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1.
Cancer Immunol Immunother ; 69(1): 147-157, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31900508

RESUMO

Chemotherapy is still the backbone of systemic treatment in the majority of cancers. However, immunotherapies, especially those based on checkpoint inhibition, are additional therapy options for many. For this, functional T cells are a mandatory requirement. The aim of this prospective study was to investigate the influence of chemotherapy on the cellular immune status of individual patients. Peripheral blood samples of 26 patients with solid malignancies undergoing chemotherapy were analyzed for lymphocyte populations and their subsets in a longitudinal approach. Chemotherapy decreased total B lymphocyte counts [median value (25-75 percentile): before chemotherapy 76/µl (39-160) vs. after chemotherapy 49/µl (24-106); p = 0.001]. Among B cells, specific subsets decreased particularly [naïve B cells (49/µl (21-111) vs. 25/µl (13-56); p = 0.001], memory B cells [3/µl (2-8) vs. 2/µl (1-4); p = 0.001], and class-switched B cells [11/µl (6-20) vs. 6/µl (3-12); p = 0.011]. In contrast, chemotherapy had no influence on the total numbers of CD4 + and CD8 + T lymphocytes or on their subsets (T helper cells 1, 2, and 17 as well as cytotoxic T cells in early, intermediate, late, terminal effector and exhausted status as well as both T-cell types with naïve, center memory, effector memory, activated, or regulatory phenotype). Furthermore, the count of natural killer (NK) lymphocytes showed no significant change before and after chemotherapy. In summary, this study shows a decrease of B lymphocytes during systemic chemotherapy, but no relevant effect on T lymphocytes, NK lymphocytes and their subsets. This could support the idea of an effective additive T-cell-dependent immunotherapy to chemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linfócitos B/efeitos dos fármacos , Células Matadoras Naturais/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Linfócitos T/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos B/imunologia , Separação Celular , Feminino , Citometria de Fluxo , Humanos , Células Matadoras Naturais/imunologia , Contagem de Linfócitos , Subpopulações de Linfócitos/efeitos dos fármacos , Subpopulações de Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/imunologia , Estudos Prospectivos , Linfócitos T/imunologia , Resultado do Tratamento
2.
Infect Immun ; 88(1)2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31636138

RESUMO

Salmonella is an intracellular bacterium found in the gastrointestinal tract of mammalian, avian, and reptilian hosts. Mouse models have been extensively used to model in vivo distinct aspects of human Salmonella infections and have led to the identification of several host susceptibility genes. We have investigated the susceptibility of Collaborative Cross strains to intravenous infection with Salmonella enterica serovar Typhimurium as a model of human systemic invasive infection. In this model, strain CC042/GeniUnc (CC042) mice displayed extreme susceptibility with very high bacterial loads and mortality. CC042 mice showed lower spleen weights and decreased splenocyte numbers before and after infection, affecting mostly CD8+ T cells, B cells, and all myeloid cell populations, compared with control C57BL/6J mice. CC042 mice also had lower thymus weights with a reduced total number of thymocytes and double-negative and double-positive (CD4+, CD8+) thymocytes compared to C57BL/6J mice. Analysis of bone marrow-resident hematopoietic progenitors showed a strong bias against lymphoid-primed multipotent progenitors. An F2 cross between CC042 and C57BL/6N mice identified two loci on chromosome 7 (Stsl6 and Stsl7) associated with differences in bacterial loads. In the Stsl7 region, CC042 carried a loss-of-function variant, unique to this strain, in the integrin alpha L (Itgal) gene, the causative role of which was confirmed by a quantitative complementation test. Notably, Itgal loss of function increased the susceptibility to S. Typhimurium in a (C57BL/6J × CC042)F1 mouse background but not in a C57BL/6J mouse inbred background. These results further emphasize the utility of the Collaborative Cross to identify new host genetic variants controlling susceptibility to infections and improve our understanding of the function of the Itgal gene.


Assuntos
Bacteriemia/genética , Antígeno CD11a/deficiência , Predisposição Genética para Doença , Mutação com Perda de Função , Infecções por Salmonella/genética , Salmonella typhimurium/crescimento & desenvolvimento , Animais , Bacteriemia/imunologia , Bacteriemia/patologia , Carga Bacteriana , Medula Óssea/patologia , Modelos Animais de Doenças , Genes , Subpopulações de Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Salmonella/imunologia , Infecções por Salmonella/patologia , Sorogrupo , Baço/patologia , Análise de Sobrevida , Timo/patologia
3.
Anticancer Res ; 39(9): 4687-4698, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519568

RESUMO

BACKGROUND/AIM: Propagermanium (PG) inhibits the CCL2/CCR2 axis, and has been shown to function as an immune modulator. This study investigated its anti-tumor mechanism in patients with refractory cancers. MATERIALS AND METHODS: Five healthy volunteers and 23 patients with refractory oral (n=8) or gastric (n=15) cancer received PG (30 mg/day). We performed flow cytometry (FCM) of peripheral blood mononuclear cells and in vitro killing assays. RESULTS: FCM revealed that CD16+/CD56Dim NK cells (i.e., mature, cytolytic subset) increased, and the apoptosis induction rate of cancer cells increased after PG administration. Among gastric cancer patients, median OS was 172.0 days. Two patients showed complete remission of lung or liver metastasis. Survival of patients with oral cancer also tended to be prolonged. CONCLUSION: PG induces NK cell maturation, and may potentiate anti-tumor activity.


Assuntos
Antineoplásicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Neoplasias/imunologia , Neoplasias/mortalidade , Compostos Organometálicos/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Humanos , Estimativa de Kaplan-Meier , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Tomografia Computadorizada por Raios X
4.
Immunity ; 51(5): 885-898.e7, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31542340

RESUMO

Graft-versus-host disease (GVHD) in the gastrointestinal (GI) tract is the principal determinant of lethality following allogeneic bone marrow transplantation (BMT). Here, we examined the mechanisms that initiate GVHD, including the relevant antigen-presenting cells. MHC class II was expressed on intestinal epithelial cells (IECs) within the ileum at steady state but was absent from the IECs of germ-free mice. IEC-specific deletion of MHC class II prevented the initiation of lethal GVHD in the GI tract. MHC class II expression on IECs was absent from mice deficient in the TLR adaptors MyD88 and TRIF and required IFNγ secretion by lamina propria lymphocytes. IFNγ responses are characteristically driven by IL-12 secretion from myeloid cells. Antibiotic-mediated depletion of the microbiota inhibited IL-12/23p40 production by ileal macrophages. IL-12/23p40 neutralization prevented MHC class II upregulation on IECs and initiation of lethal GVHD in the GI tract. Thus, MHC class II expression by IECs in the ileum initiates lethal GVHD, and blockade of IL-12/23p40 may represent a readily translatable therapeutic strategy.


Assuntos
Apresentação do Antígeno/imunologia , Células Apresentadoras de Antígenos/imunologia , Microbioma Gastrointestinal/imunologia , Doença Enxerto-Hospedeiro/etiologia , Antígenos de Histocompatibilidade Classe II/imunologia , Mucosa Intestinal/imunologia , Animais , Células Apresentadoras de Antígenos/metabolismo , Biomarcadores , Citocinas/metabolismo , Suscetibilidade a Doenças , Feminino , Expressão Gênica , Doença Enxerto-Hospedeiro/mortalidade , Antígenos de Histocompatibilidade Classe II/genética , Íleo/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Estimativa de Kaplan-Meier , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Prognóstico , Regiões Promotoras Genéticas , Transdução de Sinais
5.
Arch Immunol Ther Exp (Warsz) ; 67(5): 325-334, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31363786

RESUMO

The purpose of this study is to describe both clinical and immunological features in large cohort of adult patients with IgG subclass deficiency, and response to immunoglobulin therapy. This is a retrospective study of data obtained from electronic medical records and paper charts of 78 patients with IgG subclass deficiency seen and followed at our immunology clinics from 2010 to 2016. Both isolated selective IgG subclass deficiency as well as combined (two) subclass deficiencies were observed. IgG3 subclass deficiency, isolated and in combination with other IgG subclass deficiency, is the most frequent of IgG subclass deficiency. A majority of patients presented with upper and lower respiratory tract infections, especially chronic sinusitis. Both allergic and autoimmune manifestations are common; however, there is no subclass preference. The proportions and absolute numbers of CD3+ T cells, CD4+ T and CD8+ T cells, CD19+ B cells, and CD3-CD16+CD56+ NK cells were normal in the majority of patients in all IgG subclass deficiencies. Total serum IgG levels did not correlate with IgG subclass levels across all IgG subclass deficiencies. Anti-pneumococcal polysaccharide antibody responses were impaired in 56% of patients. IgG3 subclass deficiency is the most common IgG subclass deficiency, and anti-polysaccharide antibody responses are distributed among IgG subclasses with modest preference in IgG2 subclass. The majority of patients treated with immunoglobulin responded by reduction in frequency of infections and requirement of antibiotics.


Assuntos
Deficiência de IgG/imunologia , Deficiência de IgG/patologia , Adulto , Idoso , Feminino , Humanos , Deficiência de IgG/sangue , Deficiência de IgG/tratamento farmacológico , Imunoglobulina G/administração & dosagem , Imunoglobulina G/sangue , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Vacinas Pneumocócicas/imunologia , Infecções Respiratórias/sangue , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/imunologia , Infecções Respiratórias/patologia , Estudos Retrospectivos , Sinusite/sangue , Sinusite/tratamento farmacológico , Sinusite/imunologia , Sinusite/patologia , Resultado do Tratamento , Adulto Jovem
6.
Molecules ; 24(13)2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31284478

RESUMO

Dihydroartemisinin (DHA) is a derivative of the herb Artemisia annua L. that has prominent immunomodulatory activity; however, its underlying mechanism remains elusive. Inflammatory bowel disease (IBD) is an idiopathic inflammatory condition characterized as an autoimmune disorder that includes dysfunctions in the T helper (Th)/T regulatory cell (Treg) balance, which normally plays pivotal roles in immune homeostasis. The aim of this study was to explore the potential of DHA to ameliorate IBD by restoring the Th/Treg cell balance. To this end, we established mouse models of colitis induced by oxazolone (OXA) and 2,4,6-trinitro-benzene sulfonic acid (TNBS). We then treated mice with DHA at 4, 8, or 16 mg/kg/day. DHA treatment ameliorated colitis signs and reduced lymphocyte infiltration and tissue fibrosis. Moreover, DHA decreased the numbers of Th1 and Th17 cells and Th9 and Th22 cells in TNBS- or OXA-induced colitis, respectively, and increased Tregs in both models. DHA (0.8 mg/mL) also inhibited activated CD4+ T lymphocytes, which was accompanied by apoptosis induction. Moreover, it promoted heme oxygenase-1 (HO-1) production in vitro and in vivo, concomitant with CD4+ T cell apoptosis and restoration of the Th/Treg balance, and these effects were blocked by treatment with the HO-1 inhibitor Sn-protoporphyrin IX. Overall, these results suggest that DHA is a novel and valuable candidate for IBD therapy or Th/Treg immunoregulation.


Assuntos
Apoptose , Artemisininas/uso terapêutico , Heme Oxigenase-1/biossíntese , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Ativação Linfocitária/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Animais , Apoptose/efeitos dos fármacos , Artemisininas/farmacologia , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/imunologia , Modelos Animais de Doenças , Indução Enzimática/efeitos dos fármacos , Doenças Inflamatórias Intestinais/enzimologia , Ativação Linfocitária/efeitos dos fármacos , Subpopulações de Linfócitos/efeitos dos fármacos , Subpopulações de Linfócitos/imunologia , Camundongos , Oxazolona , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/efeitos dos fármacos , Ácido Trinitrobenzenossulfônico
7.
Immunol Allergy Clin North Am ; 39(3): 345-359, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31284925

RESUMO

Early-life wheezing-associated infections with human rhinovirus (HRV) are strongly associated with the inception of asthma. The immune system of immature mice and humans is skewed toward a type 2 cytokine response. Thus, HRV-infected 6-day-old mice but not adult mice develop augmented type 2 cytokine expression, eosinophilic inflammation, mucous metaplasia, and airway hyperresponsiveness. This asthma phenotype depends on interleukin (IL)-13-producing type 2 innate lymphoid cells, the expansion of which in turn depends on release of the innate cytokines IL-25, IL-33, and thymic stromal lymphopoietin from the airway epithelium. In humans, certain genetic variants may predispose to HRV-induced childhood asthma.


Assuntos
Asma/etiologia , Infecções por Picornaviridae/complicações , Infecções por Picornaviridae/virologia , Rhinovirus , Animais , Asma/diagnóstico , Asma/metabolismo , Asma/terapia , Suscetibilidade a Doenças , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Infecções por Picornaviridae/imunologia , Rhinovirus/fisiologia
8.
Arch Immunol Ther Exp (Warsz) ; 67(5): 335-349, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31177287

RESUMO

Major causes of chronic kidney disease are primary proliferative and nonproliferative glomerulonephritides (PGN and NPGN). However, the pathogenesis of PGN and NPGN is still not fully understood. Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is a T-cell membrane receptor that plays a key role in T-cell inhibition. Despite its role in autoimmunological diseases, little is known about the involvement of CTLA-4 in the pathogenesis of PGN and NPGN. The objective of this study was to determine the role of CTLA-4 in the pathogenesis of PGN and NPGN by evaluating the frequencies of T and B lymphocytes expressing CTLA-4 and the serum concentration of the sCTLA-4 isoform in patients with PGN and NPGN in relation to clinical parameters. The study included peripheral blood (PB) samples from 40 PGN and NPGN patients and 20 healthy age- and sex-matched volunteers (control group). The viable PB lymphocytes were labeled with fluorochrome-conjugated monoclonal anti-CTLA-4 antibodies and analyzed using flow cytometry. The serum concentration of sCTLA-4 was measured using ELISA. The frequencies and absolute counts of CD4+/CTLA-4+ T lymphocytes, CD8+/CTLA-4+ T lymphocytes and CD19+/CTLA-4+ B lymphocytes and the serum sCTLA-4 concentration were lower in PGN and NPGN patients that in the control group. Reduced sCTLA-4 expression was associated with a lower concentration of serum immunoglobulins. Our results indicate that deregulation of CTLA-4 expression may result in continuous activation of T cells and contribute to the pathogenesis of PGN and NPGN.


Assuntos
Antígeno CTLA-4/genética , Regulação da Expressão Gênica , Glomerulonefrite/imunologia , Glomerulonefrite/fisiopatologia , Imunoglobulinas/sangue , Rim/fisiopatologia , Subpopulações de Linfócitos/metabolismo , Adulto , Idoso , Antígenos CD/metabolismo , Antígeno CTLA-4/sangue , Antígeno CTLA-4/metabolismo , Feminino , Humanos , Ativação Linfocitária , Contagem de Linfócitos , Subpopulações de Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Curva ROC , Adulto Jovem
9.
Int J Mol Sci ; 20(11)2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31185596

RESUMO

Almost all multiple myeloma (MM) cases have been demonstrated to be linked to earlier monoclonal gammopathy of undetermined significance (MGUS). Nevertheless, there are no identified characteristics in the diagnosis of MGUS that have been helpful in differentiating subjects whose cancer may progress to a malignant situation. Regarding malignancy, the role of lymphocyte subsets and cytokines at the beginning of neoplastic diseases is now incontestable. In this review, we have concentrated our attention on the equilibrium between the diverse lymphocyte subsets and the cytokine system and summarized the current state of knowledge, providing an overview of the condition of the entire system in MGUS and MM. In an age where the therapy of neoplastic monoclonal gammopathies largely relies on drugs capable of acting on the immune system (immunomodulants, immunological checkpoint inhibitors, CAR-T), detailed knowledge of the the differences existing in benign and neoplastic forms of gammopathy is the main foundation for the adequate and optimal use of new drugs.


Assuntos
Citocinas/sangue , Subpopulações de Linfócitos/imunologia , Gamopatia Monoclonal de Significância Indeterminada/sangue , Mieloma Múltiplo/sangue , Humanos , Monitorização Imunológica , Gamopatia Monoclonal de Significância Indeterminada/imunologia , Mieloma Múltiplo/imunologia
10.
Vet Immunol Immunopathol ; 211: 58-63, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31084895

RESUMO

There is an increasing interest toward infectious diseases and mechanisms of immune response of water buffaloes, mainly because of the growing economic impact of this species and of its high-quality milk. However, little is known about the immune system of these animals in physiological conditions. Recently, a wide number of antibodies cross reacting with buffalo antigens has been validated for use in flow cytometry (FC), allowing detailed characterization of the lymphocytic population in this species. The aim of the present study was to describe the lymphocyte subpopulations in a large number of healthy water buffaloes, providing reference intervals (RIs), and to assess whether the composition of blood lymphocyte population significantly varied with age and reproductive history. Our final aim was to lay the ground for future studies evaluating the role of host immune response in water buffaloes. One-hundred-twelve healthy buffaloes from four different herds in the South of Italy were included in the study. All animals had been vaccinated for Infectious Bovine Rhinotracheitis (IBR), Salmonellosis, Colibacillosis and Clostridiosis, and all herds were certified Brucellosis- and Tuberculosis-free. Venous blood collected into EDTA tubes was processed for FC, and the percentage of cells staining positive for the following antibodies was recorded: CD3, CD4, CD8, CD21, TCR-δ-N24, WC1-N2, WC1-N3 and WC1-N4. Absolute concentration of each lymphoid subclass was then calculated, based on automated White Blood Cell (WBC) Count. Reference Intervals were calculated according to official guidelines and are listed in the manuscript. The composition of the lymphocyte population varied with age and reproductive history, with animals <2-years-old and heifers having higher concentration of most of the subclasses. The present study provides RIs for the main lymphocytic subclasses in healthy water buffaloes, highlighting gross differences between young and old animals. Establishment of age-specific RIs is recommended in water buffaloes. The data we present may be useful as a basis for further studies concerning mechanisms of immune response toward infectious agents in water buffaloes.


Assuntos
Envelhecimento/imunologia , Búfalos/imunologia , Subpopulações de Linfócitos/imunologia , Paridade/imunologia , Fatores Etários , Animais , Búfalos/sangue , Feminino , Citometria de Fluxo/veterinária , Contagem de Linfócitos/veterinária , Subpopulações de Linfócitos/fisiologia , Valores de Referência
11.
Int J Mol Sci ; 20(10)2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31137499

RESUMO

Mouse natural killer T (NKT) cells and natural killer (NK) cells are innate immune cells that are highly abundant in the liver. In addition to their already-known antitumor and antimicrobial functions, their pathophysiological roles in the kidney have recently become evident. Under normal circumstances, the proportion of activated NKT cells in the kidney increases with age. Administration of a synthetic sphingoglycolipid ligand (alpha-galactosylceramide) further activates NKT cells, resulting in injury to renal vascular endothelial cells via the perforin-mediated pathway and tubular epithelial cells via the TNF-α/Fas ligand pathway, causing acute kidney injury (AKI) with hematuria. Activation of NKT cells by common bacterial DNA (CpG-ODN) also causes AKI. In addition, NKT cells together with B cells play significant roles in experimental lupus nephritis in NZB/NZW F1 mice through their Th2 immune responses. Mouse NK cells are also assumed to be involved in various renal diseases, and there may be complementary roles shared between NKT and NK cells. Human CD56+ T cells, a functional counterpart of mouse NKT cells, also damage renal cells through a mechanism similar to that of mice. A subpopulation of human CD56+ NK cells also exert strong cytotoxicity against renal cells and contribute to the progression of renal fibrosis.


Assuntos
Lesão Renal Aguda/imunologia , Células Matadoras Naturais/imunologia , Células T Matadoras Naturais/imunologia , Animais , Humanos , Subpopulações de Linfócitos/imunologia
12.
Immunity ; 50(6): 1425-1438.e5, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31128962

RESUMO

The perinatal period is a critical window for distribution of innate tissue-resident immune cells within developing organs. Despite epidemiologic evidence implicating the early-life environment in the risk for allergy, temporally controlled lineage tracing of group 2 innate lymphoid cells (ILC2s) during this period remains unstudied. Using complementary fate-mapping approaches and reporters for ILC2 activation, we show that ILC2s appeared in multiple organs during late gestation like tissue macrophages, but, unlike the latter, a majority of peripheral ILC2 pools were generated de novo during the postnatal window. This period was accompanied by systemic ILC2 priming and acquisition of tissue-specific transcriptomes. Although perinatal ILC2s were variably replaced across tissues with age, the dramatic increases in tissue ILC2s following helminth infection were mediated through local expansion independent of de novo generation by bone marrow hematopoiesis. We provide comprehensive temporally controlled fate mapping of an innate lymphocyte subset with notable nuances as compared to tissue macrophage ontogeny.


Assuntos
Imunidade Inata , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Animais , Feminino , Marcação de Genes , Camundongos , Camundongos Transgênicos , Especificidade de Órgãos/imunologia , Gravidez , Locos de Características Quantitativas , Receptores de Interleucina-7/metabolismo , Transdução de Sinais
13.
Immunity ; 50(4): 832-850, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995502

RESUMO

The common cytokine receptor γ chain, γc, is a component of the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21. Mutation of the gene encoding γc results in X-linked severe combined immunodeficiency in humans, and γc family cytokines collectively regulate development, proliferation, survival, and differentiation of immune cells. Here, we review the basic biology of these cytokines, highlighting mechanisms of signaling and gene regulation that have provided insights for immunodeficiency, autoimmunity, allergic diseases, and cancer. Moreover, we discuss how studies of this family stimulated the development of JAK3 inhibitors and present an overview of current strategies targeting these pathways in the clinic, including novel antibodies, antagonists, and partial agonists. The diverse roles of these cytokines on a range of immune cells have important therapeutic implications.


Assuntos
Citocinas/classificação , Subunidade gama Comum de Receptores de Interleucina/genética , Família Multigênica/imunologia , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Citocinas/genética , Citocinas/imunologia , Evolução Molecular , Regulação da Expressão Gênica , Terapia Genética , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/terapia , Janus Quinase 3/antagonistas & inibidores , Janus Quinases/antagonistas & inibidores , Janus Quinases/fisiologia , Subpopulações de Linfócitos/imunologia , Camundongos , Terapia de Alvo Molecular , Família Multigênica/genética , Neoplasias/genética , Neoplasias/imunologia , Subunidades Proteicas , Fatores de Transcrição STAT/fisiologia , Transdução de Sinais , Pesquisa Médica Translacional , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/imunologia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/terapia
14.
Immunity ; 50(4): 851-870, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995503

RESUMO

The discovery of interleukin (IL)-6 and its receptor subunits provided a foundation to understand the biology of a group of related cytokines: IL-12, IL-23, and IL-27. These family members utilize shared receptors and cytokine subunits and influence the outcome of cancer, infection, and inflammatory diseases. Consequently, many facets of their biology are being therapeutically targeted. Here, we review the landmark discoveries in this field, the combinatorial biology inherent to this family, and how patient datasets have underscored the critical role of these pathways in human disease. We present significant knowledge gaps, including how similar signals from these cytokines can mediate distinct outcomes, and discuss how a better understanding of the biology of the IL-12 family provides new therapeutic opportunities.


Assuntos
Citocinas/imunologia , Interleucina-12/imunologia , Família Multigênica/imunologia , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Citocinas/antagonistas & inibidores , Citocinas/genética , Humanos , Imunidade Celular , Inflamação/imunologia , Interleucina-12/antagonistas & inibidores , Interleucina-12/genética , Interleucina-27/uso terapêutico , Subpopulações de Linfócitos/imunologia , Linfopoese , Camundongos , Camundongos Knockout , Família Multigênica/genética , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/terapia , Subunidades Proteicas , Relação Estrutura-Atividade
15.
Immunity ; 50(4): 871-891, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995504

RESUMO

Cytokines are among the most important effector and messenger molecules in the immune system. They profoundly participate in immune responses during infection and inflammation, protecting against or contributing to diseases such as allergy, autoimmunity, and cancer. Manipulating cytokine pathways, therefore, is one of the most effective strategies to treat various diseases. IL-10 family cytokines exert essential functions to maintain tissue homeostasis during infection and inflammation through restriction of excessive inflammatory responses, upregulation of innate immunity, and promotion of tissue repairing mechanisms. Their important functions in diseases are supported by data from many preclinical models, human genetic studies, and clinical interventions. Despite significant efforts, however, there is still no clinically approved therapy through manipulating IL-10 family cytokines. Here, we summarize the recent progress in understanding the biology of this family of cytokines, suggesting more specific strategies to maneuver these cytokines for the effective treatment of inflammatory diseases and cancers.


Assuntos
Imunidade Inata , Interleucina-10/imunologia , Interleucinas/imunologia , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Citocinas/classificação , Citocinas/genética , Regulação da Expressão Gênica , Humanos , /terapia , Inflamação/imunologia , Inflamação/terapia , Interleucina-10/genética , Interleucinas/genética , Subpopulações de Linfócitos/imunologia , Camundongos , Família Multigênica , Células Mieloides/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Transdução de Sinais , Fatores de Transcrição/fisiologia
16.
Immunity ; 50(4): 992-1006, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995511

RESUMO

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract. Cytokine-targeted therapies have transformed the treatment of IBD, providing control of symptoms and longer relapse-free periods. However, many patients fail to respond, highlighting the need for therapies tailored to the underlying cell and molecular disease drivers. Here we discuss the progression of IBD from the perspective of remodeling of cytokine networks. We place well-established and under-studied cytokine modules in the context of cellular interactions, their dynamic regulation in early and late stages of disease (i.e., fibrosis), and their current and potential use in the clinic. Examining how particular cytokine networks drive distinct features and phases of IBD will shed light on the etiology of IBD and provide a basis for more effective treatments.


Assuntos
Citocinas/imunologia , Doenças Inflamatórias Intestinais/fisiopatologia , Animais , Antirreumáticos/uso terapêutico , Citocinas/genética , Progressão da Doença , Resistência a Medicamentos , Células Epiteliais/imunologia , Estudos de Associação Genética , Homeostase , Humanos , Imunidade Inata , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Intestinos/imunologia , Intestinos/patologia , Subpopulações de Linfócitos/imunologia , Camundongos , Células Mieloides/imunologia , Fator de Transcrição STAT3/biossíntese , Análise de Célula Única , Fator de Necrose Tumoral alfa/antagonistas & inibidores
17.
APMIS ; 127(4): 228-235, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30908772

RESUMO

Our aim was to evaluate the cost-effectiveness of a minimal lymphocyte subset quantification (LSQ) by flow cytometry as the first screening in children with clinically suspected primary immunodeficiency (PID). Two hundred sixty-eight Brazilian patients (0-21 years old) were studied. They were divided by clinical and phenotypical features into those fulfilling criteria for PID (PID phenotype) according to the 2017 International Union of Immunological Societies (IUIS) classification and those not fulfilling these criteria (non-PID phenotype). We evaluated how many patients had values below the 10th percentile for five lymphocyte subsets in peripheral blood, (suggestive of PID) according to reference values for Brazil, Italy and USA. Three lymphocyte subsets (T CD3/CD4, B CD19 and NK CD16/CD56) had p-value < 0.05 and Odds Ratio (OR) indicating a risk at least two times higher for the diagnosis of a PID phenotype. The application of Kappa coefficient (k) on Brazilian vs Italian and Brazilian vs US data sets resulted in k compatible with strong or excellent level of agreement between the three classification systems. The authors conclude that a number of CD3+ /CD4+ , CD19+ and CD16+ /CD56+ (NK) cells in peripheral blood <10th percentile represented a significant risk for the diagnosis of PID in this cohort. Natural killer (NK) deficiency is quite rare and has a very specific clinical profile. So, the analysis of these cells could be requested only in some cases, saving even more costs. The minimal immunophenotyping, with quantification of T CD4+ , CD19+ and in some cases CD16+ /CD56+ cells, may be a useful tool for the first screening of PID, saving costs, especially in developing countries.


Assuntos
Análise Custo-Benefício , Citometria de Fluxo/métodos , Infecções por HIV/diagnóstico , Imunofenotipagem/métodos , Contagem de Linfócitos/métodos , Subpopulações de Linfócitos/imunologia , Programas de Rastreamento/métodos , Adolescente , Antígenos CD/análise , Brasil , Criança , Pré-Escolar , Estudos Transversais , Citometria de Fluxo/economia , Infecções por HIV/patologia , Humanos , Imunofenotipagem/economia , Lactente , Recém-Nascido , Contagem de Linfócitos/economia , Programas de Rastreamento/economia , Adulto Jovem
18.
Innate Immun ; 25(3): 186-202, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30894094

RESUMO

The present study investigated clinical and immunological modulations due to intramuscular injection of Escherichia coli LPS in 49-wk-old laying hens over 48 h post injection (p.i.). LPS induced characteristic sickness behavior but no significant body temperature alterations ( P > 0.05). During experimental period decreases in blood albumin, calcium, phosphorus and tryptophan concentrations, hyperglycemia, increased plasma nitrite concentrations, leucopenia, decreased thrombocyte counts, lymphopenia, heterophilia and an increased heterophilic granulocyte/lymphocyte (H/L) ratio were observed after LPS administration. Time-dependent effects were shown on T and B cell subsets in caecal tonsils (CT) and on splenic CD3+/CD4+/CD8+ proportions, on IL-1ß and -10 and inducible NO synthase mRNA expression in peripheral blood lymphocytes (PBL), liver, spleen and CT, and on the mRNA expression of the TLR4 in PBL, liver and spleen p.i. ( P < 0.05). The main responding period of mentioned alterations due to LPS appears to include the period from 2 until 8 h p.i. According to the H/L ratio, the most stressful phase was 5 h p.i. T and B cell subsets in CT, the IL-1ß and TLR4 mRNA expression in liver and plasma nitrite concentrations seemed to be affected for a longer period.


Assuntos
Linfócitos B/imunologia , Infecções por Escherichia coli/imunologia , Escherichia coli/fisiologia , Lipopolissacarídeos/imunologia , Subpopulações de Linfócitos/imunologia , Tonsila Palatina/imunologia , Linfócitos T/imunologia , Animais , Proteínas Aviárias/genética , Proteínas Aviárias/metabolismo , Galinhas , Feminino , Hiperglicemia , Injeções Intramusculares , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
19.
Front Immunol ; 10: 196, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30873151

RESUMO

Apicomplexans are a diverse and complex group of protozoan pathogens including Toxoplasma gondii, Plasmodium spp., Cryptosporidium spp., Eimeria spp., and Babesia spp. They infect a wide variety of hosts and are a major health threat to humans and other animals. Innate immunity provides early control and also regulates the development of adaptive immune responses important for controlling these pathogens. Innate immune responses also contribute to immunopathology associated with these infections. Natural killer (NK) cells have been for a long time known to be potent first line effector cells in helping control protozoan infection. They provide control by producing IL-12 dependent IFNγ and killing infected cells and parasites via their cytotoxic response. Results from more recent studies indicate that NK cells could provide additional effector functions such as IL-10 and IL-17 and might have diverse roles in immunity to these pathogens. These early studies based their conclusions on the identification of NK cells to be CD3-, CD49b+, NK1.1+, and/or NKp46+ and the common accepted paradigm at that time that NK cells were one of the only lymphoid derived innate immune cells present. New discoveries have lead to major advances in understanding that NK cells are only one of several populations of innate immune cells of lymphoid origin. Common lymphoid progenitor derived innate immune cells are now known as innate lymphoid cells (ILC) and comprise three different groups, group 1, group 2, and group 3 ILC. They are a functionally heterogeneous and plastic cell population and are important effector cells in disease and tissue homeostasis. Very little is known about each of these different types of ILCs in parasitic infection. Therefore, we will review what is known about NK cells in innate immune responses during different protozoan infections. We will discuss what immune responses attributed to NK cells might be reconsidered as ILC1, 2, or 3 population responses. We will then discuss how different ILCs may impact immunopathology and adaptive immune responses to these parasites.


Assuntos
Imunidade Adaptativa , Apicomplexa/imunologia , Imunidade Inata , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Infecções por Protozoários/imunologia , Infecções por Protozoários/parasitologia , Animais , Biomarcadores , Plasticidade Celular/imunologia , Citocinas/metabolismo , Interações Hospedeiro-Parasita , Humanos , Imunofenotipagem , Mediadores da Inflamação/metabolismo , Plasmodium/imunologia
20.
Clin Sci (Lond) ; 133(6): 741-760, 2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30890652

RESUMO

Primary biliary cholangitis (PBC), an autoimmune liver disease occurring predominantly in women, is characterized by high titers of serum anti-mitochondrial antibodies (AMAs) and progressive intrahepatic cholestasis. The immune system plays a critical role in PBC pathogenesis and a variety of immune cell subsets have been shown to infiltrate the portal tract areas of patients with PBC. Amongst the participating immune cells, CD4 T cells are important cytokine-producing cells that foster an inflammatory microenvironment. Specifically, these cells orchestrate activation of other immune cells, including autoreactive effector CD8 T cells that cause biliary epithelial cell (BEC) injury and B cells that produce large quantities of AMAs. Meanwhile, other immune cells, including dendritic cells (DCs), natural killer (NK) cells, NKT cells, monocytes, and macrophages are also important in PBC pathogenesis. Activation of these cells initiates and perpetuates bile duct damage in PBC patients, leading to intrahepatic cholestasis, hepatic damage, liver fibrosis, and eventually cirrhosis or even liver failure. Taken together, the body of accumulated clinical and experimental evidence has enhanced our understanding of the immunopathogenesis of PBC and suggests that immunotherapy may be a promising treatment option. Herein, we summarize current knowledge regarding immunological abnormalities of PBC patients, with emphasis on underlying pathogenic mechanisms. The differential immune response which occurs over decades of disease activity suggests that different therapies may be needed at different stages of disease.


Assuntos
Doenças Autoimunes/imunologia , Cirrose Hepática Biliar/imunologia , Doenças Autoimunes/genética , Doenças Autoimunes/terapia , Ductos Biliares Intra-Hepáticos/imunologia , Citocinas/imunologia , Predisposição Genética para Doença , Humanos , Imunoterapia/métodos , Mediadores da Inflamação/imunologia , Cirrose Hepática Biliar/genética , Cirrose Hepática Biliar/terapia , Subpopulações de Linfócitos/imunologia , Macrófagos/imunologia , Monócitos/imunologia
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