RESUMEN
Caspase-dependent apoptosis accounts for approximately 90% of homeostatic cell turnover in the body1, and regulates inflammation, cell proliferation, and tissue regeneration2-4. How apoptotic cells mediate such diverse effects is not fully understood. Here we profiled the apoptotic metabolite secretome and determined its effects on the tissue neighbourhood. We show that apoptotic lymphocytes and macrophages release specific metabolites, while retaining their membrane integrity. A subset of these metabolites is also shared across different primary cells and cell lines after the induction of apoptosis by different stimuli. Mechanistically, the apoptotic metabolite secretome is not simply due to passive emptying of cellular contents and instead is a regulated process. Caspase-mediated opening of pannexin 1 channels at the plasma membrane facilitated the release of a select subset of metabolites. In addition, certain metabolic pathways continued to remain active during apoptosis, with the release of only select metabolites from a given pathway. Functionally, the apoptotic metabolite secretome induced specific gene programs in healthy neighbouring cells, including suppression of inflammation, cell proliferation, and wound healing. Furthermore, a cocktail of apoptotic metabolites reduced disease severity in mouse models of inflammatory arthritis and lung-graft rejection. These data advance the concept that apoptotic cells are not inert cells waiting for removal, but instead release metabolites as 'good-bye' signals to actively modulate outcomes in tissues.
Asunto(s)
Apoptosis/fisiología , Microambiente Celular , Sistemas de Mensajero Secundario/fisiología , Animales , Artritis , Caspasas/metabolismo , Línea Celular , Proliferación Celular/genética , Supervivencia Celular/genética , Conexinas/metabolismo , Modelos Animales de Enfermedad , Rechazo de Injerto , Humanos , Inflamación/genética , Trasplante de Pulmón , Linfocitos/enzimología , Linfocitos/metabolismo , Macrófagos/enzimología , Macrófagos/metabolismo , Ratones , Proteínas del Tejido Nervioso/metabolismo , Fagocitos/metabolismo , Cicatrización de Heridas/genéticaRESUMEN
Ex vivo expansion followed by reinfusion of tumor-infiltrating leukocytes (TILs) has been used successfully for the treatment of multiple malignancies. Most protocols rely on the use of the cytokine IL-2 to expand TILs prior to reinfusion. In addition, TIL administration relies on systemic administration of IL-2 after reinfusion to support transferred cell survival. The use of IL-2, however, can be problematic because of its preferential expansion of regulatory T and myeloid cells as well as its systemic side effects. In this study, we describe the use of a novel IL-2 mutant retargeted to NKG2D rather than the high-affinity IL-2R for TIL-mediated immunotherapy in a murine model of malignant melanoma. We demonstrate that the NKG2D-retargeted IL-2 (called OMCPmutIL-2) preferentially expands TIL-resident CTLs, such as CD8+ T cells, NK cells, and γδT cells, whereas wild-type IL-2 provides a growth advantage for CD4+Foxp3+ T cells as well as myeloid cells. OMCPmutIL-2-expanded CTLs express higher levels of tumor-homing receptors, such as LFA-1, CD49a, and CXCR3, which correlate with TIL localization to the tumor bed after i.v. injection. Consistent with this, OMCPmutIL-2-expanded TILs provided superior tumor control compared with those expanded in wild-type IL-2. Our data demonstrate that adoptive transfer immunotherapy can be improved by rational retargeting of cytokine signaling to NKG2D-expressing CTLs rather than indiscriminate expansion of all TILs.
Asunto(s)
Traslado Adoptivo , Interleucina-2/inmunología , Leucocitos/inmunología , Melanoma/inmunología , Melanoma/terapia , Subfamilia K de Receptores Similares a Lectina de Células NK/genética , Animales , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Subfamilia K de Receptores Similares a Lectina de Células NK/inmunología , Transducción de Señal/inmunologíaRESUMEN
Pathways regulating lung alloimmune responses differ from most other solid organs and remain poorly explored. Based on our recent work identifying the unique role of eosinophils in downregulating lung alloimmunity, we sought to define pathways contributing to eosinophil migration and homeostasis. Using a murine lung transplant model, we have uncovered that immunosuppression increases eosinophil infiltration into the allograft in an IL-5-dependent manner. IL-5 production depends on immunosuppression-mediated preservation of donor-derived group 2 innate lymphoid cells (ILC2). We further describe that ischemia reperfusion injury upregulates the expression of IL-33, which functions as the dominant and nonredundant mediator of IL-5 production by graft-resident ILC2. Our work thus identifies unique cellular mechanisms that contribute to lung allograft acceptance. Notably, ischemia reperfusion injury, widely considered to be solely deleterious to allograft survival, can also downregulate alloimmune responses by initiating unique pathways that promote IL-33/IL-5/eosinophil-mediated tolerance.
Asunto(s)
Interleucina-33 , Daño por Reperfusión , Aloinjertos , Animales , Inmunidad Innata , Interleucina-33/metabolismo , Interleucina-5/metabolismo , Pulmón/metabolismo , Linfocitos , Ratones , Daño por Reperfusión/metabolismoRESUMEN
Natural killer (NK) cells play a critical role in controlling malignancies. Susceptibility or resistance to lung cancer, for example, specifically depends on NK cell function. Nevertheless, intrinsic factors that control NK cell-mediated clearance of lung cancer are unknown. Here we report that NK cells exposed to exogenous major histocompatibility class I (MHCI) provide a significant immunologic barrier to the growth and progression of malignancy. Clearance of lung cancer is facilitated by up-regulation of NKG2D, NKp46, and other activating receptors upon exposure to environmental MHCI. Surface expression of the inhibitory receptor Ly49C/I, on the other hand, is down-regulated upon exposure to tumor-bearing tissue. We thus demonstrate that NK cells exhibit dynamic plasticity in surface expression of both activating and inhibitory receptors based on the environmental context. Our data suggest that altering the activation state of NK cells may contribute to immunologic control of lung and possibly other cancers.
Asunto(s)
Antígenos Ly/inmunología , Células Asesinas Naturales/inmunología , Neoplasias Pulmonares/inmunología , Subfamilia A de Receptores Similares a Lectina de Células NK/inmunología , Subfamilia K de Receptores Similares a Lectina de Células NK/inmunología , Receptor 1 Gatillante de la Citotoxidad Natural/inmunología , Receptores Inmunológicos/inmunología , Receptores de Células Asesinas Naturales/metabolismo , Animales , Citotoxicidad Inmunológica , Regulación hacia Abajo , Antígenos de Histocompatibilidad Clase I/metabolismo , Neoplasias Pulmonares/metabolismo , Ratones , Ratones Endogámicos C57BL , Regulación hacia ArribaRESUMEN
Cyanidin 3-O-galactoside (Cy3Gal) is one of the most widespread anthocyanins that positively impacts the health of animals and humans. Since it is available from a wide range of natural sources, such as fruits (apples and berries in particular), substantial studies were performed to investigate its biosynthesis, chemical stability, natural occurrences and content, extraction methods, physiological functions, as well as potential applications. In this review, we focus on presenting the previous studies on the abovementioned aspects of Cy3Gal. As a conclusion, Cy3Gal shares a common biosynthesis pathway and analogous stability with other anthocyanins. Galactosyltransferase utilizing uridine diphosphate galactose (UDP-galactose) and cyanidin as substrates is unique for Cy3Gal biosynthesis. Extraction employing different methods reveals chokeberry as the most practical natural source for mass-production of this compound. The antioxidant properties and other health effects, including anti-inflammatory, anticancer, antidiabetic, anti-toxicity, cardiovascular, and nervous protective capacities, are highlighted in purified Cy3Gal and in its combination with other polyphenols. These unique properties of Cy3Gal are discussed and compared with other anthocyanins with related structure for an in-depth evaluation of its potential value as food additives or health supplement. Emphasis is laid on the description of its physiological functions confirmed via various approaches.
Asunto(s)
Antocianinas/farmacología , Antiinflamatorios/farmacología , Antineoplásicos/farmacología , Productos Biológicos/farmacología , Galactósidos/farmacología , Hipoglucemiantes/farmacología , Fitoquímicos/farmacología , Extractos Vegetales/farmacología , Animales , Frutas/química , HumanosRESUMEN
Cripto-1 (CR1), an oncofetal protein, had been implied to reactivate in some cancers. However, the relationship between CR1 expression and patient outcomes and the tumor biological function of CR1 contributing to invasion and metastasis in hepatocellular carcinoma (HCC) is poorly defined. In this study, we demonstrated that CR1 was expressed in over 80% of HCCs in a training cohort (n = 242) and a validation cohort (n = 159). High CR1 expression was significantly correlated with aggressive HCC phenotypes (i.e. portal vein tumor thrombus, microscopic vascular invasion, multiple tumors and poor tumor differentiation). In both the training and validation cohorts, patients with high CR1 expression had remarkably shorter disease-free survival and overall survival rates than those with low CR1 expression. A series in vitro and in vivo assays showed that CR1 substantially promoted HCC cell migration, invasion and metastasis. Mechanistically, we demonstrated that CR1 induced HCC cells to undergo epithelial-mesenchymal transition through activating the Akt/NFκB/p65 signaling. Chromatin immunoprecipitation assay showed that NFκB/p65 enhanced CR1 expression by binding its promoter. Thus, CR1 and NFκB/p65 form a positive feedback loop that sustained the process of migration and invasion of HCC. Therefore, CR1 plays an important role in HCC invasion and metastasis and may be an effective and reliable prognostic biomarker for HCC recurrence after resection. Targeting CR1 may be a promising treatment for HCC.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/patología , Proteínas Ligadas a GPI/metabolismo , Regulación Neoplásica de la Expresión Génica , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Pulmonares/secundario , Proteínas de Neoplasias/metabolismo , Animales , Apoptosis , Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/cirugía , Movimiento Celular , Proliferación Celular , Femenino , Proteínas Ligadas a GPI/genética , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/cirugía , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/cirugía , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Invasividad Neoplásica , Proteínas de Neoplasias/genética , Pronóstico , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Cripto-1 (CR1), an oncofetal protein, had been implied to reactivate in some cancers. However, the relationship between CR1 expression and patient outcomes and the tumor biological function of CR1 contributing to invasion and metastasis in hepatocellular carcinoma (HCC) is poorly defined. In this study, we demonstrated that CR1 was expressed in over 80% of HCCs in a training cohort (n = 242) and a validation cohort (n = 159). High CR1 expression was significantly correlated with aggressive HCC phenotypes (i.e. portal vein tumor thrombus, microscopic vascular invasion, multiple tumors and poor tumor differentiation). In both the training and validation cohorts, patients with high CR1 expression had remarkably shorter disease-free survival and overall survival rates than those with low CR1 expression. A series in vitro and in vivo assays showed that CR1 substantially promoted HCC cell migration, invasion and metastasis. Mechanistically, we demonstrated that CR1 induced HCC cells to undergo epithelial-mesenchymal transition through activating the Akt/NFκB/p65 signaling. Chromatin immunoprecipitation assay showed that NFκB/p65 enhanced CR1 expression by binding its promoter. Thus, CR1 and NFκB/p65 form a positive feedback loop that sustained the process of migration and invasion of HCC. Therefore, CR1 plays an important role in HCC invasion and metastasis and may be an effective and reliable prognostic biomarker for HCC recurrence after resection. Targeting CR1 may be a promising treatment for HCC.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/patología , Proteínas Ligadas a GPI/metabolismo , Regulación Neoplásica de la Expresión Génica , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Pulmonares/secundario , Proteínas de Neoplasias/metabolismo , Animales , Apoptosis , Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/cirugía , Movimiento Celular , Proliferación Celular , Femenino , Proteínas Ligadas a GPI/genética , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/cirugía , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/cirugía , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Invasividad Neoplásica , Proteínas de Neoplasias/genética , Pronóstico , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Eosinophils are rare granulocytes that belong to the innate arm of the immune system. This cell population is traditionally defined as a destructive and cytotoxic mediator in asthma and helminth infection. Limited data in transplantation have suggested that eosinophils play a similar role in potentiating deleterious organ inflammation and immunologic rejection. Contrary to this long-held notion, recent data have uncovered the possibility that eosinophils play an alternative role in immune homeostasis, defense against a wide range of pathogens, as well as downregulation of deleterious inflammation. Specifically, translational data from small animal models of lung transplantation have demonstrated a critical role for eosinophils in the downregulation of alloimmunity. These findings shed new light on the unique immunologic features of the lung allograft and demonstrate that environmental polarization may alter the phenotype and function of leukocyte populations previously thought to be static in nature. In this review, we provide an update on eosinophils in the homeostasis of the lung as well as other solid organs.
Asunto(s)
Eosinófilos , Trasplante de Pulmón , Animales , Sistema Inmunológico , Inflamación , PulmónRESUMEN
Despite standardized postoperative care, some lung transplant patients suffer multiple episodes of acute and chronic rejection while others avoid graft problems for reasons that are poorly understood. Using an established model of C57BL/10 to C57BL/6 minor antigen mismatched single lung transplantation, we now demonstrate that the recipient microbiota contributes to variability in the alloimmune response. Specifically, mice from the Envigo facility in Frederick, Maryland contain nearly double the number of CD4+ Foxp3+ regulatory T cells (Tregs ) than mice from the Jackson facility in Bar Harbor, Maine or the Envigo facility in Indianapolis, Indiana (18 vs 9 vs 7%). Lung graft recipients from the Maryland facility thus do not develop acute or chronic rejection. Treatment with broad-spectrum antibiotics decreases Tregs and increases both acute and chronic graft rejection in otherwise tolerant strains of mice. Constitutive depletion of regulatory T cells, using Foxp3-driven expression of diphtheria toxin receptor, leads to the development of chronic rejection and supports the role of Tregs in both acute and chronic alloimmunity. Taken together, our data demonstrate that the microbiota of certain individuals may contribute to tolerance through Treg -dependent mechanisms and challenges the practice of indiscriminate broad-spectrum antibiotic use in the perioperative period.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Comercio/normas , Factores de Transcripción Forkhead/fisiología , Rechazo de Injerto/prevención & control , Enfermedades Pulmonares/inmunología , Trasplante de Pulmón/efectos adversos , Microbiota , Linfocitos T Reguladores/inmunología , Aloinjertos , Animales , Linfocitos T CD4-Positivos/microbiología , Rechazo de Injerto/etiología , Rechazo de Injerto/metabolismo , Supervivencia de Injerto/inmunología , Enfermedades Pulmonares/microbiología , Enfermedades Pulmonares/cirugía , Masculino , Ratones , Ratones Endogámicos C57BL , Linfocitos T Reguladores/microbiología , Receptores de TrasplantesRESUMEN
BACKGROUND AND OBJECTIVES: Delayed patient admission to the intensive care unit (ICU) from the ED is common in China. Patients with severe sepsis or septic shock requiring ICU admission are in need of specialised monitoring and tailored treatment. Delayed admission to the ICU might be associated with adverse clinical outcomes for patients with sepsis. METHODS: Patients with sepsis admitted to the ICU from the ED from January 2010 to April 2018 were retrospectively identified from a clinical data warehouse. The primary endpoint was in-hospital mortality. Length of stay in ED (EDLOS) was compared between survivors and non-survivors. A multivariable regression model was employed to adjust for potential confounding due to patient clinical condition. RESULTS: A total of 1997 patients, including 473 non-survivors and 1524 survivors, were included. The crude mortality rate for patients with EDLOS <6 hours was 21.4%, which was significantly lower than patients with EDLOS of 12-24 hours (31.9%), and those with EDLOS >24 hours (31.8%). After adjusting for PaO2/FiO2, serum creatinine, age, Sequential Organ Failure Assessment, body mass index, lactate, comorbidities and infection site, EDLOS continued to be independently associated with increased risk of hospital mortality. Compared with the group with EDLOS <6 hours, those with EDLOS between 12and24 hours (OR 1.82, 95% CI 1.28 to 2.58) and EDLOS >24 hours (OR 1.79, 95% CI 1.27 to 2.52) showed a significantly increased risk of death. CONCLUSIONS: Our study shows that prolonged EDLOS is independently associated with increased risk of hospital mortality in patients with sepsis requiring ICU admission.
Asunto(s)
Servicio de Urgencia en Hospital/normas , Tiempo de Internación/estadística & datos numéricos , Sepsis/complicaciones , Sepsis/mortalidad , Factores de Tiempo , Adulto , Anciano , Anciano de 80 o más Años , China/epidemiología , Servicio de Urgencia en Hospital/organización & administración , Servicio de Urgencia en Hospital/estadística & datos numéricos , Femenino , Mortalidad Hospitalaria , Hospitalización/estadística & datos numéricos , Humanos , Unidades de Cuidados Intensivos/organización & administración , Unidades de Cuidados Intensivos/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Riesgo , Sepsis/epidemiologíaRESUMEN
BACKGROUND: Conflicting results were found between radiofrequency-assisted liver resection (RF-LR) and clamp-crush liver resection (CC-LR) during liver surgery. We conducted a systematic review and meta-analysis that included randomized controlled trials (RCTs) and non-RCTs to compare the effectiveness and safety of RF-LR versus CC-LR during liver surgery. METHODS: Articles comparing RF-LR and CC-LR that were published before December 2012 were retrieved and subjected to a systematic review and meta-analysis. Data synthesis and statistical analysis were carried out by Review Manager Version 5.2 software. RESULTS: In all, four RCTs and five nonrandomized studies evaluating 728 patients were included. Compared with CC-LR, the RF-LR group had significantly reduced total intraoperative blood loss (weighted mean difference [WMD] = -187 mL; 95% confidence interval [CI] = -312, -62; data on 628 patients), and blood loss during liver transection (WMD = -143.7 mL; 95% CI = -200, -87; data on 190 patients). However, RF-LR is associated with a higher rate of intra-abdominal abscess than the clamp-crushing method (odds ratio = 3.61; 95% CI = 1.26, 10.32; data on 366 patients). No significant difference was observed between both the groups for the incidence of both blood transfusion and bile leak. CONCLUSIONS: There is currently not sufficient evidence to support or refute the use of RF-LR in liver surgery. RF-LR has advantages in terms of reducing blood loss. However, RF-LR may increase the rates of both bile leak and abdominal abscess. So, the safety of RF-LR has not been established. Future well-designed RCTs are awaited to further investigate the efficacy and safety of RF devices in liver resection.
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Ablación por Catéter/métodos , Hemostasis Quirúrgica/métodos , Hepatectomía/métodos , Hepatopatías/cirugía , Neoplasias Hepáticas/cirugía , Hepatectomía/instrumentación , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Instrumentos QuirúrgicosRESUMEN
Respiratory failure occurs more frequently after thoracic surgery than abdominal surgery. Although the etiology for this complication is frequently attributed to underlying lung disease present in patients undergoing thoracic surgery, this notion is often unfounded because many patients with normal preoperative pulmonary function often require prolonged oxygen supplementation even after minimal resection of lung tissue. Using a murine model of pulmonary resection and peripheral blood samples from patients undergoing resection of the lung or abdominal organs, we demonstrated that lung surgery initiates a proinflammatory loop that results in damage to the remaining lung tissue, noncardiogenic pulmonary edema, hypoxia, and even death. Specifically, we demonstrated that resection of murine lung tissue increased concentrations of the homeostatic cytokine interleukin-7, which led to local and systemic activation of type 2 innate lymphoid cells. This process activated lung-resident eosinophils and facilitated stress-induced eosinophil maturation in the bone marrow in a granulocyte-macrophage colony-stimulating factor-dependent manner, resulting in systemic eosinophilia in both mice and humans. Up-regulation of inducible nitric oxide synthase in lung-resident eosinophils led to tissue nitrosylation, pulmonary edema, hypoxia, and, at times, death. Disrupting this activation cascade at any stage ameliorated deleterious outcomes and improved survival after lung resection in the mouse model. Our data suggest that repurposing US Food and Drug Administration-approved eosinophil-targeting strategies may potentially offer a therapeutic intervention to improve outcomes for patients who require lung resection for benign or malignant etiology.
Asunto(s)
Eosinófilos , Pulmón , Animales , Eosinófilos/metabolismo , Pulmón/patología , Humanos , Ratones , Complicaciones Posoperatorias/etiología , Estrés Fisiológico , Ratones Endogámicos C57BL , Masculino , Óxido Nítrico Sintasa de Tipo II/metabolismo , FemeninoRESUMEN
While the function of many leukocytes in transplant biology has been well defined, the role of eosinophils is controversial and remains poorly explored. Conflicting data exist regarding eosinophils' role in alloimmunity. Due to their prevalence in the lung, and their defined role in other pulmonary pathologies such as asthma, we set out to explore the role of eosinophils in the long-term maintenance of the lung allograft. We noted that depletion of eosinophils results in the generation of donor-specific antibodies. Eosinophil depletion increased memory B cell, plasma cell, and antibody-secreting cell differentiation and resulted in de novo generation of follicular germinal centers. Germinal center formation depended on the expansion of CD4+Foxp3-Bcl6+CXCR5+PD-1+ T follicular helper (Tfh) cells, which increase in number after eosinophil depletion. Mechanistically, we demonstrate that eosinophils prevent Tfh cell generation by acting as the dominant source of IFN-γ in an established lung allograft, thus facilitating Th1 rather than Tfh polarization of naive CD4+ T cells. Our data thus describe what we believe is a unique and previously unknown role for eosinophils in maintaining allograft tolerance and suggest that indiscriminate administration of eosinophil-lytic corticosteroids for treatment of acute cellular rejection may inadvertently promote humoral alloimmunity.
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Eosinófilos , Trasplante de Pulmón , Centro Germinal , Anticuerpos , Trasplante Homólogo , Trasplante de Pulmón/efectos adversosRESUMEN
Gluten network formed by oxidation of glutenin sulfhydryl groups is the determinant of dough rheological properties, while chemical reagents including oxidants and reductants are both used as dough rheology improvers under different circumstances. This study compares the impact of sodium metabisulfite (SMBS) and azodicarbonamide (ADA), as the representative reductive and oxidative dough improvers, at series of concentrations that offer or remove the same number of electrons form dough, respectively. The alveographic characterization, protein distribution and glutenin composition analysis, and free sulfhydryl measurement were performed on dough containing redox equivalent SMBS or ADA. Finally, at each optimal concentration, the dough protein network was analyzed with confocal microscopy. Results showed that SMBS increased the free sulfhydryl content, loosened the microstructure of gluten network, and thus enhanced dough extensibility. ADA reduced the free sulfhydryl content, compacted the dough microstructure, thus enhanced the tenacity and baking strength of dough. It is therefore proposed that the reductants reduce disulfide bonds in gluten network and renders the formation of one-dimensional gluten network while oxidants promote the disulfide linkage and formation of three-dimensional gluten network. This study offers a theoretic foundation of differentiating dough rheology improvers for their specified application.
Asunto(s)
Pan , Harina , Pan/análisis , Harina/análisis , Glútenes/química , Oxidación-Reducción , Estrés Oxidativo , Reología , Triticum/químicaRESUMEN
Eosinophils are bone-marrow-derived granulocytes known for their ability to facilitate clearance of parasitic infections and their association with asthma and other inflammatory diseases. The purpose of this review is to discuss the currently available human observational and animal experimental data linking eosinophils to the immunologic response in solid organ transplantation. First, we present observational human studies that demonstrate a link between transplantation and eosinophils yet were unable to define the exact role of this cell population. Next, we describe published experimental models and demonstrate a defined mechanistic role of eosinophils in downregulating the alloimmune response to murine lung transplants. The overall summary of this data suggests that further studies are needed to define the role of eosinophils in multiple solid organ allografts and points to the possibility of manipulating this cell population to improve graft survival.
Asunto(s)
Trasplante de Pulmón , Trasplante de Órganos , Animales , Eosinófilos/fisiología , Supervivencia de Injerto , Humanos , Trasplante de Pulmón/efectos adversos , Ratones , Trasplante HomólogoRESUMEN
BACKGROUND: Long-term survival of lung transplants lags behind other solid organs due to early onset of a fibrotic form of chronic rejection known as chronic lung allograft dysfunction (CLAD). Preventing CLAD is difficult as multiple immunologic and physiologic insults contribute to its development. Targeting fibroblast activation, which is the final common pathway leading to CLAD, offers the opportunity to ameliorate fibrosis irrespective of the initiating insult. Thy-1 is a surface glycoprotein that controls fibroblast differentiation and activation. METHODS: To study the role of Thy-1 in CLAD, we utilized the minor antigen mismatched C57BL/6 (B6wild-type) or B6Thy-1-/-âC57BL/10 (B10) model of murine orthotopic lung transplantation with postoperative bacterial infection modeled by intratracheal lipopolysaccharide (LPS) administration. The effects of LPS on Thy-1 expression, proliferation, and gene expression were assessed in fibroblasts in vitro and the therapeutic potential of Thy-1 replacement was assessed in vivo. RESULTS: More severe CLAD was evident in B6Thy-1-/- âB10 grafts compared to B6wild-type âB10 grafts. LPS further accentuated fibrosis in B6wild-type âB10 grafts with some, but limited, effects on B6Thy-1-/- âB10 grafts. LPS contributed to Thy-1 loss from Thy-1(+) fibroblasts in vitro due to a decrease in mRNA expression. In addition, LPS promoted proliferation and upregulation of multiple inflammatory pathways in Thy-1(-) fibroblasts by gene expression analysis. Most importantly, replacement of Thy-1 through exogenous administration ameliorated the fibrotic phenotype post-LPS mediated modeling of infection. CONCLUSIONS: Our findings suggest that the loss of Thy-1 on fibroblasts is a previously unrecognized cause of CLAD and its replacement may offer therapeutic applications for amelioration of this disease post-transplantation in the setting of infectious stress responses.
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Lipopolisacáridos , Trasplante de Pulmón , Aloinjertos , Animales , Fibrosis , Lipopolisacáridos/metabolismo , Lipopolisacáridos/farmacología , Pulmón/patología , Ratones , Ratones Endogámicos C57BL , Células del EstromaRESUMEN
Cytokine therapy is limited by undesirable off-target side effects as well as terminal differentiation and exhaustion of chronically stimulated T cells. Here, we describe the signaling properties of a potentially unique cytokine by design, where T cell surface binding and signaling are separated between 2 different families of receptors. This fusion protein cytokine, called OMCPmutIL-2, bound with high affinity to the cytotoxic lymphocyte-defining immunoreceptor NKG2D but signaled through the common γ chain cytokine receptor. In addition to precise activation of cytotoxic T cells due to redirected binding, OMCPmutIL-2 resulted in superior activation of both human and murine CD8+ T cells by improving their survival and memory cell generation and decreasing exhaustion. This functional improvement was the direct result of altered signal transduction based on the reorganization of surface membrane lipid rafts that led to Janus kinase-3-mediated phosphorylation of the T cell receptor rather than STAT/AKT signaling intermediates. This potentially novel signaling pathway increased CD8+ T cell response to low-affinity antigens, activated nuclear factor of activated T cells transcription factors, and promoted mitochondrial biogenesis. OMCPmutIL-2 thus outperformed other common γ chain cytokines as a catalyst for in vitro CD8+ T cell expansion and in vivo CD8+ T cell-based immunotherapy.
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Linfocitos T CD8-positivos , Citocinas , Animales , Citocinas/metabolismo , Humanos , Inmunoterapia , Ratones , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Citocinas/metabolismoRESUMEN
Lymph node (LN) fibroblastic reticular cells (FRCs) define LN niches and regulate lymphocyte homeostasis through producing diverse extracellular matrix (ECM) components. We examined the role of ECM laminin α4 (Lama4) using FRC-Lama4 conditional KO Pdgfrb-Cre-/- × Lama4fl/fl mice. Single-cell RNA-sequencing (scRNA-Seq) data showed the promoter gene Pdgfrb was exclusively expressed in FRCs. Depleting FRC-Lama4 reduced Tregs and dendritic cells, decreased high endothelial venules, impaired the conduit system, and downregulated T cell survival factors in LNs. FRC-Lama4 depletion impaired the homing of lymphocytes to LNs in homeostasis and after allografting. Alloantigen-specific T cells proliferated, were activated to greater degrees in LNs lacking FRC-Lama4, and were more prone to differentiate into effector phenotypes relative to the Treg phenotype. In murine cardiac transplantation, tolerogenic immunosuppression was not effective in FRC-Lama4 recipients, which produced more alloantibodies than WT. After lung transplantation, FRC-Lama4-KO mice had more severe graft rejection with fewer Tregs in their LNs. Overall, FRC-Lama4 critically contributes to a tolerogenic LN niche by supporting T cell migration, constraining T cell activation and proliferation, and promoting Treg differentiation. Hence, it serves as a therapeutic target for immunoengineering.
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Laminina , Ganglios Linfáticos , Reticulina , Linfocitos T , Animales , Laminina/inmunología , Ganglios Linfáticos/inmunología , Ratones , Receptor beta de Factor de Crecimiento Derivado de Plaquetas , Reticulina/inmunología , Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Inmunología del TrasplanteRESUMEN
Gamma delta (γδ) T cells can effectively recognize and kill colorectal cancer (CRC) cells, thereby suppressing tumor progression via multiple mechanisms. They also have abilities to exert a protumor effect via secreting interleukin-17 (IL-17). γδ T cells have been selected as potential immunocytes for antitumor treatment because of their significant cytotoxic activity. Immunotherapy is another potential anti-CRC strategy after an operation, chemotherapy, and radiotherapy. γδ T cell-based immunotherapy for CRC shows fewer side effects and better toleration. This review will outline the immune functions and the mechanisms of γδ T cells in the growth and progression of CRC in recent years, and summarize the immunotherapies based on γδ T cells, thus providing a direction for future γδ T cells in CRC research.
Asunto(s)
Neoplasias Colorrectales/etiología , Neoplasias Colorrectales/metabolismo , Susceptibilidad a Enfermedades , Linfocitos Intraepiteliales/inmunología , Linfocitos Intraepiteliales/metabolismo , Animales , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/inmunología , Transformación Celular Neoplásica/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Citocinas/metabolismo , Citotoxicidad Inmunológica , Susceptibilidad a Enfermedades/inmunología , Humanos , Inmunoterapia/efectos adversos , Inmunoterapia/métodos , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/etiología , Enfermedades Inflamatorias del Intestino/metabolismo , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Resultado del Tratamiento , Escape del Tumor/inmunologíaRESUMEN
Despite the accepted notion that granulocytes play a universally destructive role in organ and tissue grafts, it has been recently described that eosinophils can facilitate immunosuppression-mediated acceptance of murine lung allografts. The mechanism of eosinophil-mediated tolerance, or their role in regulating alloimmune responses in the absence of immunosuppression, remains unknown. Using lung transplants in a fully MHC-mismatched BALB/c (H2d) to C57BL/6 (H2b) strain combination, we demonstrate that eosinophils downregulate T cell-mediated immune responses and play a tolerogenic role even in the absence of immunosuppression. We further show that such downregulation depends on PD-L1/PD-1-mediated synapse formation between eosinophils and T cells. We also demonstrate that eosinophils suppress T lymphocyte responses through the inhibition of T cell receptor/CD3 (TCR/CD3) subunit association and signal transduction in an inducible NOS-dependent manner. Increasing local eosinophil concentration, through administration of intratracheal eotaxin and IL-5, can ameliorate alloimmune responses in the lung allograft. Thus, our data indicate that eosinophil mobilization may be utilized as a novel means of lung allograft-specific immunosuppression.