Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 365
Filtrar
1.
Diabetologia ; 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31659408

RESUMO

AIMS/HYPOTHESIS: MicroRNAs (miRNAs) are a novel class of potential biomarkers emerging in many diseases, including type 1 diabetes. Here, we aim to analyse a panel of circulating miRNAs in non-obese diabetic (NOD) mice and individuals with type 1 diabetes. METHODS: We adopted standardised methodologies for extracting miRNAs from small sample volumes to evaluate a profiling panel of mature miRNAs in paired plasma and laser-captured microdissected immune-infiltrated islets of recently diabetic and normoglycaemic NOD mice. Moreover, we validated the findings during disease progression and remission after anti-CD3 therapy in NOD mice, as well as in individuals with type 1 diabetes. RESULTS: Plasma levels of five miRNAs were downregulated in diabetic vs normoglycaemic mice. Of those, miR-409-3p was also downregulated in situ in the immune islet infiltrates of diabetic mice, suggesting an association with disease pathogenesis. Target-prediction tools linked miR-409-3p to immune- and metabolism-related signalling molecules. In situ miR-409-3p expression correlated with insulitis severity, and CD8+ central memory T cells were found to be enriched in miR-409-3p. Plasma miR-409-3p levels gradually decreased during diabetes development and improved with disease remission after anti-CD3 antibody therapy. Finally, plasma miR-409-3p levels were lower in people recently diagnosed with type 1 diabetes compared with a non-diabetic control group, and levels were inversely correlated with HbA1c levels. CONCLUSIONS/INTERPRETATION: We propose that miR-409-3p may represent a new circulating biomarker of islet inflammation and type 1 diabetes severity.

2.
J Diabetes Sci Technol ; : 1932296819882752, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31633384

RESUMO

BACKGROUND: Twenty-four hour fasting periods are being used to scrutinize basal insulin infusion rates for pump-treated patients with type 1 diabetes. METHODS: Data from 339 consecutive in-patients with adult type 1 diabetes on insulin pump therapy undergoing a 24-hour fast as a basal rate test were retrospectively analyzed. Hourly programmed basal insulin infusion rates and plasma glucose concentrations within, below, or above arbitrarily defined target ranges were assessed for periods of the day of special interest (eg, 01:00-07:00 am, "dawn" period, 04:00-07:00 pm, and "dusk" period). Statistics: χ2-tests, paired t-tests were used. RESULTS: Basal rates (mean: 0.90 ± 0.02 IU/h) showed circadian variations with peaks corresponding to "dawn" (1.07 ± 0.02 IU/h from 01:00 to 07:00 am) and, less prominently, "dusk" (0.95 ± 0.02 IU/h from 03:00 to 07:00 pm). Individual mean plasma glucose concentrations averaged 6.6 ± 0.1 mmol/L, with 53.1% in the predefined "strict" (4.4-7.2 mmol/L) target range. Interestingly, during the "dawn" period, plasma glucose was significantly higher (by 0.5 ± 0.1 mmol/L [95% confidence interval: 0.3-0.8 mmol/L; P < .0001]) and the odds ratio for hypoglycemia was significantly lower compared to the reference period. INTERPRETATION: Twenty-four hour fasting periods as basal rate tests frequently unravel periods with inappropriate basal insulin infusion rates potentially responsible for fasting hyper- or hypoglycemia. Notably, the higher basal insulin infusion rate found during the "dawn" period seems to be justified and may need to be accentuated.

3.
Endocrinology ; 160(11): 2759-2772, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504428

RESUMO

Thyroid hormones (THs) are crucial regulators of glucose metabolism and insulin sensitivity. Moreover, inactivating mutations in type 2 deiodinase (DIO2), the major TH-activating enzyme, have been associated with type 2 diabetes mellitus in both humans and mice. We studied the link between Dio2 deficiency and glucose homeostasis in fasted males of two different Dio2 knockout (KO) zebrafish lines. Young adult Dio2KO zebrafish (6 to 9 months) were hyperglycemic. Both insulin and glucagon expression were increased, whereas ß and α cell numbers in the main pancreatic islet were similar to those in wild-types. Insulin receptor expression in skeletal muscle was decreased at 6 months, accompanied by a strong downregulation of hexokinase and pyruvate kinase expression. Blood glucose levels in Dio2KO zebrafish, however, normalized around 1 year of age. Older mutants (18 to 24 months) were normoglycemic, and increased insulin and glucagon expression was accompanied by a prominent increase in pancreatic islet size and ß and α cell numbers. Older Dio2KO zebrafish also showed strongly decreased expression of glucagon receptors in the gastrointestinal system as well as decreased expression of glucose transporters GLUT2 and GLUT12, glucose-6-phosphatase, and glycogen synthase 2. This study shows that Dio2KO zebrafish suffer from transient hyperglycemia, which is counteracted with increasing age by a prominent hyperplasia of the endocrine pancreas together with decreases in hepatic glucagon sensitivity and intestinal glucose uptake. Further research on the mechanisms allowing compensation in older Dio2KO zebrafish may help to identify new therapeutic targets for (TH deficiency-related) hyperglycemia.

4.
Diabetologia ; 62(11): 2118-2128, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31338546

RESUMO

AIMS/HYPOTHESIS: This study aimed to determine the characteristics and pregnancy outcomes across different subtypes of gestational diabetes mellitus (GDM) based on insulin resistance. METHODS: GDM subtypes were defined in 1813 pregnant women from a multicentre prospective cohort study, stratified according to insulin resistance, based on Matsuda index below the 50th percentile of women with normal glucose tolerance (NGT), during a 75 g OGTT at 24-28 weeks' gestation. GDM was diagnosed in 12.4% (n = 228) of all participants based on the 2013 WHO criteria. RESULTS: Compared with women with NGT (1113 [61.4%] of the total cohort) and insulin-sensitive women with GDM (39 [17.1%] women with GDM), women with GDM and high insulin resistance (189 [82.9%] women with GDM) had a significantly higher BMI, systolic BP, fasting plasma glucose (FPG), fasting total cholesterol, LDL-cholesterol and triacylglycerol levels in early pregnancy. Compared with women with NGT, insulin-sensitive women with GDM had a significantly lower BMI but similar BP, FPG and fasting lipid levels in early pregnancy. Compared with women with NGT, women with GDM and high insulin resistance had higher rates of preterm delivery (8.5% vs 4.7%, p = 0.030), labour induction (42.7% vs 28.1%, p < 0.001), Caesarean section (total Caesarean sections: 28.7% vs 19.4%, p = 0.004; emergency Caesarean sections: 16.0% vs 9.7%, p = 0.010), neonatal hypoglycaemia (15.4% vs 3.5%, p < 0.001) and neonatal intensive care unit admissions (16.0% vs 8.9%, p = 0.003). In multivariable logistic regression analyses using different models to adjust for demographics, BMI, FPG, HbA1c, lipid levels and gestational weight gain in early pregnancy, preterm delivery (OR 2.41 [95% CI 1.08, 5.38]) and neonatal hypoglycaemia (OR 4.86 [95% CI 2.04, 11.53]) remained significantly higher in women with GDM and high insulin resistance compared with women with NGT. Insulin-sensitive women with GDM had similar pregnancy outcomes as women with NGT. The need for insulin treatment during pregnancy and the rate of glucose intolerance in the early postpartum period were not significantly different among the GDM subtypes. CONCLUSIONS/INTERPRETATION: GDM with high insulin resistance represents a more adverse metabolic profile with a greater risk of adverse pregnancy outcomes.

5.
Acta Clin Belg ; : 1-8, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31259665

RESUMO

Screening for gestational diabetes mellitus (GDM) is important to improve pregnancy outcomes and to prevent type 2 diabetes after pregnancy. The 'International Association of Diabetes and Pregnancy Study Groups' (IADPSG) recommends a universal one-step approach with the 75 g oral glucose tolerance test (OGTT) for screening of GDM. The IADPSG recommendation remains controversial due to the important increase in GDM prevalence and increased workload. After review of the latest evidence and based on data from the 'Belgian Diabetes in Pregnancy' study, members of the Diabetes Liga, the Flemish associations of general physicians (Domus Medica), obstetricians (VVOG), midwives (VVOB), diabetes nurse educators (BVVDV) and clinical chemists (RBSLM) have reached a new consensus on screening for GDM in Flanders. This new consensus recommends universal screening for overt diabetes when planning pregnancy or at the latest at first prenatal contact, preferably by measuring the fasting plasma glucose by using the same diagnostic criteria as in the non-pregnant state. In women with impaired fasting glycaemia, but also in normoglycemic obese women and women with a previous history of GDM, lifestyle counselling is advised with screening for GDM with a 75 g OGTT at 24 weeks. In all other women, we recommend a two-step screening strategy with a 50 g glucose challenge test (GCT) at 24 weeks followed by a 75 g OGTT when the glucose level 1 hour after the GCT ≥130 mg/dl. Diagnosis of GDM is made using the IADPSG criteria for GDM. Postpartum screening for subsequent glucose abnormalities should be advocated and organized for every woman with GDM.

6.
Diabetes Care ; 42(9): 1716-1723, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31177179

RESUMO

OBJECTIVE: While sodium-glucose cotransporter inhibitor (SGLTi) therapy has been evaluated in type 1 diabetes (T1D) trials, patient reactions to benefits and risks are unknown. Using established methodology, we evaluated patient preferences for different adjunct-to-insulin therapy options in T1D. RESEARCH DESIGN AND METHODS: An online survey, completed by 701 respondents with T1D (231 U.S., 242 Canada, and 228 Germany), used conjoint analysis to present six hypothetical, masked, pairwise drug profile choices composed of different benefit-risk attributes and effect ranges. Data used in analyses were derived from actual phase 3 trials of a low-dose SGLTi (comparable to oral empagliflozin 2.5 mg q.d.), a high-dose SGLTi (comparable to oral sotagliflozin 400 mg q.d.), and an available adjunct-to-insulin therapy (comparable to subcutaneous pramlintide 60 µg t.i.d.). RESULTS: Conjoint analysis identified diabetic ketoacidosis risk as most important to patients (23% relative score; z test, P < 0.05); ranked second were HbA1c reduction (14%), risk of severe hypoglycemia (13%), oral versus injectable treatment (12%), and risk of genital infection (12%). Next was risk of nausea (11%), followed by weight reduction (8%) and the risk of diarrhea (7%). A low-dose SGLTi drug profile was identified by conjoint analysis as the top patient preference (83% of participants; z test, P < 0.05) versus high-dose SGLTi (8%) or pramlintide (9%). Separate from conjoint analysis, when respondents were asked to choose their preferred adjunct-to-insulin therapy (masked to drug name/dose), 69%, 17%, 6%, and 9% of respondents chose low-dose SGLTi, high-dose SGLTi, pramlintide, and insulin therapy alone, respectively. CONCLUSIONS: Low-dose SGLTi profile was the favored adjunct-to-insulin therapy by persons with T1D.

9.
Diabetes Care ; 42(8): 1593-1603, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31177185

RESUMO

Improvements in sensor accuracy, greater convenience and ease of use, and expanding reimbursement have led to growing adoption of continuous glucose monitoring (CGM). However, successful utilization of CGM technology in routine clinical practice remains relatively low. This may be due in part to the lack of clear and agreed-upon glycemic targets that both diabetes teams and people with diabetes can work toward. Although unified recommendations for use of key CGM metrics have been established in three separate peer-reviewed articles, formal adoption by diabetes professional organizations and guidance in the practical application of these metrics in clinical practice have been lacking. In February 2019, the Advanced Technologies & Treatments for Diabetes (ATTD) Congress convened an international panel of physicians, researchers, and individuals with diabetes who are expert in CGM technologies to address this issue. This article summarizes the ATTD consensus recommendations for relevant aspects of CGM data utilization and reporting among the various diabetes populations.

10.
Diabetes Obes Metab ; 21(9): 2039-2047, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31144428

RESUMO

Fast-acting insulin aspart (faster aspart) is a novel formulation of insulin aspart (IAsp) containing the additional excipients niacinamide and L-arginine. The improved pharmacological profile and greater early glucose-lowering action of faster aspart compared with IAsp suggests that faster aspart may be advantageous for people with diabetes using continuous subcutaneous insulin infusion (CSII). The recent onset 5 trial was the first to evaluate the efficacy and safety of an ultra-fast-acting insulin in CSII therapy in a large number of participants with type 1 diabetes (T1D). Non-inferiority of faster aspart to IAsp in terms of change from baseline in HbA1c was confirmed, with an estimated treatment difference (ETD) of 0.09% (95% CI, 0.01; 0.17; P < 0.001 for non-inferiority [0.4% margin]). Faster aspart was superior to IAsp in terms of change from baseline in 1-hour post-prandial glucose (PPG) increment after a meal test (ETD [95% CI], -0.91 mmol/L [-1.43; -0.39]; P = 0.001), with statistically significant improvements also at 30 minutes and 2 hours. The overall rate of severe or blood glucose-confirmed hypoglycaemia was not statistically significantly different between treatments, with an estimated rate ratio of 1.00 (95% CI, 0.85; 1.16). A numerical imbalance in severe hypoglycaemic episodes between faster aspart and IAsp was seen in the treatment (21 vs 7) and the 4-week run-in periods (4 vs 0). Experience from clinical practice indicates that all pump settings should be reviewed when initiating faster aspart with CSII, and that the use of continuous glucose monitoring or flash glucose monitoring, along with a good understanding of meal content and bolus type, may also facilitate optimal use. This review summarizes the available clinical evidence for faster aspart administered via CSII and highlights practical considerations based on clinical experience that may help healthcare providers and individuals with T1D successfully initiate and adjust faster aspart with CSII.

11.
Eur J Endocrinol ; 180(6): 353-363, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31120231

RESUMO

Objective: Since many European countries use risk factor screening for gestational diabetes mellitus (GDM), we aimed to determine the performance of selective screening for GDM based on the 2013 WHO criteria. Design and Methods: Overall, 1811 women received universal screening with a 75 g oral glucose tolerance test (OGTT) with GDM in 12.5% (n = 231) women based on the 2013 WHO criteria. We retrospectively applied different European selective screening guidelines to this cohort and evaluated the performance of different clinical risk factors to screen for GDM. Results: By retrospectively applying the English, Irish, French and Dutch guidelines for selective screening, respectively 28.5% (n = 526), 49.7% (n = 916), 48.5% (n = 894) and 50.7% (n = 935) had at least one risk factor, with GDM prevalence of respectively 6.5% (n = 120), 7.9% (n = 146), 8.0% (n = 147) and 8.4% (n = 154). Using maternal age ≥30 and/or BMI ≥25 for screening, positive rate was 69.9% (n = 1288), GDM prevalence 10.2% (n = 188), sensitivity 81.4% (CI: 75.8­86.2%) and specificity 31.8% (CI: 29.5­34.1%). Adding other clinical risk factors did not improve detection. GDM women without risk factors had more neonatal hypoglycemia (14.4 vs 4.0%, P = 0.001) and labor inductions (39.7 vs 25.9%, P = 0.020) than normal-glucose tolerant women, and less cesarean sections than GDM women with risk factors (13.8 vs 31.0%, P = 0.010). Conclusions: By applying selective screening by European guidelines, about 50% of women would need an OGTT with the lowest number of missed cases (33%) by the Dutch guidelines. Screening with age ≥30 years and/or BMI ≥25, reduced the number of missed cases to 18.6% but 70% would need an OGTT.


Assuntos
Índice de Massa Corporal , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/epidemiologia , Idade Materna , Organização Mundial da Saúde , Adulto , Diabetes Gestacional/sangue , Europa (Continente)/epidemiologia , Feminino , Teste de Tolerância a Glucose/normas , Humanos , Gravidez , Estudos Retrospectivos , Fatores de Risco
12.
Diabetes Care ; 42(6): 1081-1087, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30967434

RESUMO

OBJECTIVE: This pooled analysis assessed continuous glucose monitoring (CGM) in patients with inadequately controlled type 1 diabetes (HbA1c ≥7.7 to ≤11.0% [≥61 to ≤97 mmol/mol]) who received dapagliflozin as an adjunct to adjustable insulin. RESEARCH DESIGN AND METHODS: CGM data were pooled from two 24-week, double-blind, randomized, phase 3 studies: Dapagliflozin Evaluation in Patients with Inadequately Controlled Type 1 Diabetes (DEPICT-1 and DEPICT-2). These studies comprised 1,591 patients receiving dapagliflozin 5 mg (n = 530), dapagliflozin 10 mg (n = 529), or placebo (n = 532). RESULTS: Baseline characteristics were balanced between treatment groups. Patients receiving dapagliflozin 5 mg or 10 mg both spent more time with blood glucose in the range >3.9 to ≤10.0 mmol/L (>70 to ≤180 mg/dL) over 24 h than those receiving the placebo. The adjusted mean (SE) change from baseline at week 24 was 6.48% (0.60) with dapagliflozin 5 mg, 8.08% (0.60) with dapagliflozin 10 mg, and -2.59% (0.61) with placebo. At week 24, the mean amplitude of glucose excursion over 24 h, mean 24-h glucose values, and postprandial glucose values were also improved in patients receiving dapagliflozin over those receiving placebo. No marked differences were found at week 24 between dapagliflozin 5 or 10 mg and placebo in the percentage of glucose values ≤3.9 mmol/L (≤70 mg/dL) or ≤3.0 mmol/L (≤54 mg/dL) over 24 h, or in nocturnal (0000-0559 h) glucose values ≤3.9 mmol/L (≤70 mg/dL). CONCLUSIONS: In patients with type 1 diabetes, treatment with dapagliflozin over 24 weeks improved time in range, mean glucose, and glycemic variability without increasing the time spent in the range indicating hypoglycemia.

13.
Cell Death Dis ; 10(4): 309, 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30952835

RESUMO

The 78-kDa glucose-regulated protein (GRP78) is an ubiquitously expressed endoplasmic reticulum chaperone, with a central role in maintaining protein homeostasis. Recently, an alternative role for GRP78 under stress conditions has been proposed, with stress-induced extracellular secretion and translocation of GRP78 to the cell surface where it acts as a multifunctional signaling receptor. Here we demonstrate translocation of GRP78 to the surface of human EndoC-ßH1 cells and primary human islets upon cytokine exposure, in analogy to observations in rodent INS-1E and MIN6 beta cell lines. We show that GRP78 is shuttled via the anterograde secretory pathway, through the Golgi complex and secretory granules, and identify the DNAJ homolog subfamily C member 3 (DNAJC3) as a GRP78-interacting protein that facilitates its membrane translocation. Evaluation of downstream signaling pathways, using N- and C-terminal anti-GRP78 blocking antibodies, demonstrates that both GRP78 signaling domains initiate pro-apoptotic signaling cascades in beta cells. Extracellular GRP78 itself is identified as a ligand for cell surface GRP78 (sGRP78), increasing caspase 3/7 activity and cell death upon binding, which is accompanied by enhanced Chop and Bax mRNA expression. These results suggest that inflammatory cytokines induce a self-destructive pro-apoptotic feedback loop through the secretion and membrane translocation of GRP78. This proapoptotic function distinguishes the role of sGRP78 in beta cells from its reported anti-apoptotic and proliferative role in cancer cells, opening the road for the use of compounds that block sGRP78 as potential beta cell-preserving therapies in type 1 diabetes.

17.
Diabetes Care ; 42(4): 625-634, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30765434

RESUMO

OBJECTIVE: The kinetics and risk factors of diabetic nephropathy after kidney transplantation remain unclear. This study investigated the posttransplant occurrence of diabetic nephropathy and the contribution of posttransplant glycemic control. RESEARCH DESIGN AND METHODS: We performed a single-center prospective cohort study of 953 renal allograft recipients and 3,458 protocol-specified renal allograft biopsy specimens up to 5 years after transplantation. The effects of pretransplant diabetes and glycemic control (glycated hemoglobin levels) on the posttransplant histology were studied. RESULTS: Before transplantation, diabetes was present in 164 (17.2%) renal allograft recipients, primarily type 2 (n = 146 [89.0%]). Despite intensive glycemic control (glycated hemoglobin 7.00 ± 1.34% [53 ± 14.6 mmol/mol], 6.90 ± 1.22% [52 ± 13.3 mmol/mol], and 7.10 ± 1.13% [54 ± 12.4 mmol/mol], at 1, 2, and 5 years after transplantation), mesangial matrix expansion reached a cumulative incidence of 47.7% by 5 years in the pretransplant diabetes group versus 27.1% in patients without diabetes, corresponding to a hazard ratio of 1.55 (95% CI 1.07-2.26; P = 0.005). Mesangial matrix expansion was not specific for diabetic nephropathy and associated independently with increasing age. Pretransplant diabetes was associated with posttransplant proteinuria but not with estimated glomerular filtration rate, graft failure, or any other structural changes of the glomerular, vascular, or tubulointerstitial renal compartments. The occurrence of diabetic nephropathy was independent of posttransplant glycated hemoglobin levels. CONCLUSIONS: Mesangial matrix expansion, an early indicator of diabetic nephropathy, can occur rapidly in patients with diabetes before transplantation, despite intensive glycemic control. Prevention of diabetic nephropathy requires more than pursuing low levels of glycated hemoglobin.


Assuntos
Nefropatias Diabéticas/etiologia , Transplante de Rim/efeitos adversos , Taxa de Filtração Glomerular , Hemoglobina A Glicada/análise , Humanos , Estudos Prospectivos , Proteinúria/complicações , Fatores de Risco , Transplante Homólogo
18.
Diabetes Care ; 42(6): 1147-1154, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30728224

RESUMO

Sodium-glucose cotransporter (SGLT) inhibitors are new oral antidiabetes medications shown to effectively reduce glycated hemoglobin (A1C) and glycemic variability, blood pressure, and body weight without intrinsic properties to cause hypoglycemia in people with type 1 diabetes. However, recent studies, particularly in individuals with type 1 diabetes, have demonstrated increases in the absolute risk of diabetic ketoacidosis (DKA). Some cases presented with near-normal blood glucose levels or mild hyperglycemia, complicating the recognition/diagnosis of DKA and potentially delaying treatment. Several SGLT inhibitors are currently under review by the U.S. Food and Drug Administration and European regulatory agencies as adjuncts to insulin therapy in people with type 1 diabetes. Strategies must be developed and disseminated to the medical community to mitigate the associated DKA risk. This Consensus Report reviews current data regarding SGLT inhibitor use and provides recommendations to enhance the safety of SGLT inhibitors in people with type 1 diabetes.


Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Cetoacidose Diabética , Inibidores do Transportador 2 de Sódio-Glicose , Consenso , Glucose , Humanos , Hipoglicemiantes , Gestão de Riscos , Sódio
19.
Lancet Diabetes Endocrinol ; 7(3): 162-163, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30679094
20.
J Steroid Biochem Mol Biol ; 188: 103-110, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30605776

RESUMO

Graft-versus-host disease (GVHD) is the most lethal complication after allogeneic bone marrow transplantation (allo-BMT). Current approaches to prevent GVHD rely on donor lymphocyte/T cell depletion or general immunosuppression, leading to opportunistic infections and cancer relapse. Tolerogenic dendritic cells can induce regulatory T cells (Tregs) with the ability to suppress inflammation and prevent transplant rejection, making them an attractive cellular therapy to control GVHD. Active vitamin D (1α,25-dihydroxyvitamin D3; 1α,25(OH)2D3) promotes the generation of tolerogenic dendritic cells (1,25D3-DCs). This study aimed to determine the ability of ex vivo generated 1,25D3-DCs to trigger the expansion of Tregs that are able to control lethal xenogeneic GVHD in humanized NOD/LtSz-PrkdcscidIL2rγtm1Wjl (NSG) mice. We demonstrate that 1,25D3-DCs express lower levels of HLA-DR and costimulatory molecules, such as CD80 and CD86, and produce higher levels of IL-10 and TNF-α and lower amounts of IL-12, compared to vehicle-treated DCs. Moreover, these cells express increased levels of various co-inhibitory molecules such as PD-L1 and ILT-3 and the glycoprotein CD52 that is known to suppress T cell activation. Consequently, 1,25D3-DCs are poor stimulators of alloantigen-primed T cells, but foster the generation of antigen-specific suppressive Tregs. When adoptively transferred in humanized NSG mice, these 1,25D3-DC-induced Tregs delayed GVHD caused by the co-transferred autologous human peripheral blood mononuclear cells (PBMCs). These results indicate that 1,25D3-DC-induced Tregs can inhibit xenogeneic GVHD and maintain their immunomodulatory function under conditions of inflammation.


Assuntos
Calcitriol/farmacologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/transplante , Doença Enxerto-Hospedeiro/terapia , Linfócitos T Reguladores/imunologia , Vitaminas/farmacologia , Animais , Células Cultivadas , Células Dendríticas/imunologia , Doença Enxerto-Hospedeiro/imunologia , Humanos , Camundongos Endogâmicos NOD
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA