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PURPOSE: Ketogenic diets are proposed as a therapeutic approach for type 1 and type 2 diabetes due to their low glucose intake. However, their potential effects on the immune system need investigation. This study aims to explore how glucose concentration and beta-hydroxybutyrate (BHB) impact T cell phenotype, metabolism, and function, with a focus on systemic inflammatory response (T2D) and autoimmunity (T1D). METHODS: T cells from healthy donors were cultured in vitro under varying glucose concentrations with or without BHB. Flow cytometry was employed to analyze changes in T cell phenotype, while proliferation was evaluated through a CFSE dilution assay. Additionally, we used a novel flow cytometry method allowing a direct assessment of T cell metabolism. RESULTS: Culturing T cells in low glucose concentrations revealed their dependency on glucose metabolism, leading to reduced proliferation rates, overexpression of exhaustion markers and increased susceptibility to Treg suppression and the influence of immune-modulating drugs such as rapamycin, FK506, and MMF. Notably, T cells cultured in low glucose concentrations increased the expression of BDH1 to utilize BHB as an alternative fuel source. Finally, the addition of BHB to the culture effectively rescued T cell impairments caused by insufficient glucose levels. CONCLUSIONS: T cells display limited capacity to adapt to low glucose levels, resulting in profound functional impairment. However, T cell functions can be efficiently recovered by the presence of 2mM BHB.
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Associations between indoor air pollution from fine particulate matter (PM with aerodynamic diameter dp < 2.5 µm) and human health are poorly understood. Here, we analyse the concentration-response curves for fine and ultrafine PM, the gene expression, and the methylation patterns in human bronchial epithelial cells (BEAS-2B) exposed at the air-liquid interface (ALI) within a classroom in downtown Rome. Our results document the upregulation of aryl hydrocarbon receptor (AhR) and genes associated with xenobiotic metabolism (CYP1A1 and CYP1B1) in response to single exposure of cells to fresh urban aerosols at low fine PM mass concentrations within the classroom. This is evidenced by concentrations of ultrafine particles (UFPs, dp < 0.1 µm), polycyclic aromatic hydrocarbons (PAH), and ratios of black carbon (BC) to organic aerosol (OA). Additionally, an interleukin 18 (IL-18) down-regulation was found during periods of high human occupancy. Despite the observed gene expression dysregulation, no changes were detected in the methylation levels of the promoter regions of these genes, indicating that the altered gene expression is not linked to changes in DNA methylation and suggesting the involvement of another epigenetic mechanism in the gene regulation. Gene expression changes at low exposure doses have been previously reported. Here, we add the possibility that lung epithelial cells, when singly exposed to real environmental concentrations of fine PM that translate into ultra-low doses of treatment, may undergo epigenetic alteration in the expression of genes related to xenobiotic metabolism. Our findings provide a perspective for future indoor air quality regulations. We underscore the potential role of indoor UFPs as carriers of toxic molecules with low-pressure weather conditions, when rainfall and strong winds may favour low levels of fine PM.
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Type 1 diabetes (T1D) presents a persistent medical challenge, demanding innovative strategies for sustained glycemic control and enhanced patient well-being. Beta cells are specialized cells in the pancreas that produce insulin, a hormone that regulates blood sugar levels. When beta cells are damaged or destroyed, insulin production decreases, which leads to T1D. Allo Beta Cell Transplantation has emerged as a promising therapeutic avenue, with the goal of reinstating glucose regulation and insulin production in T1D patients. However, the path to success in this approach is fraught with complex immunological hurdles that demand rigorous exploration and resolution for enduring therapeutic efficacy. This exploration focuses on the distinct immunological characteristics inherent to Allo Beta Cell Transplantation. An understanding of these unique challenges is pivotal for the development of effective therapeutic interventions. The critical role of glucose regulation and insulin in immune activation is emphasized, with an emphasis on the intricate interplay between beta cells and immune cells. The transplantation site, particularly the liver, is examined in depth, highlighting its relevance in the context of complex immunological issues. Scrutiny extends to recipient and donor matching, including the utilization of multiple islet donors, while also considering the potential risk of autoimmune recurrence. Moreover, unanswered questions and persistent gaps in knowledge within the field are identified. These include the absence of robust evidence supporting immunosuppression treatments, the need for reliable methods to assess rejection and treatment protocols, the lack of validated biomarkers for monitoring beta cell loss, and the imperative need for improved beta cell imaging techniques. In addition, attention is drawn to emerging directions and transformative strategies in the field. This encompasses alternative immunosuppressive regimens and calcineurin-free immunoprotocols, as well as a reevaluation of induction therapy and recipient preconditioning methods. Innovative approaches targeting autoimmune recurrence, such as CAR Tregs and TCR Tregs, are explored, along with the potential of stem stealth cells, tissue engineering, and encapsulation to overcome the risk of graft rejection. In summary, this review provides a comprehensive overview of the inherent immunological obstacles associated with Allo Beta Cell Transplantation. It offers valuable insights into emerging strategies and directions that hold great promise for advancing the field and ultimately improving outcomes for individuals living with diabetes.
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Diabetes Mellitus Tipo 1 , Células Secretoras de Insulina , Insulinas , Transplante das Ilhotas Pancreáticas , Humanos , Células Secretoras de Insulina/metabolismo , GlucoseRESUMO
Adoptive regulatory T-cell (Treg) transfer has emerged as a promising therapeutic strategy for regulating immune responses in organ transplantation, graft versus host disease, and autoimmunity, including Type 1 diabetes. Traditionally, Treg for adoptive therapy have been sorted and expanded in vitro using high doses of IL-2, demonstrating stability and suppressive capabilities. However, limitations in their long-term survival post-infusion into patients have been observed. To address this challenge, we investigated a novel expansion protocol incorporating interleukin-7 (IL-7) alongside the traditional method utilizing IL-2 (referred to as IL-7 method, IL-7M). Our study revealed that naïve Treg express significant levels of CD127 and display robust responsiveness to IL-7, characterized by STAT-5 phosphorylation. Expanding naïve Treg with the IL-7M protocol led to a substantial enrichment of CD45RA+ CD62L+ CD95+ Treg but showing a reduction in the final cell yield and suppressive function. Moreover, Treg expanded with the IL-7M exhibited preserved telomere length and demonstrated enhanced resistance to cytokine withdrawal and fas-mediated apoptosis. When transferred into NSG mice IL-7M-Treg persisted longer and reduced the expansion of T cells, but did not significantly reduce the severity of xenoGvHD. In conclusion, our data demonstrate the feasibility of expanding naïve Treg in the presence of IL-7 to generate a Treg product enriched in poorly differentiated CD45RA+ cells with enhanced survival capabilities.
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Interleucina-7 , Linfócitos T Reguladores , Humanos , Camundongos , Animais , Interleucina-2 , Citocinas , Transferência Adotiva/métodos , Antígenos Comuns de Leucócito , Fatores de Transcrição ForkheadRESUMO
Aim: In a recent randomized, multicenter trial (NCT02814838) a short-term anti-inflammatory treatment with ladarixin (LDX; an inhibitor of the CXCR1/2 chemokine receptors) did not show benefit on preserving residual beta cell function in new-onset type 1 diabetes. We present a post hoc analysis of trial patients in the predefined subgroup analysis developed according to baseline daily insulin requirement (DIR) tertiles. Method: A double-blind, randomized (2:1), placebo-controlled study was conducted in 45 men and 31 women (aged 18-46 years) within 100 days of the first insulin administration. Patients received LDX (400 mg twice daily) for three cycles of 14 days on/14 days off, or placebo. The primary endpoint was the area under the curve for C-peptide [AUC (0-120 min)] in response to a 2-h mixed meal tolerance test (MMTT) at week 13 ± 1. Seventy-five patients completed the week 13 MMTT and were divided into three groups according to the DIR tertiles: lower, ≤ 0.23U/kg/die (n = 25); middle, 0.24-0.40 U/kg/die (n = 24); upper, ≥ 0.41 U/kg/die (n = 26). Results: When considering the patients in the upper tertile (HIGH-DIR), C-peptide AUC (0-120 min) at 13 weeks was higher in the LDX group (n = 16) than in the placebo (n = 10) group [difference: 0.72 nmol/L (95% CI 0.9-1.34), p = 0.027]. This difference reduced over time (0.71 nmol/L at 26 weeks, p = 0.04; 0.42 nmol/L at 52 weeks, p = 0.29), while it has never been significant at any time in patients in the lower and/or middle tertile (LOW-DIR). We characterized at baseline the HIGH-DIR and found that endo-metabolic (HOMA-B, adiponectin, and glucagon-to-C-peptide ratio) and immunologic (chemokine (C-C motif) ligand 2 (CCL2)/monocyte chemoattractant protein 1 (MCP1) and Vascular Endothelial Growth Factor (VEGF)) features distinguished this group from LOW-DIR. Conclusion: While LDX did not prevent the progressive loss of beta-cell function in the majority of treated subjects, the post hoc analysis suggests that it could work in subjects with HIGH-DIR at baseline. As we found differences in endo-metabolic and immunologic parameters within this subgroup, this generates the hypothesis that the interactions between host factors and drug action can contribute to its efficacy. Further research is needed to evaluate this hypothesis.
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Diabetes Mellitus Tipo 1 , Masculino , Humanos , Feminino , Diabetes Mellitus Tipo 1/tratamento farmacológico , Peptídeo C/metabolismo , Estudos Prospectivos , Fator A de Crescimento do Endotélio Vascular , Insulina/uso terapêuticoRESUMO
In this Letter, we present a scheme for detecting fiber-bending eavesdropping based on feature extraction and machine learning (ML). First, 5-dimensional features from the time-domain signal are extracted from the optical signal, and then a long short-term memory (LSTM) network is applied for eavesdropping and normal event classification. Experimental data are collected from a 60â km single-mode fiber transmission link with eavesdropping implemented by a clip-on coupler. Results show that the proposed scheme achieves a 95.83% detection accuracy. Furthermore, since the scheme focuses on the time-domain waveform of the received optical signal, additional devices and a special link design are not required.
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Aprendizado de Máquina , Redes Neurais de ComputaçãoRESUMO
Due to its importance in airborne disease transmission, especially because of the COVID-19 pandemic, much attention has recently been devoted by the scientific community to the analysis of dispersion of particle-laden air clouds ejected by humans during different respiratory activities. In spite of that, a lack of knowledge is still present particularly with regard to the velocity of the emitted particles, which could differ considerably from that of the air phase. The velocity of the particles is also expected to vary with their size. In this work, simultaneous measurements of size and velocity of particles emitted by humans while speaking have been performed by means of Interferometric Laser Imaging Droplet Sizing (ILIDS). This technique allowed us to detect emitted particles with size down to 2 µm as well as to quantify all three components of the velocity vector and the particle concentration. The outcomes of this work may be used as boundary conditions for numerical simulations of infected respiratory cloud transmission.
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Induced pluripotent stem cells (iPSCs) represent a source from which ß cells can be derived for diabetes replacement therapy. However, their application may be hindered by immune-mediated responses. Although abrogation of major histocompatibility complex class I (MHC-I) can address this issue, it may trigger natural killer (NK) cells through missing-self recognition mechanisms. By profiling the relevant NK-activating ligands on iPSCs during in vitro differentiation into pancreatic ß cells, we find that they express high levels of B7-H3 and CD155. Hypothesizing that such surface ligands could be involved in the amplification of NK-activating signals following missing-self, we generate MHC-I-deprived B7-H3-/-, CD155-/-, and B7-H3-/-/CD155-/- iPSCs. All engineered lines correctly differentiate into insulin-secreting ß cells and are protected from cell lysis mediated by CD16dim and CD16+ NK subpopulations both in vitro and in vivo in NSG mice. Our data support targeted disruption of NK-activating ligands to enhance the transplant compatibility of MHC-I-/- iPSC pancreatic derivatives.
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Células-Tronco Pluripotentes Induzidas , Células Secretoras de Insulina , Insulinas , Animais , Antígenos de Histocompatibilidade Classe I/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Células Secretoras de Insulina/metabolismo , Ligantes , CamundongosRESUMO
Autoreactive T cells with the phenotype and function of different memory subsets are present in patients who developed type 1 diabetes (TID). According to the progressive differentiation model, memory subsets generate from naïve precursors in a linear and unidirectional path depending on the strength and quality of stimulatory signals. By observing human naïve T cells in contact with GAD65 loaded autologous dendritic cells, we observed that approximately 10% of cells divided with the plane of cell division parallel to the one of the immune synapse, causing phenotypic asymmetries in the proximal and distal daughter T cells. After the first T cell division, proximal and distal daughter T cells showed different phenotype, metabolic signature and commitment to differentiate towards long-lived memory T cells or T cells with effector function. Subjects with or without T1D showed a similar frequency of asymmetric T cell division (ATCD) for autoantigens and recall antigens specific T cells, however the frequency of ATCD is significantly increased in autoreactive T cells in patients with T1D when IL-7 was added to the culture. An increased upregulation of GLUT1 in response to IL-7 in patients with T1D was related to the rate of ATCD. Our results showed that ATCD is associated with an early divergence in the differentiation fate of naïve T cells specific for GAD65 during first antigen encounter.
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Diabetes Mellitus Tipo 1 , Autoantígenos , Diferenciação Celular , Divisão Celular , Transportador de Glucose Tipo 1/metabolismo , Humanos , Memória Imunológica , Interleucina-7/metabolismo , Células T de Memória , Subpopulações de Linfócitos TRESUMO
Air pollution and heat stress are major concerns associated with the liveability, resilience and sustainability of cities. They directly affect health and comfort and are associated with augmented morbidity and mortality and an increase in the energy demand for building ventilation, air cleaning and cooling. Nevertheless, the detrimental effects of poor air quality may partly be mitigated by increased urban ventilation. This strategy is closely related to the level of urbanization and the urban morphology. Therefore, detailed investigations on the impact of different morphologies on urban ventilation are of paramount importance. Computational Fluid Dynamics simulations have been widely used during the last decades to investigate the effects of the urban morphology on the urban ventilation. However, most of these studies focused on idealized building arrangements, while detailed investigations about the role of real urban morphologies are scarce. This study investigates the ventilation in a compact area in the city of Rome, Italy. 3D steady-state Reynolds-averaged Navier-Stokes simulations are performed to analyze the impact of Morphological Parameters (MP) on the urban ventilation. The results show a considerable worsening of urban ventilation with increasing building density with a reduction in the mean wind velocity up to 62% experienced at the pedestrian level (zp). Correlations between five MPs, e.g., plan area density, area-weighted mean building height, volume density, façade area density, and non-dimensional mean velocity at pedestrian level and at 10 m height are evaluated, and simple models are obtained using linear regression analysis. Among the selected MPs, the building façade area density shows a remarkable correlation with the non-dimensional mean velocity at zp (R2 = 0.82). Such correlations can be valuable tools for practitioners and urban designers, particularly during the first stage of planning, for highlighting areas potentially vulnerable to poor air conditions without running computationally expensive simulations.
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Poluição do Ar , Respiração , Cidades , Cidade de Roma , VentilaçãoRESUMO
AIM: The aim of this study was to investigate whether treatment with rapamycin plus vildagliptin restores ß-cell function in patients with long-standing type 1 diabetes. METHODS: A phase 2, single-center, randomized, double-blind, placebo-controlled study was conducted in long-standing type 1 diabetes patients randomly assigned (1:1:1) to 4 weeks of rapamycin (group 2), 4 weeks of rapamycin plus 12 weeks of vildagliptin (group 3), or double placebo (group 1). The primary outcome was the proportion of participants with a positive response to the Mixed-Meal Tolerance Test (C-peptide at 90 minutesâ >â 0.2 nmol/L) at weeks 4 and 12. Secondary end points included insulin requirement, standard measures of glycemic control, and hormonal and immunological profile. RESULTS: Fifty-five patients were randomly assigned to group 1 (nâ =â 18), group 2 (nâ =â 19), or group 3 (nâ =â 18). No patient in any group showed a positive C-peptide response, and there was no significant difference at 4 and 12 weeks for the primary outcome. At 4 weeks, insulin requirement decreased from 0.54 to 0.48 U/kg/day in group 2 (Pâ =â .013), from 0.59 to 0.51 U/kg/day in group 3 (Pâ <â .001), whereas it did not change in group 1. At 12 weeks, glycated hemoglobin significantly decreased both in group 2 (from 7.3% [56 mmol/mol] to 7% [53 mmol/mol]; Pâ =â .045] and in group 3 (from 7.2% [55.5 mmol/mol] to 6.9% [52 mmol/mol]; Pâ =â .001]. Rapamycin treatment was associated with a decrease in insulin antibody titer and changes in hormonal/immunological profile. CONCLUSIONS: Rapamycin reduced insulin requirement, but did not restore ß-cell function in patients with long-standing type 1 diabetes.
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Diabetes Mellitus Tipo 1/tratamento farmacológico , Células Secretoras de Insulina/efeitos dos fármacos , Sirolimo/administração & dosagem , Vildagliptina/administração & dosagem , Adulto , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/fisiopatologia , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Células Secretoras de Insulina/fisiologia , Itália , Masculino , Pessoa de Meia-Idade , Placebos , Recuperação de Função Fisiológica/efeitos dos fármacos , Sirolimo/farmacologia , Resultado do Tratamento , Vildagliptina/farmacologia , Adulto JovemRESUMO
The induction of antigen (Ag)-specific tolerance represents a therapeutic option for autoimmune diabetes. We demonstrated that administration of a lentiviral vector enabling expression of insulin B chain 9-23 (InsB9-23) (LV.InsB) in hepatocytes arrests ß-cell destruction in prediabetic NOD mice by generating InsB9-23-specific FoxP3+ T regulatory cells (Tregs). LV.InsB in combination with a suboptimal dose of anti-CD3 monoclonal antibody (combined therapy [CT], 1 × 5 µg [CT5]) reverts diabetes and prevents recurrence of autoimmunity after islet transplantation in â¼50% of NOD mice. We investigated whether CT optimization could lead to abrogation of recurrence of autoimmunity. Therefore, alloislets were transplanted after optimized CT tolerogenic conditioning (1 × 25 µg [CT25]). Diabetic NOD mice conditioned with CT25 when glycemia was <500 mg/dL remained normoglycemic for 100 days after alloislet transplantation and displayed reduced insulitis, but independently from the graft. Accordingly, cured mice showed T-cell unresponsiveness to InsB9-23 stimulation and increased Treg frequency in islet infiltration and pancreatic lymph nodes. Additional studies revealed a complex mechanism of Ag-specific immune regulation driven by CT25, in which both Tregs and PDL1 costimulation cooperate to control diabetogenic cells, while transplanted islets play a crucial role, although transient, recruiting diabetogenic cells. Therefore, CT25 before alloislet transplantation represents an Ag-specific immunotherapy to resolve autoimmune diabetes in the presence of residual endogenous ß-cell mass.
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Diabetes Mellitus Tipo 1/cirurgia , Hepatócitos/metabolismo , Células Secretoras de Insulina/metabolismo , Transplante das Ilhotas Pancreáticas/métodos , Peptídeos/uso terapêutico , Animais , Autoimunidade/efeitos dos fármacos , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/prevenção & controle , Técnicas de Transferência de Genes , Sobrevivência de Enxerto/imunologia , Hepatócitos/imunologia , Células Secretoras de Insulina/imunologia , Transplante das Ilhotas Pancreáticas/imunologia , Camundongos , Camundongos Endogâmicos NOD , Recidiva , Prevenção Secundária , Linfócitos T Reguladores/imunologiaRESUMO
The orchestration of T cell responses is intimately linked to the execution of metabolic processes, both in homeostasis and disease. In cancer tissues, metabolic alterations that characterize malignant transformation profoundly affect the composition of the immune microenvironment and the accomplishment of an effective anti-tumor response. The growing understanding of the metabolic regulation of immune cell function has shed light on the possibility to manipulate metabolic pathways as a strategy to improve T cell function in cancer. Among others, glucose metabolism through the glycolytic pathway is central in shaping T cell responses and emerges as an ideal target to improve cancer immunotherapy. However, metabolic manipulation requires a deep level of control over side-effects and development of biomarkers of response. Here, we summarize the metabolic control of T cell function and focus on the implications of metabolic manipulation for the design of immunotherapeutic strategies. Integrating our understanding of T cell function and metabolism will hopefully foster the forthcoming development of more effective immunotherapeutic strategies.
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Better understanding of pancreatic diseases, including pancreatic ductal adenocarcinoma (PDAC), is an urgent medical need, with little advances in preoperative differential diagnosis, preventing rational selection of therapeutic strategies. The clinical management of pancreatic cancer patients would benefit from the identification of variables distinctively associated with the multiplicity of pancreatic disorders. We investigated, by 1H nuclear magnetic resonance, the metabolomic fingerprint of pancreatic juice (the biofluid that collects pancreatic products) in 40 patients with different pancreatic diseases. Metabolic variables discriminated PDAC from other less aggressive pancreatic diseases and identified metabolic clusters of patients with distinct clinical behaviors. PDAC specimens were overtly glycolytic, with significant accumulation of lactate, which was probed as a disease-specific variable in pancreatic juice from a larger cohort of 106 patients. In human PDAC sections, high expression of the glucose transporter GLUT-1 correlated with tumor grade and a higher density of PD-1+ T cells, suggesting their accumulation in glycolytic tumors. In a preclinical model, PD-1+ CD8 tumor-infiltrating lymphocytes differentially infiltrated PDAC tumors obtained from cell lines with different metabolic consumption, and tumors metabolically rewired by knocking down the phosphofructokinase (Pfkm) gene displayed a decrease in PD-1+ cell infiltration. Collectively, we introduced pancreatic juice as a valuable source of metabolic variables that could contribute to differential diagnosis. The correlation of metabolic markers with immune infiltration suggests that upfront evaluation of the metabolic profile of PDAC patients could foster the introduction of immunotherapeutic approaches for pancreatic cancer.
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Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/patologia , Linfócitos do Interstício Tumoral/imunologia , Metaboloma , Suco Pancreático/metabolismo , Neoplasias Pancreáticas/patologia , Receptor de Morte Celular Programada 1/metabolismo , Idoso , Animais , Linfócitos T CD8-Positivos/imunologia , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/metabolismo , Células Cultivadas , Técnicas de Cocultura , Feminino , Transportador de Glucose Tipo 1/metabolismo , Humanos , Leucócitos Mononucleares/imunologia , Masculino , Camundongos , Camundongos Transgênicos , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Receptor de Morte Celular Programada 1/imunologia , Taxa de SobrevidaAssuntos
Diabetes Mellitus Tipo 1 , Sangue Fetal , Subunidade alfa de Receptor de Interleucina-7 , Gravidez em Diabéticas , Adulto , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/imunologia , Feminino , Sangue Fetal/imunologia , Sangue Fetal/metabolismo , Humanos , Lactente , Recém-Nascido , Subunidade alfa de Receptor de Interleucina-7/sangue , Subunidade alfa de Receptor de Interleucina-7/imunologia , Masculino , Gravidez , Gravidez em Diabéticas/sangue , Gravidez em Diabéticas/imunologiaRESUMO
An increasing body of evidence indicates that bio-energetic metabolism of T cells can be manipulated to control T cell responses. This potentially finds a field of application in the control of the T cell responses in autoimmune diseases, including in type 1 diabetes (T1D). Of the possible metabolic targets, Glut1 gained considerable interest because of its pivotal role in glucose uptake to fuel glycolysis in activated T cells, and the recent development of a novel class of small molecules that act as selective inhibitor of Glut1. We believe we can foresee a possible application of pharmacological Glut1 blockade approach to control autoreactive T cells that destroy insulin producing beta cells. However, Glut1 is expressed in a broad range of cells in the body and off-target and side effect are possible complications. Moreover, the duration of the treatment and the age of patients are critical aspects that need to be addressed to reduce toxicity. In this paper, we will review recent literature to determine whether it is possible to design a pharmacological Glut1 blocking strategy and how to apply this to autoimmunity in T1D.
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Autoimunidade , Transportador de Glucose Tipo 1/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/etiologia , Doenças Autoimunes/metabolismo , Autoimunidade/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Regulação da Expressão Gênica , Transportador de Glucose Tipo 1/antagonistas & inibidores , Transportador de Glucose Tipo 1/química , Transportador de Glucose Tipo 1/genética , Humanos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Terapia de Alvo Molecular , Transdução de Sinais , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacosRESUMO
BACKGROUND: Results in murine and nonhuman primate suggested that the bone marrow (BM) might be an alternative site for pancreatic islet transplantation. METHODS: We report the results of 2 clinical studies in patients with type 1 diabetes receiving an intra-BM allogeneic islet transplantation: a feasibility study in patients with hepatic contraindications for liver islet allotransplantation receiving a single intra-BM islet infusion (n = 4) and a pilot randomized trial (1:1 allocation using blocks of size 6) in which patients were randomized to receive islets into either the liver (n = 6) or BM (n = 3) to evaluate islet transplant function and survival. RESULTS: We observed no adverse events related to the intrabone injection procedure or the presence of islets in the BM. None of the recipient of an intra-BM allogeneic islet transplantation had a primary nonfunction, as shown by measurable posttransplantation C-peptide levels and histopathological evidence of insulin-producing cells or molecular markers of endocrine tissue in BM biopsy samples collected during follow-up. All patients receiving islets in the BM except 1 lost islet function during the first 4 months after infusion (2 with an early graft loss). Based on biopsies and immunomonitoring, we concluded that the islet loss was primarily caused by the recurrence of autoimmunity. CONCLUSIONS: Bone marrow is not a suitable alternative site for pancreatic islet allotransplantation in patients with type 1 diabetes.
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Medula Óssea/cirurgia , Diabetes Mellitus Tipo 1/cirurgia , Transplante das Ilhotas Pancreáticas/métodos , Biópsia , Medula Óssea/patologia , Diabetes Mellitus Tipo 1/imunologia , Humanos , Projetos Piloto , Transplante HomólogoRESUMO
Stem memory T cells (Tscm) constitute the earliest developmental stage of memory T cells, displaying stem cell-like properties, such as self-renewal capacity. Their superior immune reconstitution potential has sparked interest in cancer immune therapy, vaccine development, and immune reconstitution, whereas their role in autoimmunity is largely unexplored. Here we show that autoreactive CD8+ Tscm specific for ß-cell antigens GAD65, insulin, and IGRP are present in patients with type 1 diabetes (T1D). In vitro, the generation of autoreactive Tscm from naive precursors required the presence of the homeostatic cytokine interleukin-7 (IL-7). IL-7 promotes glucose uptake via overexpression of GLUT1 and upregulation of the glycolytic enzyme hexokinase 2. Even though metabolism depends on glucose uptake, the subsequent oxidation of pyruvate in the mitochondria was necessary for Tscm generation from naive precursors. In patients with T1D, high expression of GLUT1 was a hallmark of circulating Tscm, and targeting glucose uptake via GLUT1 using the selective inhibitor WZB117 resulted in inhibition of Tscm generation and expansion. Our results suggest that autoreactive Tscm are present in patients with T1D and can be selectively targeted by inhibition of glucose metabolism.
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Autoimunidade/imunologia , Linfócitos T CD8-Positivos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Células Progenitoras Linfoides/imunologia , Subpopulações de Linfócitos T/imunologia , Adolescente , Adulto , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Criança , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Glucose/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Glucose-6-Fosfatase/imunologia , Glutamato Descarboxilase/imunologia , Hexoquinase/metabolismo , Humanos , Hidroxibenzoatos/farmacologia , Memória Imunológica/imunologia , Técnicas In Vitro , Insulina/imunologia , Interleucina-7/imunologia , Linfopoese/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/metabolismo , Regulação para CimaRESUMO
Activation and maintenance of the T cell response occurs concurrently with metabolic reprogramming. This ensures the T cell response is supported by sufficient energy and substrates necessary for cell survival, growth and proliferation. Different metabolic programs are associated with differentiation into different cell subsets, effector function and development of long-lasting memory. This provides an opportunity to improve the T cell response through manipulation of metabolism, which is instrumental to ameliorate the current protocols for cancer immunotherapy. Using drugs and molecules targeting selective metabolic pathways it is now possible to generate T cells that can mount a durable and stable anti-tumor response. On the other hand, cancer cells can take advantage of the metabolic requirements of T cells to evade the immune response. In this brief review we discuss recent findings of T cell metabolism in quiescence and activation, how the tumor microenvironment can affect T cell metabolism, and how T cell metabolism can be manipulated to improve the T cell response to tumors.