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1.
Rev Med Suisse ; 15(660): 1512-1515, 2019 Aug 28.
Artigo em Francês | MEDLINE | ID: mdl-31496176

RESUMO

The emergence of immunotherapy has generated great enthusiasm in oncology improving the prognosis of pathologies such as melanoma, lung cancer, kidney cancer, bladder and head and neck cancers. This enthusiasm concerns also older patients in view of the good tolerance of immunotherapy in young people. However, advanced age is linked to changes in the immune system, called immunosenescence, which could have a negative impact on the efficacy and toxicity of immunotherapy treatment. Knowledge in terms of efficacy and tolerance is limited for geriatric patients, few being included in clinical studies. This article summarizes the experience of immunotherapy in large clinical trials. It appears that the immune checkpoint inhibitors are effective and well tolerated in the elderly.


Assuntos
Imunoterapia , Neoplasias , Fatores Etários , Humanos , Tolerância Imunológica , Imunossenescência , Oncologia/tendências , Neoplasias/terapia
2.
Khirurgiia (Mosk) ; (9): 80-85, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31532171

RESUMO

This article discusses the need to implement effective methods for monitoring immune status and rehabilitation of patients after kidney transplantation. Induction of immunological tolerance which allows minimizing or even completely canceling supportive immunosuppressive therapy is one of the key tasks in the field of organ transplantation. Regulatory T-cells (TREGs) play an important role in maintaining immunological homeostasis, including limiting kidney transplant rejection, and potentially contribute to the development of immunological tolerance. At the same time, for the introduction of TREG therapy into clinical practice, it is necessary to overcome a number of unsolved problems, such as induction and cultivation of a sufficient number of TREG cells for therapeutic action as well as reducing the risks associated with TREG conversion to effector lymphocytes or an undesirable non-specific immunosuppressive effect. This review examines both the impact of common post-transplant pharmacological immunosuppression approaches on TREGs and the therapeutic potential of TREG cell cultures in prevention of kidney transplant rejection. The questions of ex vivo TREG manufacturing process and possible threats of applying cell technologies in this branch of transplantology were considered.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Transplante de Rim/efeitos adversos , Linfócitos T Reguladores/imunologia , Rejeição de Enxerto/etiologia , Humanos , Tolerância Imunológica/imunologia , Imunossupressão/métodos , Imunossupressores/uso terapêutico , Transplante de Rim/reabilitação , Imunologia de Transplantes/imunologia
3.
Cancer Immunol Immunother ; 68(9): 1501-1513, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31489465

RESUMO

INTRODUCTION: Brain metastases are a significant source of morbidity and mortality for patients with lung cancer. Lung cancer can induce local and systemic immunosuppression, promoting tumor growth and dissemination. One mechanism of immunosuppression is tumor-induced expansion of programmed death-ligand 1 (PD-L1) expressing myeloid cells. Here, we investigate peripheral blood immune phenotype in NSCLC patients with or without brain metastasis. METHODS: Peripheral blood was collected from patients with lung metastatic brain tumors and pre-metastatic lung cancer. Immunosuppressive monocytes, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs) were quantified through flow cytometry. T cell reactivity was analyzed via ELISpot. Brain metastasis conditioned media was collected from tumor-derived cell cultures and analyzed for cytokines by ELISA. Naïve monocytes were stimulated with brain metastasis conditioned media to evaluate PD-L1 stimulation. RESULTS: Patients with brain metastatic lung carcinoma demonstrated increased peripheral monocyte PD-L1, MDSC abundance, and Treg percentage compared to early stage pre-metastatic patients and healthy controls. Patients with elevated peripheral monocyte PD-L1 had less reactive T cells and worse survival. Brain metastasis conditioned media stimulation increased monocyte PD-L1, and conditioned media IL-6 levels correlated with PD-L1 induction. Treatment with anti-IL-6 or anti-IL-6 receptor antibodies reduced PD-L1 expression. In summary, patients with lung cancer and brain metastases exhibit multiple markers of peripheral immunosuppression. CONCLUSIONS: The frequency of PD-L1+ myeloid cells correlated with the presence of brain metastases. Tumor-derived IL-6 was capable of inducing PD-L1+ myeloid cells in vitro, suggesting that monitoring of immunosuppressive factors in peripheral blood may identify new targets for therapeutic intervention in selected patients.


Assuntos
Neoplasias Encefálicas/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Neoplasias Pulmonares/imunologia , Células Supressoras Mieloides/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Antígeno B7-H1/metabolismo , Neoplasias Encefálicas/secundário , Carcinogênese , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/secundário , Células Cultivadas , ELISPOT , Feminino , Citometria de Fluxo , Humanos , Tolerância Imunológica , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sobrevida , Regulação para Cima
4.
Cancer Immunol Immunother ; 68(10): 1573-1583, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31511925

RESUMO

Desmoid tumors (DTs) are local aggressive neoplasms, whose therapeutic approach has remained so far unsolved and in many instances controversial. Nowadays, immunotherapy appears to play a leading role in the treatment of various tumor types. Characterization of the tumor immune microenvironment (TME) and immune checkpoints can possibly help identify new immunotherapeutic targets for DTs. We performed immunohistochemistry (IHC) on 33 formalin-fixed paraffin-embedded (FFPE) tissue sections from DT samples to characterize the TME and the immune checkpoint expression profile. We stained for CD3, CD4, CD8, CD20, FoxP3, CD45RO, CD56, CD68, NKp46, granzyme B, CD27, CD70, PD1 and PD-L1. We investigated the expression of the markers in the tumoral stroma, as well as at the periphery of the tumor. We found that most of the tumors showed organization of lymphocytes into lymphoid aggregates at the periphery of the tumor, strongly resembling tertiary lymphoid organs (TLOs). The tumor expressed a significant number of memory T cells, both at the periphery and in the tumoral stroma. In the lymphoid aggregates, we also recognized a significant proportion of regulatory T cells. The immune checkpoint ligand PD-L1 was negative on the tumor cells in almost all samples. On the other hand, PD1 was partially expressed in lymphocytes at the periphery of the tumor. To conclude, we are the first to show that DTs display a strong immune infiltration at the tumor margins, with formation of lymphoid aggregates. Moreover, we demonstrated that there is no PD-L1-driven immune suppression present in the tumor cells.


Assuntos
Antígeno B7-H1/fisiologia , Fibromatose Agressiva/imunologia , Tolerância Imunológica , Adolescente , Adulto , Idoso , Antígenos CD20/análise , Ligante CD27/análise , Feminino , Fibromatose Agressiva/patologia , Humanos , Antígenos Comuns de Leucócito/análise , Masculino , Pessoa de Meia-Idade , Microambiente Tumoral , Adulto Jovem
5.
Adv Exp Med Biol ; 1155: 13-24, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468382

RESUMO

Taurine is a sulfur-containing amino acid which has strong activities in enhancing immunity. Gut microbiota is closely interrelated with intestinal mucosal immunity, but the effects and mechanisms of taurine on intestinal microbiota and mucosal immune cells under an immunosuppressive condition remain unclear. This study was conducted to investigate the effect of taurine on gut microbiota and immune cells in Peyer's patches (PPs) of dexamethasone (Dex)-induced immunosuppressive mice. Mice (4-week-old, Male) were randomly divided into three groups: the Control group (n = 12), the Dex-induced immunosuppressive model group (n = 12) and the taurine intervention group (n = 12). The model was established by Dex injection for 7 days and the taurine intervention group was gavaged 100 mg/kg soluble taurine for 30 days. The changes of intestinal microbiota and immune cells in PPs were tested by denaturing gradient gel electrophoresis (DGGE) and flow cytometry, respectively. Results showed that the microbiota in immunosuppressive mice was obvious different compared with control group, in which, the Lachnospiraceae and Ruminococcaceae groups were significantly reduced, and their reduction were reversed after taurine intervention. Compared to the control group, the total cell number in PPs, as well as the subsets of CD3+ cells (T cells), CD19+ cells (B cells) in model groups were significantly lower, and they were dramatically improved after taurine treatment. Our results suggested that taurine has a positive effect on i ntestinal homeostasis of the immunosuppressive mice.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Tolerância Imunológica , Nódulos Linfáticos Agregados/efeitos dos fármacos , Taurina/farmacologia , Animais , Homeostase , Masculino , Camundongos , Distribuição Aleatória
6.
Int J Nanomedicine ; 14: 5229-5242, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371958

RESUMO

Purpose: Dexamethasone (Dex) has long been used as a potent immunosuppressive agent in the treatment of inflammatory and autoimmune diseases, despite serious side effects. In the present study, Dex and model antigen ovalbumin (OVA) were encapsulated with poly(lactic-co-glycolic acid) to deliver Dex and OVA preferentially to phagocytic cells, reducing systemic side effects of Dex. The OVA-specific immune tolerance-inducing activity of the nanoparticles (NPs) was examined. Methods: Polymeric NPs containing OVA and Dex (NP[OVA+Dex]) were prepared by the water-in-oil-in-water double emulsion solvent evaporation method. The effects of NP[OVA+Dex] on the maturation and function of immature dendritic cells (DCs) were examined in vitro. Furthermore, the OVA-specific immune tolerizing effects of NP[OVA+Dex] were confirmed in mice that were intravenously injected or orally fed with the NPs. Results: Immature DCs treated in vitro with NP[OVA+Dex] did not mature into immunogenic DCs but instead were converted into tolerogenic DCs. Furthermore, profoundly suppressed generation of OVA-specific cytotoxic T cells and production of OVA-specific IgG were observed in mice injected with NP[OVA+Dex], whereas regulatory T cells were concomitantly increased. Feeding of mice with NP[OVA+Dex] also induced OVA-specific immune tolerance. Conclusion: The present study demonstrates that oral feeding as well as intravenous injection of poly(lactic-co-glycolic acid) NPs encapsulating both antigen and Dex is a useful means of inducing antigen-specific immune tolerance, which is crucial for the treatment of autoimmune diseases.


Assuntos
Antígenos/imunologia , Materiais Biocompatíveis/química , Dexametasona/farmacologia , Epitopos/imunologia , Tolerância Imunológica , Nanopartículas/química , Administração Oral , Animais , Apresentação do Antígeno/efeitos dos fármacos , Citocinas/biossíntese , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Feminino , Fatores de Transcrição Forkhead/metabolismo , Imunidade/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Nanopartículas/administração & dosagem , Ovalbumina/imunologia , Fagocitose/efeitos dos fármacos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo
7.
Cancer Immunol Immunother ; 68(9): 1429-1441, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31428800

RESUMO

MHC class I-related chain A (MICA) is one of the major ligands for natural killer group 2 member D (NKG2D), which is an activating NK receptor. MICA is expressed on the surface of human epithelial tumor cells, and its shedding from tumor cells leads to immunosuppression. To activate immune response in the tumor microenvironment, we designed an anti-VEGFR2-MICA bispecific antibody (JZC01), consisting of MICA and an anti-VEGFR2 single chain antibody fragment (JZC00) and explored its potential anti-tumor activity. JZC01 targeted vascular endothelial growth factor receptor 2 (VEGFR2) and inhibited tumorigenesis by blocking the VEGFR2 signaling pathway. Additionally, JZC01 promoted NK and CD8+ T cells to release IFN-γ and engaged activated lymphocytes to lysis of VEGFR2-expressing tumor cells. The in vivo anti-tumor activity of JZC01 was investigated by establishing a Lewis lung cancer cell-transplanted mouse model. It effectively reduced the tumor vascular density and increased the infiltration and activation of NK and CD8+ T cells in the tumor microenvironment. Thus, JZC01 functions in anti-tumor angiogenesis and anti-tumor immune activation, and showed improved anti-tumor efficacy combined with docetaxel, which provides a new insight into anti-tumor therapy.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Imunoterapia/métodos , Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/terapia , Linfócitos do Interstício Tumoral/imunologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/imunologia , Animais , Anticorpos Biespecíficos/genética , Apoptose , Carcinoma Pulmonar de Lewis , Citotoxicidade Imunológica , Modelos Animais de Doenças , Humanos , Tolerância Imunológica , Interferon gama/metabolismo , Neoplasias Pulmonares/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral
8.
Cancer Res ; 79(13): 3169-3171, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31262832

RESUMO

Inhibiting myeloid-derived suppressor cells (MDSC) might be the ultimate barrier to break down tumor defenses and recover the preexisting T-cell immunity required to respond to immunotherapy. However, selectively intercepting MDSCs to prove their etiologic role in cancer progression is not an easy task. In this issue of Cancer Research, Yin and colleagues demonstrate unequivocally that the Aurora A kinase inhibitor, alisertib, specifically neutralizes MDSCs and triggers the rapid accrual of cytotoxic T cells, with consequent tumor clearance potentiated by PD-L1 blockade. Translating this approach into the clinic might rescue tumor immunity in immune-desert landscapes.See related article by Yin et al., p. 3431.


Assuntos
Células Supressoras Mieloides/imunologia , Neoplasias , Humanos , Tolerância Imunológica , Imunossupressão , Imunoterapia
9.
BMC Infect Dis ; 19(1): 573, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31269923

RESUMO

BACKGROUND: Solid organ transplantation (SOT) is a well-established and life-saving treatment for patients with end-stage organ failure. Organ rejection and infections are among the main complications to SOT and largely determines the clinical outcome. The correct level of immunosuppression is of major importance to prevent these complications. However, it is a consistent observation that in recipients on the same immunosuppressive regimens the clinical outcome varies, and no reliable marker exists to monitor immune function. METHODS: In a prospective, observational study, we plan to enroll 630 adult patients with a planned organ transplantation at Rigshospitalet, University of Copenhagen, Denmark. Prior to and on different time points up to two years after transplantation we will perform a complete immunological profile on the recipients. This profile will consist of classical descriptive immune phenotyping (flow cytometry and circulating biomarkers) and the functional assay TruCulture®. In TruCulture® whole blood is incubated ex vivo with stimulants imitating bacterial, viral and fungal infections, where after a panel of selected cytokines is quantified. Clinical data from electronic health records will be obtained from the PERSIMUNE (Centre of Excellence for Personalized Medicine of Infections Complications in Immune Deficiency at Rigshospitalet, Copenhagen) data repository, a warehouse of data generated as part of routine care including vital signs, biochemistry, microbiology, pathology as well as medication, demographics, diagnoses, hospital contacts, surgical procedures and mortality. DISCUSSION: This will be the first large scale study to determine several aspects of immune function and perform a complete immunological profiling in SOT recipients. It is expected that knowledge generated will provide information to generate prediction models identifying patients at increased risk of infection and/or rejection. If the study is successful, we will subsequently use the generated prediction models to propose personalized immunosuppressive regimens to be tested in future randomized controlled trials. TRIAL REGISTRATION: This study has been approved by the Regional ethical committee (H-17024315), the Danish Data Protection Agency (RH-2016-47, RH-2015-04, I-Suite 03605) and the Danish National board of Health (3-3013-1060/1). The trial is retrospectively registered at clinicaltrials.gov ( NCT03847285 ) the 20th February 2019.


Assuntos
Infecção/etiologia , Transplante de Órgãos/efeitos adversos , Transplante de Órgãos/métodos , Adulto , Biomarcadores/sangue , Citocinas/sangue , Humanos , Tolerância Imunológica , Imunossupressão , Imunossupressores/uso terapêutico , Estudos Observacionais como Assunto , Estudos Prospectivos
10.
Nat Commun ; 10(1): 3031, 2019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31292453

RESUMO

Maternal immune dysregulation seems to affect fetal or postnatal immune development. Preeclampsia is a pregnancy-associated disorder with an immune basis and is linked to atopic disorders in offspring. Here we show reduction of fetal thymic size, altered thymic architecture and reduced fetal thymic regulatory T (Treg) cell output in preeclamptic pregnancies, which persists up to 4 years of age in human offspring. In germ-free mice, fetal thymic CD4+ T cell and Treg cell development are compromised, but rescued by maternal supplementation with the intestinal bacterial metabolite short chain fatty acid (SCFA) acetate, which induces upregulation of the autoimmune regulator (AIRE), known to contribute to Treg cell generation. In our human cohorts, low maternal serum acetate is associated with subsequent preeclampsia, and correlates with serum acetate in the fetus. These findings suggest a potential role of acetate in the pathogenesis of preeclampsia and immune development in offspring.


Assuntos
Acetatos/sangue , Feto/imunologia , Pré-Eclâmpsia/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Linfócitos T Reguladores/imunologia , Acetatos/administração & dosagem , Acetatos/imunologia , Acetatos/metabolismo , Adulto , Animais , Animais Recém-Nascidos , Estudos de Casos e Controles , Desenvolvimento Infantil , Pré-Escolar , Suplementos Nutricionais , Feminino , Feto/citologia , Feto/diagnóstico por imagem , Microbioma Gastrointestinal/imunologia , Vida Livre de Germes/imunologia , Humanos , Tolerância Imunológica/imunologia , Lactente , Recém-Nascido , Estudos Longitudinais , Troca Materno-Fetal/imunologia , Camundongos , Tamanho do Órgão/imunologia , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/diagnóstico , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Estudos Prospectivos , Timo/citologia , Timo/diagnóstico por imagem , Timo/crescimento & desenvolvimento , Timo/imunologia , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo , Ultrassonografia Pré-Natal , Adulto Jovem
11.
BMC Neurol ; 19(1): 148, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31269910

RESUMO

BACKGROUND: Almost 40% of stroke patients have a poor outcome at 3 months after the index event. Predictors for stroke outcome in the early acute phase may help to tailor stroke treatment. Infection and inflammation are considered to influence stroke outcome. METHODS: In a prospective multicenter study in Germany and Spain, including 486 patients with acute ischemic stroke, we used multivariable regression analysis to investigate the association of poor outcome with monocytic HLA-DR (mHLA-DR) expression, interleukin 6 (IL-6), interleukin 10 (IL-10), tumor necrosis factor alpha (TNF-alpha) and lipopolysaccharide-binding protein (LBP) as markers for immunodepression, inflammation and infection. Outcome was assessed at 3 months after stroke via a structured telephone interview using the modified Rankin Scale (mRS). Poor outcome was defined as a mRS score of 3 or higher which included death. Furthermore, a time-to-event analysis for death within 3 months was performed. RESULTS: Three-month outcome data was available for 391 patients. Female sex, older age, diabetes mellitus, atrial fibrillation, stroke-associated pneumonia (SAP) and higher National Institute of Health Stroke Scale (NIHSS) score as well as lower mHLA-DR levels, higher IL-6 and LBP-levels at day 1 were associated with poor outcome at 3 months in bivariate analysis. Furthermore, multivariable analysis revealed that lower mHLA-DR expression was associated with poor outcome. Female sex, older age, atrial fibrillation, SAP, higher NIHSS score, lower mHLA-DR expression and higher IL-6 levels were associated with shorter survival time in bivariate analysis. In multivariable analysis, SAP and higher IL-6 levels on day 1 were associated with shorter survival time. CONCLUSIONS: SAP, lower mHLA-DR-expression and higher IL-6 levels on day one are associated with poor outcome and shorter survival time at 3 months after stroke onset. TRIAL REGISTRATION: www.clinicaltrials.gov, NCT01079728 , March 3, 2010.


Assuntos
Isquemia Encefálica/imunologia , Antígenos HLA-DR/sangue , Interleucina-6/sangue , Pneumonia/etiologia , Acidente Vascular Cerebral/imunologia , Proteínas da Fase Aguda , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/complicações , Biomarcadores/sangue , Isquemia Encefálica/sangue , Isquemia Encefálica/complicações , Isquemia Encefálica/mortalidade , Proteínas de Transporte/sangue , Diabetes Mellitus , Feminino , Alemanha , Humanos , Tolerância Imunológica , Inflamação/complicações , Interleucina-10/sangue , Masculino , Glicoproteínas de Membrana/sangue , Pessoa de Meia-Idade , Pneumonia/mortalidade , Estudos Prospectivos , Espanha , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/mortalidade , Fatores de Tempo , Fator de Necrose Tumoral alfa/sangue
12.
Zhonghua Shao Shang Za Zhi ; 35(7): 548-551, 2019 Jul 20.
Artigo em Chinês | MEDLINE | ID: mdl-31357829

RESUMO

Persistent inflammation-immunosuppression-catabolism syndrome (PICS) is a clinical syndrome in patients surviving from severe trauma or sepsis, which is characterized by prolonged stays in intensive care unit, persistent inflammation response, immune suppression, high protein catabolism, and high mortality. This article aims to review the proposed process of the concept, the mechanism, the clinical features, and the diagnosis and treatment progress of PICS, which is helpful for further understanding pathogenesis and pathophysiological mechanism of PICS in patients with severe burns and improving clinical curative efficacy and prognosis of patients with severe burns.


Assuntos
Queimaduras/patologia , Queimaduras/terapia , Tolerância Imunológica , Inflamação/patologia , Estado Terminal , Humanos , Síndrome
13.
Scand J Immunol ; 90(5): e12804, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31267559

RESUMO

Immune checkpoint inhibitors are among the newest, cutting-edge methods for the treatment of cancer. Currently, they primarily influence T cell adaptive immunotherapy targeting the PD-1/PD-L1 and CTLA-4/B7 signalling pathways. These inhibitors fight cancer by reactivating the patient's own adaptive immune system, with good results in many cancers. With the discovery of the "Don't Eat Me" molecule, CD47, antibody-based drugs that target the macrophage-related innate immunosuppressive signalling pathway, CD47-SIRPα, have been developed and have achieved stunning results in the laboratory and the clinic, but there remain unexplained instances of tumour immune escape. While investigating the immunological tolerance of cancer to anti-CD47 antibodies, a second "Don't Eat Me" molecule on tumour cells, beta 2 microglobulin (ß2m), a component of MHC class I, was described. Some tumour cells reduce their surface expression of MHC class I to escape T cell recognition. However, other tumour cells highly express ß2m complexed with the MHC class I heavy chain to send a "Don't Eat Me" signal by binding to leucocyte immunoglobulin-like receptor family B, member 1 (LILRB1) on macrophages, leading to a loss of immune surveillance. Investigating the mechanisms underlying this immunosuppressive MHC class I-LILRB1 signalling axis in tumour-associated macrophages will be useful in developing therapies to restore macrophage function and control MHC class I signalling in patient tumours. The goal is to promote adaptive immunity while suppressing the innate immune response to tumours. This work will identify new therapeutic targets for the development of pharmaceutical-based tumour immunotherapy.


Assuntos
Antígenos CD/imunologia , Tolerância Imunológica/imunologia , Receptor B1 de Leucócitos Semelhante a Imunoglobulina/imunologia , Neoplasias/terapia , Evasão Tumoral/imunologia , Microglobulina beta-2/imunologia , Imunidade Adaptativa/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Imunidade Inata/imunologia , Macrófagos/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia
14.
Scand J Immunol ; 90(5): e12807, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31282004

RESUMO

Exosomes are a potent means for intercellular communication. However, exosomes have received intensive research focus in immunobiology only relatively recently. Because they transport proteins, lipids and genetic material between cells, they are especially suited to amplify their parental cell's message and overcome the physical constraints of cell-to-cell contact, that is exosome release gives cells the ability to alter distant, non-contiguous cells. As progress is made in this field, it has become increasingly obvious that exosomes are involved in most biological processes. In the immune system, exosomes are fundamental tools used by every immune cell type to fulfil its function and promote inflammation or tolerance. In this review, we first summarize key aspects of immune cell-specific exosomes and their functions. Then, we describe how exosomes have been shown to be indispensable orchestrators of the immune response in two immunological scenarios, namely transplant rejection or tolerance, and tumour evasion or initiation of anti-tumour immune responses.


Assuntos
Exossomos/metabolismo , Rejeição de Enxerto/imunologia , Tolerância Imunológica/imunologia , Neoplasias/imunologia , Evasão Tumoral/imunologia , Linfócitos B/imunologia , Transporte Biológico/fisiologia , Comunicação Celular/fisiologia , Células Dendríticas/imunologia , Humanos , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia
15.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 36(3): 515-520, 2019 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-31232558

RESUMO

Glioma is one of the most common primary tumors in the human brain with poor prognosis. The local and systemic immunosuppressive environment created by glioma cells enables them to evade immunosurveillance. Myeloid-derived suppressor cells (MDSCs) are a critical component of the immunosuppression system. They are a heterogeneous cell population composed of early myeloid progenitor cells and precursor cells. Although the cells are diverse in phenotypes and functions, they all have strong immunosuppressive functions. MDSCs are extensively infiltrated into tumor tissues and play an important role in the glioma immunosuppressive microenvironment, which also hinders the immunotherapeutic effects of glioma. This article will review the phenotypic characteristics of MDSCs in the glioma microenvironment and their role in the progression of glioma. It is of positive significance to better understand the pathogenesis of glioma and explore effective comprehensive treatments.


Assuntos
Glioma/patologia , Células Supressoras Mieloides/citologia , Microambiente Tumoral , Humanos , Tolerância Imunológica
16.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(6): 613-618, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31208519

RESUMO

Food allergen-specific immune tolerance is defined as nonresponsiveness of the adaptive immune system to food antigens. Failed development or inhibition of such tolerance may cause food allergy. With the increasing incidence rate of food allergy year by year, more and more studies have found the association between food allergy and various diseases. The development of food allergen-specific immune tolerance in childhood has been taken more and more seriously. In recent years, many studies have shown that the development of food allergen-specific immune tolerance is influenced by various factors, which can be roughly divided into antigens, organisms, and environment. This article reviews the influencing factors for the development of immune tolerance to food allergens in children, in order to provide help for reducing the incidence of food allergy and improving the prognosis of food allergy.


Assuntos
Hipersensibilidade Alimentar , Alérgenos , Criança , Humanos , Tolerância Imunológica , Incidência
17.
Biochemistry (Mosc) ; 84(6): 617-626, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31238861

RESUMO

D-Galactose (D-Gal) promotes accumulation of reactive oxygen species and formation of advanced glycation end-products, ultimately resulting in oxidative stress. D-Gal has been widely used to induce accelerated aging in anti-aging medical research. Although thymic epithelial cells are particularly sensitive to oxidative stress, there are few reports on the thymus changes accompanying D-Gal-induced aging in mice. To study the effect of D-Gal on rodent thymus, we investigated the degree of thymus atrophy and changes in the atrophy relative index in C57BL/6J mice following subcutaneous injection of D-Gal at different doses (200, 500, 1000 mg/kg per day) for 60 days. Compared with the vehicle-treated (0.9% saline) and young controls, D-Gal at doses of 500 and 1000 mg/kg per day led to a significant thymic atrophy; the latter dose caused atrophy similar to that observed in naturally aged (18-20-month-old) mice. Mice treated with high-dose D-Gal exhibited greater immunosenescence, defective central immune tolerance, increased levels of activated splenic immune cell, and chronic low-grade inflammation, i.e., outcomes similar to those observed in natural aging in mice. Taken together, our results indicate that mice treated with high-dose D-Gal may be a valid model for studying induced thymic atrophy and effects of aging on the immune system.


Assuntos
Envelhecimento/efeitos dos fármacos , Galactose/administração & dosagem , Tolerância Imunológica , Animais , Relação Dose-Resposta a Droga , Feminino , Galactose/farmacologia , Injeções Subcutâneas , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Timo/efeitos dos fármacos , Timo/patologia
18.
Adv Exp Med Biol ; 1136: 113-121, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31201720

RESUMO

Long-term studies of anti-pathogen and anti-tumor immunity have provided complementary genetic and pharmacological evidence for the immunosuppressive and immunomodulatory effects of Hypoxia-HIF-1α and adenosine-mediated suppression via the A2A adenosine receptor signaling pathway (Hypoxia-A2A-adenosinergic). This pathway is life saving when it protects inflamed tissues of vital organs from collateral damage by overactive anti-pathogen immune cells or enables the differentiation of cells of adaptive immunity. However, the Hypoxia-A2A-adenosinergic immunosuppression can also prevent tumor rejection by inhibiting the anti-tumor effects of T and NK cells. In addition, this suppressive pathway has been shown to mask tumors due to the hypoxia-HIF-α-mediated loss of MHC Class I molecules on tumor cells. It is suggested that it will be impossible to realize the full anti-tumor capacities of current cancer immunotherapies without simultaneous administration of anti-Hypoxia-A2A-Adenosinergic drugs that inactivate this tumor-protecting mechanism in hypoxic and adenosine-rich tumors.Here, we overview the supporting evidence for the conceptually novel immunotherapeutic motivation to breathe supplemental oxygen (40-60%) or to repurpose already available oxygenation agents in combination with current immunotherapies. Preclinical studies provide strong support for oxygen immunotherapy to enable much stronger tumor regression by weakening immunosuppression by A2A adenosine receptors and by the Hypoxia➔HIF-1α axis. The results of these studies emphasize the value of systemic oxygenation as clinically feasible, promising, and as a valuable tool for mechanistic investigations of tumor biology and cancer immunology. Perhaps the most effective and feasible among individual members of this novel class of anti-tumor drugs are oxygenation agents.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Imunossupressão , Neoplasias/patologia , Hipóxia Tumoral , Hipóxia Celular , Linhagem Celular Tumoral , Humanos , Tolerância Imunológica , Receptor A2A de Adenosina/fisiologia , Transdução de Sinais
19.
Immunol Med ; 42(1): 22-28, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31169082

RESUMO

Bullous pemphigoid (BP) is an organ-specific autoantibody-mediated autoimmune blistering skin disorder that tends to affect the elderly. Tense blister formation associated with itchy urticarial erythema is clinically observed in BP, and subepidermal blister formation with eosinophilic infiltration is a histopathological characteristic. BP autoantibodies target two hemidesmosomal components in basal keratinocytes: BP180 and BP230. Anti-BP180 autoantibodies play major roles in blister formation. Although the autoantibody-mediated pathomechanism of blister formation has been extensively studied, little is known about how and why immune tolerance to BP180 may be broken in certain elderly individuals. Recently, BP has been increasingly reported in diabetes mellites (DM) patients receiving dipeptidyl peptidase-IV inhibitors (DPP4is), which are widely used anti-DM drugs. Pharmacovigilance and cohort studies have revealed that DPP4is, especially vildagliptin, teneligliptin, and linagliptin, are a potential risk factor for BP onset. Interestingly, it has been revealed that Japanese DPP4i-BP tends to show a non-inflammatory phenotype, with less erythema than normal BP, and that DPP4i-BP autoantibodies target distinct epitopes on BP180. In addition, human leukocyte antigen-DQB1*03:01 was identified as the major haplotype in Japanese DPP4i-BP. This review summarizes the latest understanding of the pathogenesis of BP, with a special focus on the recently recognized DPP4i-BP.


Assuntos
Autoimunidade , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Hipoglicemiantes/administração & dosagem , Penfigoide Bolhoso/induzido quimicamente , Penfigoide Bolhoso/imunologia , Grupo com Ancestrais do Continente Asiático , Autoanticorpos , Autoantígenos/imunologia , Epitopos , Cadeias beta de HLA-DQ/genética , Haplótipos , Humanos , Tolerância Imunológica/imunologia , Linagliptina/efeitos adversos , Colágenos não Fibrilares/imunologia , Penfigoide Bolhoso/genética , Pirazóis/efeitos adversos , Fatores de Risco , Tiazolidinas/efeitos adversos , Vildagliptina/efeitos adversos
20.
Nat Commun ; 10(1): 2498, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31175312

RESUMO

Allogeneic mesenchymal stem cells (MSCs) exhibit immunoregulatory function in human autoimmune diseases such as systemic lupus erythematosus (SLE), but the underlying mechanisms remain incompletely understood. Here we show that the number of peripheral tolerogenic CD1c+ dendritic cells (DCs) and the levels of serum FLT3L are significantly decreased in SLE patients especially with lupus nephritis, compared to healthy controls. Transplantation of allogeneic umbilical cord-derived MSCs (UC-MSCs) significantly up-regulates peripheral blood CD1c+DCs and serum FLT3L. Mechanistically, UC-MSCs express FLT3L that binds to FLT3 on CD1c+DCs to promote the proliferation and inhibit the apoptosis of tolerogenic CD1c+DCs. Conversely, reduction of FLT3L with small interfering RNA in MSCs abolishes the up-regulation of tolerogenic CD1c+DCs in lupus patients treated with MSCs. Interferon-γ induces FLT3L expression in UC-MSCs through JAK/STAT signaling pathway. Thus, allogeneic MSCs might suppress inflammation in lupus through up-regulating tolerogenic DCs.


Assuntos
Antígenos CD1/imunologia , Células Dendríticas/imunologia , Glicoproteínas/imunologia , Tolerância Imunológica/imunologia , Lúpus Eritematoso Sistêmico/terapia , Proteínas de Membrana/imunologia , Transplante de Células-Tronco Mesenquimais , Adulto , Antígenos CD1/metabolismo , Estudos de Casos e Controles , Células Dendríticas/metabolismo , Feminino , Glicoproteínas/metabolismo , Humanos , Interferon gama/farmacologia , Janus Quinases/efeitos dos fármacos , Janus Quinases/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/terapia , Masculino , Proteínas de Membrana/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Pessoa de Meia-Idade , Fatores de Transcrição STAT/efeitos dos fármacos , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transplante Homólogo , Adulto Jovem
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