMO

CD8+ cytotoxic T-lymphocytes are essential components of the anti-tumor immunity. To better understand the expansion of CD8+ T-cells we used multiplex fluorescence immunohistochemistry to study Ki67+CD8+ cells in normal lymphoid tissues, selected inflammatory diseases and cancers in 41 large sections/ microenvironment tissue microarrays (TMAs) as well as 765 samples in a conventional TMA format. The evaluation of more than 20 different compartments of normal lymphoid tissues revealed that the percentage of proliferating (ki67+) CD8+ cells did commonly not exceed 3%. In inflammations, the percentage of Ki67+CD8+ cells was more variable and higher compared to normal tissues. In cancers, the percentage of Ki67+CD8+ cells was higher in the tumor center than at the invasive margin. In the tumor center of 765 colorectal cancers, the density of Ki67+CD8+ cells and the percentage of proliferating CD8+ cytotoxic T-cells was significantly associated with microsatellite instability (p<0.0001), pT (p<0.0002) and pN category (p<0.0098). In summary, these data show that the percentage of Ki67+CD8+ cells is usually at a baseline proliferation rate below 3% in healthy secondary lymphoid organs. This rate is often markedly higher in inflammatory and neoplastic diseases compared to normal tissues. The striking link with unfavorable tumor features in colorectal cancer suggest a potential clinical utility of assessing the percentage of Ki67+CD8+ cells to predict patients outcome.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Neoplasias Colorretais/imunologia , Inflamação/imunologia , Tecido Linfoide/imunologia , Proliferação de Células , Neoplasias Colorretais/patologia , Humanos , Antígeno Ki-67/metabolismo , Fenótipo
10.
Front Immunol ; 12: 688886, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34135912

RESUMO

Background: Despite successful ART in people living with HIV infection (PLHIV) they experience increased morbidity and mortality compared with HIV-negative controls. A dominant paradigm is that gut-associated lymphatic tissue (GALT) destruction at the time of primary HIV infection leads to loss of gut integrity, pathological microbial translocation across the compromised gastrointestinal barrier and, consequently, systemic inflammation. We aimed to identify and measure specific changes in the gastrointestinal barrier that might allow bacterial translocation, and their persistence despite initiation of antiretroviral therapy (ART). Method: We conducted a cross-sectional study of the gastrointestinal (GIT) barrier in PLHIV and HIV-uninfected controls (HUC). The GIT barrier was assessed as follows: in vivo mucosal imaging using confocal endomicroscopy (CEM); the immunophenotype of GIT and circulating lymphocytes; the gut microbiome; and plasma inflammation markers Tumour Necrosis Factor-α (TNF-α) and Interleukin-6 (IL-6); and the microbial translocation marker sCD14. Results: A cohort of PLHIV who initiated ART early, during primary HIV infection (PHI), n=5), and late (chronic HIV infection (CHI), n=7) infection were evaluated for the differential effects of the stage of ART initiation on the GIT barrier compared with HUC (n=6). We observed a significant decrease in the CD4 T-cell count of CHI patients in the left colon (p=0.03) and a trend to a decrease in the terminal ileum (p=0.13). We did not find evidence of increased epithelial permeability by CEM. No significant differences were found in microbial translocation or inflammatory markers in plasma. In gut biopsies, CD8 T-cells, including resident intraepithelial CD103+ cells, did not show any significant elevation of activation in PLHIV, compared to HUC. The majority of residual circulating activated CD38+HLA-DR+ CD8 T-cells did not exhibit gut-homing integrins α4ß7, suggesting that they did not originate in GALT. A significant reduction in the evenness of species distribution in the microbiome of CHI subjects (p=0.016) was observed, with significantly higher relative abundance of the genus Spirochaeta in PHI subjects (p=0.042). Conclusion: These data suggest that substantial, non-specific increases in epithelial permeability may not be the most important mechanism of HIV-associated immune activation in well-controlled HIV-positive patients on antiretroviral therapy. Changes in gut microbiota warrant further study.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Translocação Bacteriana , Microbioma Gastrointestinal , Infecções por HIV/tratamento farmacológico , Sobreviventes de Longo Prazo ao HIV , Mucosa Intestinal/microbiologia , Adulto , Biomarcadores/sangue , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Estudos de Casos e Controles , Estudos Transversais , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Imunidade nas Mucosas , Interleucina-6/sangue , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Receptores de Lipopolissacarídeos/sangue , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Masculino , Pessoa de Meia-Idade , Permeabilidade , Projetos Piloto , Resultado do Tratamento , Fator de Necrose Tumoral alfa/sangue
11.
Front Immunol ; 12: 665968, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34135894

RESUMO

Through food intake, humans obtain a variety of nutrients that are essential for growth, cellular function, tissue development, energy, and immune defense. A special interaction between nutrients and gut-associated lymphoid tissue occurs in the intestinal tract. Enterocytes of the intestinal barrier act as sensors for antigens from nutrients and the intestinal microbiota, which they deliver to the underlying immune system of the lamina propria, triggering an immune response. Studies investigating the mechanism of influence of nutrition on immunological outcomes have highlighted an important role of macronutrients (proteins, carbohydrates, fatty acids) and micronutrients (vitamins, minerals, phytochemicals, antioxidants, probiotics) in modulating immune homeostasis. Nutrients exert their role in innate immunity and inflammation by regulating the expression of TLRs, pro- and anti-inflammatory cytokines, thus interfering with immune cell crosstalk and signaling. Chemical substrates derived from nutrient metabolism may act as cofactors or blockers of enzymatic activity, influencing molecular pathways and chemical reactions associated with microbial killing, inflammation, and oxidative stress. Immune cell function appears to be influenced by certain nutrients that form parts of the cell membrane structure and are involved in energy production and prevention of cytotoxicity. Nutrients also contribute to the initiation and regulation of adaptive immune responses by modulating B and T lymphocyte differentiation, proliferation and activation, and antibody production. The purpose of this review is to present the available data from the field of nutritional immunology to elucidate the complex and dynamic relationship between nutrients and the immune system, the delineation of which will lead to optimized nutritional regimens for disease prevention and patient care.


Assuntos
Imunidade/imunologia , Mucosa Intestinal/imunologia , Tecido Linfoide/imunologia , Nutrientes/imunologia , Anticorpos/imunologia , Células Apresentadoras de Antígenos/imunologia , Citocinas/imunologia , Microbioma Gastrointestinal/imunologia , Humanos , Mucosa Intestinal/microbiologia , Linfócitos/imunologia , Micronutrientes/deficiência , Micronutrientes/imunologia , Nutrientes/deficiência
12.
Cell Immunol ; 366: 104396, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34157462

RESUMO

Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections are characterized by dramatic alterations in the mucosal CD4 T cell compartment. Though viremia is effectively suppressed, and peripheral CD4 T cell numbers recover to near healthy levels after highly active anti-retroviral therapy (HAART), some of the dysfunctional consequences of HIV infection continue to persist during therapy. We hypothesized that CD4 T follicular helper (Tfh) cell deficiencies may play a role in this process. Using the macaque model we show that SIV infection was associated with a significant loss of Tfh cells in the GALT that drain the mesentery lining the gastrointestinal tract (GIT). Loss of Tfh cells significantly correlated with the depletion of the overall memory CD4 T cell compartment; most Tfh cells in the GALT expressed a CD95+CD28+ memory phenotype suggesting that infection of the memory compartment likely drives the loss of GALT Tfh cells during infection. Continuous anti-retroviral therapy (cART) was accompanied by a significant repopulation of Tfh cells in the GALT to levels similar to those of uninfected animals. Repopulating Tfh cells displayed significantly higher capacity to produce IL-21 as compared to SIV infected animals suggesting that cART fully restores Tfh cells that are functionally capable of supporting GC reactions in the GALT.


Assuntos
Terapia Antirretroviral de Alta Atividade/métodos , Linfócitos T CD4-Positivos/imunologia , Centro Germinativo/imunologia , Infecções por HIV/tratamento farmacológico , HIV-1/fisiologia , Intestinos/imunologia , Tecido Linfoide/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Vírus da Imunodeficiência Símia/fisiologia , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Movimento Celular , Modelos Animais de Doenças , Infecções por HIV/imunologia , Humanos , Memória Imunológica , Interleucinas/metabolismo , Linfopenia , Macaca , Receptor de Morte Celular Programada 1/metabolismo , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia
13.
Eur J Immunol ; 51(9): 2188-2205, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34189723

RESUMO

Innate lymphoid cells (ILCs), a critical component of the immune system, have recently been nominated as emerging players associated with tumor progression and inhibition. ILCs are classified into five groups: natural killer (NK) cells, ILC1s, ILC2s, ILC3s, and lymphoid tissue inducer (LTis) cells. NK cells and ILC1s are mainly involved in antitumor activities due to their cytotoxic and cytokine production capabilities, respectively. The current understanding of the heterogeneous behavior of ILC2s and ILC3s in tumors is limited and incomplete. Mostly, their dual roles are modulated by their resident tissues, released cytokines, cancer types, and plasticity. Based on overlap RORγt and cytokine expression, the LTi cells were previously considered part of the ILC3s ontogeny, which are essential for the formation of the secondary lymphoid organs during embryogenesis. Indeed, these facts highlight the urgency in understanding the respective mechanisms that shape the phenotypes and responses of ILCs, either on the repressive or proliferative side in the tumor microenvironment (TME). This review aims to provide an updated view of ILCs biology with respect to tumorigenesis, including a description of ILC plasticity, their interaction with other immune cells and communication with components of the TME. Taken together, targeting ILCs for cancer immunotherapy could be a promising approach against tumors that needs to be further study.


Assuntos
Imunidade Inata/imunologia , Células Matadoras Naturais/imunologia , Subpopulações de Linfócitos/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias/imunologia , Microambiente Tumoral/imunologia , Carcinogênese/imunologia , Carcinogênese/patologia , Citocinas/imunologia , Humanos , Imunoterapia/métodos , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Neoplasias/patologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia
14.
PLoS Pathog ; 17(5): e1009575, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33961680

RESUMO

HIV-infected infants are at an increased risk of progressing rapidly to AIDS in the first weeks of life. Here, we evaluated immunological and virological parameters in 25 SIV-infected infant rhesus macaques to understand the factors influencing a rapid disease outcome. Infant macaques were infected with SIVmac251 and monitored for 10 to 17 weeks post-infection. SIV-infected infants were divided into either typical (TypP) or rapid (RP) progressor groups based on levels of plasma anti-SIV antibody and viral load, with RP infants having low SIV-specific antibodies and high viral loads. Following SIV infection, 11 out of 25 infant macaques exhibited an RP phenotype. Interestingly, TypP had lower levels of total CD4 T cells, similar reductions in CD4/CD8 ratios and elevated activation of CD8 T cells, as measured by the levels of HLA-DR, compared to RP. Differences between the two groups were identified in other immune cell populations, including a failure to expand activated memory (CD21-CD27+) B cells in peripheral blood in RP infant macaques, as well as reduced levels of germinal center (GC) B cells and T follicular helper (Tfh) cells in spleens (4- and 10-weeks post-SIV). Reduced B cell proliferation in splenic germinal GCs was associated with increased SIV+ cell density and follicular type 1 interferon (IFN)-induced immune activation. Further analyses determined that at 2-weeks post SIV infection TypP infants exhibited elevated levels of the GC-inducing chemokine CXCL13 in plasma, as well as significantly lower levels of viral envelope diversity compared to RP infants. Our findings provide evidence that early viral and immunologic events following SIV infection contributes to impairment of B cells, Tfh cells and germinal center formation, ultimately impeding the development of SIV-specific antibody responses in rapidly progressing infant macaques.


Assuntos
Progressão da Doença , Imunidade Humoral , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/imunologia , Animais , Linfócitos B/imunologia , Linfócitos B/virologia , Variação Genética , Centro Germinativo/imunologia , Centro Germinativo/virologia , Humanos , Interferon Tipo I/imunologia , Tecido Linfoide/imunologia , Tecido Linfoide/virologia , Macaca mulatta , Fenótipo , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/genética , Carga Viral
15.
Front Immunol ; 12: 607282, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33854497

RESUMO

Over the past decade, immunotherapies have revolutionized the treatment of cancer. Although the success of immunotherapy is remarkable, it is still limited to a subset of patients. More than 1500 clinical trials are currently ongoing with a goal of improving the efficacy of immunotherapy through co-administration of other agents. Preclinical, small-animal models are strongly desired to increase the pace of scientific discovery, while reducing the cost of combination drug testing in humans. Human immune system (HIS) mice are highly immune-deficient mouse recipients rtpeconstituted with human hematopoietic stem cells. These HIS-mice are capable of growing human tumor cell lines and patient-derived tumor xenografts. This model allows rapid testing of multiple, immune-related therapeutics for tumors originating from unique clinical samples. Using a cord blood-derived HIS-BALB/c-Rag2nullIl2rγnullSIRPαNOD (BRGS) mouse model, we summarize our experiments testing immune checkpoint blockade combinations in these mice bearing a variety of human tumors, including breast, colorectal, pancreatic, lung, adrenocortical, melanoma and hematological malignancies. We present in-depth characterization of the kinetics and subsets of the HIS in lymph and non-lymph organs and relate these to protocol development and immune-related treatment responses. Furthermore, we compare the phenotype of the HIS in lymph tissues and tumors. We show that the immunotype and amount of tumor infiltrating leukocytes are widely-variable and that this phenotype is tumor-dependent in the HIS-BRGS model. We further present flow cytometric analyses of immune cell subsets, activation state, cytokine production and inhibitory receptor expression in peripheral lymph organs and tumors. We show that responding tumors bear human infiltrating T cells with a more inflammatory signature compared to non-responding tumors, similar to reports of "responding" patients in human immunotherapy clinical trials. Collectively these data support the use of HIS mice as a preclinical model to test combination immunotherapies for human cancers, if careful attention is taken to both protocol details and data analysis.


Assuntos
Modelos Animais de Doenças , Xenoenxertos , Sistema Imunitário , Imunoterapia , Neoplasias/imunologia , Neoplasias/terapia , Animais , Quimerismo , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Neoplasias/etiologia , Fenótipo , Ensaios Antitumorais Modelo de Xenoenxerto
16.
J Virol ; 95(12)2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-33789991

RESUMO

Recombinant influenza A viral (IAV) vectors are potential to stimulate systemic and mucosal immunity, but the packaging capacity is limited and only one or a few epitopes can be carried. Here, we report the generation of a replication-competent IAV vector that carries a full-length HIV-1 p24 gene linked to the 5'-terminal coding region of the neuraminidase segment via a protease cleavage sequence (IAV-p24). IAV-p24 was successfully rescued and stably propagated, and P24 protein was efficiently expressed in infected mammalian cells. In BALB/c mice, IAV-p24 showed attenuated pathogenicity compared to that of the parental A/PR/8/34 (H1N1) virus. An intranasal inoculation with IAV-p24 elicited moderate HIV-specific cell-mediated immune (CMI) responses in the airway and vaginal tracts and in the spleen, and an intranasal boost with a replication-incompetent adenovirus type 2 vector expressing the HIV-1 gag gene (Ad2-gag) greatly improved these responses. Importantly, compared to an Ad2-gag prime plus IAV-p24 boost regimen, the IAV-p24 prime plus Ad2-gag boost regimen had a greater efficacy in eliciting HIV-specific CMI responses. P24-specific CD8+ T cells and antibodies were robustly provoked both systemically and in mucosal sites and showed long-term durability, revealing that IAV-p24 may be used as a mucosa-targeted priming vaccine. Our results illustrate that IAV-p24 is able to prime systemic and mucosal immunity against HIV-1 and warrants further evaluation in nonhuman primates.IMPORTANCE An effective HIV-1 vaccine remains elusive despite nearly 40 years of research. CD8+ T cells and protective antibodies may both be desirable for preventing HIV-1 infection in susceptible mucosal sites. Recombinant influenza A virus (IAV) vector has the potential to stimulate these immune responses, but the packaging capacity is extremely limited. Here, we describe a replication-competent IAV vector expressing the HIV-1 p24 gene (IAV-p24). Unlike most other IAV vectors that carried one or several antigenic epitopes, IAV-p24 stably expressed the full-length P24 protein, which contains multiple epitopes and is highly conserved among all known HIV-1 sequences. Compared to the parental A/PR/8/34 (H1N1) virus, IAV-p24 showed an attenuated pathogenicity in BALB/c mice. When combined with an adenovirus vector expressing the HIV-1 gag gene, IAV-p24 was able to prime P24-specific systemic and mucosal immune responses. IAV-p24 as an alternative priming vaccine against HIV-1 warrants further evaluation in nonhuman primates.


Assuntos
Vacinas contra a AIDS/imunologia , Linfócitos T CD8-Positivos/imunologia , Anticorpos Anti-HIV/análise , Proteína do Núcleo p24 do HIV/imunologia , HIV-1/imunologia , Imunidade nas Mucosas , Adenoviridae/genética , Animais , Anticorpos Antivirais/sangue , Líquido da Lavagem Broncoalveolar/imunologia , Feminino , Genes gag , Anticorpos Anti-HIV/sangue , Proteína do Núcleo p24 do HIV/genética , Infecções por HIV/prevenção & controle , Imunidade Celular , Imunização Secundária , Imunogenicidade da Vacina , Imunoglobulina A/análise , Imunoglobulina A/sangue , Imunoglobulina G/análise , Imunoglobulina G/sangue , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/patogenicidade , Vírus da Influenza A Subtipo H3N2/imunologia , Tecido Linfoide/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Vacinação , Vacinas Sintéticas/imunologia
17.
Fish Shellfish Immunol ; 112: 81-91, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33675991

RESUMO

Columnaris, a highly contagious bacterial disease caused by Flavobacterium columnare, is recognized as one of the most important infectious diseases in farmed tilapia, especially during the fry and fingerling stages of production. The disease is associated with characteristic lesions in the mucosa of affected fish, particularly their skin and gills. Vaccines delivered via the mucosa are therefore of great interest to scientists developing vaccines for this disease. In the present study, we characterized field isolates of F. columnare obtained from clinical columnaris outbreaks in red tilapia to select an isolate to use as a candidate for our vaccine study. This included characterizing its colony morphology, genotype and virulence status. The isolate was incorporated into a mucoadhesive polymer chitosan-complexed nanovaccine (CS-NE), the efficacy of which was determined by experimentally infecting red tilapia that had been vaccinated with the nanoparticles by immersion. The experimental infection was performed 30-days post-vaccination (dpv), which resulted in 89% of the unvaccinated control fish dying, while the relative percentage survival (RPS) of the CS-NE vaccinated group was 78%. Histology of the mucosal associated lymphoid tissue (MALT) showed a significantly higher presence of leucocytes and a greater antigen uptake by the mucosal epithelium in CS-NE vaccinated fish compared to control fish and whole cell vaccinated fish, respectively, and there was statistically significant up-regulation of IgT, IgM, TNF α, IL1-ß and MHC-1 genes in the gill of the CS-NE vaccinated group. Overall, the results of our study confirmed that the CS-NE particles achieved better adsorption onto the mucosal surfaces of the fish, elicited great vaccine efficacy and modulated the MALT immune response better than the conventional whole cell-killed vaccine, demonstrating the feasibility of the mucoadhesive nano-immersion vaccine as an effective delivery system for the induction of a mucosal immune response against columnaris disease in tilapia.


Assuntos
Vacinas Bacterianas/farmacologia , Materiais Biomiméticos/farmacologia , Ciclídeos/imunologia , Doenças dos Peixes/imunologia , Imunidade nas Mucosas , Tecido Linfoide/imunologia , Nanopartículas/administração & dosagem , Animais , Vacinas Bacterianas/administração & dosagem , Materiais Biomiméticos/administração & dosagem , Doenças dos Peixes/microbiologia , Infecções por Flavobacteriaceae/imunologia , Infecções por Flavobacteriaceae/microbiologia , Infecções por Flavobacteriaceae/veterinária , Flavobacterium/fisiologia , Tecido Linfoide/efeitos dos fármacos , Vacinação/veterinária
18.
Science ; 371(6536)2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33766858

RESUMO

Microbial roles in cancer formation, diagnosis, prognosis, and treatment have been disputed for centuries. Recent studies have provocatively claimed that bacteria, viruses, and/or fungi are pervasive among cancers, key actors in cancer immunotherapy, and engineerable to treat metastases. Despite these findings, the number of microbes known to directly cause carcinogenesis remains small. Critically evaluating and building frameworks for such evidence in light of modern cancer biology is an important task. In this Review, we delineate between causal and complicit roles of microbes in cancer and trace common themes of their influence through the host's immune system, herein defined as the immuno-oncology-microbiome axis. We further review evidence for intratumoral microbes and approaches that manipulate the host's gut or tumor microbiome while projecting the next phase of experimental discovery.


Assuntos
Fenômenos Fisiológicos Bacterianos , Microbiota , Neoplasias/microbiologia , Neoplasias/terapia , Imunidade Adaptativa , Antibacterianos/uso terapêutico , Antineoplásicos/uso terapêutico , Bactérias/genética , Carcinogênese , Microbioma Gastrointestinal , Engenharia Genética , Interações entre Hospedeiro e Microrganismos , Humanos , Imunomodulação , Imunoterapia , Tecido Linfoide/imunologia , Neoplasias/imunologia , Terapia Viral Oncolítica , Microambiente Tumoral , Fenômenos Fisiológicos Virais
19.
Respir Res ; 22(1): 86, 2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33731130

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by a progressive and abnormal inflammatory response in the lungs, mainly caused by cigarette smoking. Animal models exposed to cigarette smoke (CS) are used to mimic human COPD but the use of different CS protocols makes it difficult to compare the immunological and structural consequences of using a nose-only or whole-body CS exposure system. We hypothesized that when using a standardized CS exposure protocol based on particle density and CO (carbon monoxide) levels, the whole-body CS exposure system would generate a more severe inflammatory response than the nose-only system, due to possible sensitization by uptake of CS-components through the skin or via grooming. METHODS: In this study focusing on early COPD, mice were exposed twice daily 5 days a week to CS either with a nose-only or whole-body exposure system for 14 weeks to assess lung function, remodeling and inflammation. RESULTS: At sacrifice, serum cotinine levels were significantly higher in the whole-body (5.3 (2.3-6.9) ng/ml) compared to the nose-only ((2.0 (1.8-2.5) ng/ml) exposure system and controls (1.0 (0.9-1.0) ng/ml). Both CS exposure systems induced a similar degree of lung function impairment, while inflammation was more severe in whole body exposure system. Slightly more bronchial epithelial damage, mucus and airspace enlargement were observed with the nose-only exposure system. More lymphocytes were present in the bronchoalveolar lavage (BAL) and lymph nodes of the whole-body exposure system while enhanced IgA and IgG production was found in BAL and to a lesser extent in serum with the nose-only exposure system. CONCLUSION: The current standardized CS-exposure protocol resulted in a higher internal load of serum cotinine in the whole-body exposure system, which was associated with more inflammation. However, both exposure systems resulted in a similar lung function impairment. Data also highlighted differences between the two models in terms of lung inflammation and remodelling, and potential sensitization to CS. Researchers should be aware of these differences when designing their future studies for an early intervention in COPD.


Assuntos
Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Pulmão/metabolismo , Pneumonia/etiologia , Doença Pulmonar Obstrutiva Crônica/etiologia , Fumaça , Produtos do Tabaco , Animais , Biomarcadores/sangue , Líquido da Lavagem Broncoalveolar/imunologia , Cotinina/sangue , Citocinas/genética , Modelos Animais de Doenças , Imunidade Humoral , Imunoglobulina A/metabolismo , Imunoglobulina G/metabolismo , Exposição por Inalação , Pulmão/imunologia , Pulmão/patologia , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Tecido Linfoide/patologia , Masculino , Camundongos Endogâmicos C57BL , Nariz , Pneumonia/imunologia , Pneumonia/metabolismo , Pneumonia/patologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Fatores de Tempo
20.
Pathol Res Pract ; 220: 153406, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33740545

RESUMO

Gut-associated lymphoid tissue (GALT) carcinoma is a colorectal neoplasm characterized by cystically dilated neoplastic glands that extend into prominent, well-circumscribed submucosal lymphoid tissue. Although often subtle, lamina propria between and around the neoplastic glands (identified by plasma cells, scattered eosinophils, etc.) is frequent in cases with classic morphology, arguing (at least in such cases) in favor of adenoma extending into lymphoglandular complexes rather than true invasive carcinoma. Some have postulated that the tumor arises from M-cells, specialized epithelial cells overlying GALT, and others have suggested it represents a unique pathway to carcinoma, specific to the environmental conditions of epithelium overlying lymphoid tissue. Although both hypotheses are intriguing, definitive phenotypic and genetic support is currently lacking. To address these possibilities, we undertook whole exome sequencing and immunohistochemical characterization of a GALT neoplasm recently identified on our clinical service. We discovered well-known mutations in both APC and KRAS, as well as mutations in several Wnt pathway components (MED12, BCL9L, RFX4, DACT3). No immunohistochemical expression of GP2, a marker of M-cell differentiation, was identified. Expression of CDX2, SATB2, and the DNA mismatch repair proteins was observed, while expression of both CK7 and CK20 was absent. No PD-L1 expression was present on tumor cells, but PD-L1 expression was noted in a subset of tumor-adjacent mononuclear cells. Overall, the findings suggest that GALT neoplasms, although morphologically distinct, may be a precursor or early form of typical sporadic colon carcinoma.


Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Neoplasias do Colo/genética , Variação Genética , Tecido Linfoide/patologia , Sequenciamento Completo do Exoma , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Idoso , Biomarcadores Tumorais/análise , Colectomia , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Neoplasias do Colo/cirurgia , Feminino , Humanos , Imuno-Histoquímica , Tecido Linfoide/imunologia , Tecido Linfoide/cirurgia , Valor Preditivo dos Testes
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