Abstract:
:Optimal immune-based therapies for type 1 diabetes (T1D) should restore self-tolerance without inducing chronic immunosuppression. CD4+Foxp3+ regulatory T cells (Tregs) are a key cell population capable of facilitating durable immune tolerance. However, clinical trials with expanded Tregs in T1D and solid-organ transplant recipients are limited by poor Treg engraftment without host manipulation. We showed that Treg engraftment and therapeutic benefit in nonautoimmune models required ablative host conditioning. Here, we evaluated Treg engraftment and therapeutic efficacy in the nonobese diabetic (NOD) mouse model of autoimmune diabetes using nonablative, combinatorial regimens involving the anti-CD3 (αCD3), cyclophosphamide (CyP), and IAC (IL-2/JES6-1) antibody complex. We demonstrate that αCD3 alone induced substantial T-cell depletion, impacting both conventional T cells (Tconv) and Tregs, subsequently followed by more rapid rebound of Tregs Despite robust depletion of host Tconv and host Tregs, donor Tregs failed to engraft even with interleukin-2 (IL-2) support. A single dose of CyP after αCD3 depleted rebounding host Tregs and resulted in a 43-fold increase in donor Treg engraftment, yet polyclonal donor Tregs failed to reverse diabetes. However, infusion of autoantigen-specific Tregs after αCD3 alone resulted in robust Treg engraftment within the islets and induced remission in all mice. This novel combinatorial therapy promotes engraftment of autoantigen-specific donor Tregs and controls islet autoimmunity without long-term immunosuppression.
journal_name
Diabetesjournal_title
Diabetesauthors
Cabello-Kindelan C,Mackey S,Sands A,Rodriguez J,Vazquez C,Pugliese A,Bayer ALdoi
10.2337/db19-0061subject
Has Abstractpub_date
2020-02-01 00:00:00pages
215-227issue
2eissn
0012-1797issn
1939-327Xpii
db19-0061journal_volume
69pub_type
杂志文章相关文献
DIABETES文献大全abstract::Previous studies have demonstrated that the ventromedial hypothalamus (VMH) plays a critical role in sensing and responding to systemic hypoglycemia. To evaluate the mechanisms of defective counterregulation caused by iatrogenic hypoglycemia and diabetes per se, we delivered 2-deoxy-glucose (2-DG) via microdialysis in...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.48.3.584
更新日期:1999-03-01 00:00:00
abstract::Insulin receptors from rat hepatoma cells (Fao) and human placenta were partially purified by detergent solubilization and lectin purification. The insulin receptor preparations were subjected to sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis under reducing or nonreducing conditions. The proteins were...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.33.10.923
更新日期:1984-10-01 00:00:00
abstract::In this study we examined the effect of experimental diabetes and of treatment with an aldose reductase inhibitor on the level of sulfation of glomerular basement membrane (GBM) heparan sulfate, the principal glycosaminoglycan in this extracellular matrix. Glycosaminoglycans were isolated from GBM purified from contro...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.37.10.1324
更新日期:1988-10-01 00:00:00
abstract::Pancreatogenic diabetes (PD), secondary either to chronic calcific pancreatitis or to pancreatectomy, is characterized by higher frequency of hypoglycemic events during insulin therapy in comparison with type I insulin-dependent diabetes (IDD). Not only glucagon deficiency, but an enhanced peripheral tissue sensitivit...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.31.4.346
更新日期:1982-04-01 00:00:00
abstract::Eight dogs with previously established kidney allografts, immunosuppressed with cyclosporin A, received islet allografts from their respective original kidney donors. The median islet-graft functional survival was only 10.5 days, significantly less than for six similarly immunosuppressed dogs receiving only islet allo...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.38.1.s179
更新日期:1989-01-01 00:00:00
abstract::It is suggested that the maternal transmission of islet autoantibodies increases the risk of autoimmune diabetes in mice. The aim of this study was to determine whether fetal exposure to islet autoantibodies modified the risk of type 1 diabetes in humans. Islet autoantibodies were measured at birth in 720 offspring of...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.53.1.1
更新日期:2004-01-01 00:00:00
abstract::This article seeks to determine whether factors related to autoimmunity risk remain significant after the initiation of two or more diabetes-related autoantibodies and continue to contribute to type 1 diabetes (T1D) risk among autoantibody-positive children in The Environmental Determinants of Diabetes in the Young (T...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db17-0261
更新日期:2017-12-01 00:00:00
abstract::Hypoxia-inducible factor (HIF)-1 mediates hypoxia- and chronic kidney disease-induced fibrotic events. Here, we assessed whether HIF-1 blockade attenuates the manifestations of diabetic nephropathy in a type 1 diabetic animal model, OVE26. YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole], an HIF-1 inhibitor, red...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db15-0519
更新日期:2016-05-01 00:00:00
abstract::Development of beta-cell lines for cell therapy of diabetes is hindered by functional deviations of the replicating cells from the normal beta-cell phenotype. In a recently developed cell line, denoted betaTC-tet, derived from transgenic mice expressing the SV40 T antigen (Tag) under control of the tetracycline (Tc) g...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.47.9.1419
更新日期:1998-09-01 00:00:00
abstract::Chronic high-fat feeding in rats induces profound whole-body insulin resistance, mainly due to effects in oxidative skeletal muscle. The mechanisms of this reaction remain unclear, but local lipid availability has been implicated. The aim of this study was to examine the influence of three short-term physiological man...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.46.12.2022
更新日期:1997-12-01 00:00:00
abstract::Alterations in dopaminergic circuitry play a critical role in food reward and may contribute to susceptibility to obesity. Ingestion of sweets releases dopamine in striatum, and both sweet preferences and striatal D2 receptors (D2R) decline with age and may be altered in obesity. Understanding the relationships betwee...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db16-0407
更新日期:2016-09-01 00:00:00
abstract::Pancreatic beta-cell survival is critical in the setting of diabetes as well as in islet transplantation. Transgenic mice overexpressing parathyroid hormone-related protein (PTHrP) targeted to beta-cells using the rat insulin II promoter (RIP) display hyperinsulinemia, hypoglycemia, and islet hyperplasia, without a co...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.51.10.3003
更新日期:2002-10-01 00:00:00
abstract:OBJECTIVE:Genome-wide association studies have identified several variants within the MTNR1B locus that are associated with fasting plasma glucose (FPG) and type 2 diabetes. We refined the association signal by direct genotyping and examined for associations of the variant displaying the most independent effect on FPG ...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db08-1660
更新日期:2009-06-01 00:00:00
abstract::Mutations in the LMNA gene (encoding lamin A/C) underlie familial partial lipodystrophy, a syndrome of monogenic insulin resistance and diabetes. LMNA maps to the well-replicated diabetes-linkage region on chromosome 1q, and there are reported associations between LMNA single nucleotide polymorphisms (SNPs) (particula...
journal_title:Diabetes
pub_type: 杂志文章,meta分析
doi:10.2337/db06-0930
更新日期:2007-03-01 00:00:00
abstract::Fibroblast growth factor 1 (FGF1) has been shown to reverse hyperglycemia in diabetic rodent models through peripheral and central administration routes. Previous studies demonstrated that insulin is required for central and peripheral FGF1 metabolic improvements; however, it is unknown if FGF1 targets insulin secreti...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db18-1175
更新日期:2019-07-01 00:00:00
abstract::Insulin-dependent diabetes mellitus (IDDM) is characterized by a metabolic and hormonal disarray that may be more evident during exercise. However, the metabolic response to exercise of different intensities has not been evaluated in IDDM. We therefore used stable isotope techniques and indirect calorimetry to quantif...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.44.9.1066
更新日期:1995-09-01 00:00:00
abstract::On the basis of the positive outcome of animal experiments, several large placebo-controlled trials are underway and aiming for the first time at the prevention of an immune-mediated disease, type 1 diabetes. The first of these trials, The Deutsche Nicotinamide Intervention Study (DENIS), evaluated the clinical effica...
journal_title:Diabetes
pub_type: 临床试验,杂志文章,多中心研究,随机对照试验
doi:10.2337/diabetes.47.6.980
更新日期:1998-06-01 00:00:00
abstract::Exogenous ghrelin reduces glucose-stimulated insulin secretion and endogenous ghrelin protects against hypoglycemia during starvation. Islet ε-cells produce ghrelin and δ-cells express growth hormone secretagogue receptor (GHSR), suggesting the possibility of a paracrine mechanism for islet ghrelin to reach high local...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db19-0079
更新日期:2019-09-01 00:00:00
abstract::Adiponectin, an adipocyte protein important in insulin sensitization and cardioprotection, has a strong genetic component. We hypothesized that variants in the adiponectin gene (adipocyte collagen-domain containing [ACDC]) contribute to adiponectin levels in a biracial adolescent cohort. We genotyped 11 ACDC single nu...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.55.02.06.db05-0446
更新日期:2006-02-01 00:00:00
abstract::Abnormalities in the incorporation of heparan sulfate proteoglycan into the glomerular basement membrane have been implicated in the pathogenesis of various proteinuric states, including diabetes mellitus. To understand further the interactions between proteoglycans and glomerular extracellular matrices, glomeruli wer...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.38.1.130
更新日期:1989-01-01 00:00:00
abstract::The hexokinases, by converting glucose to glucose-6-phosphate, help maintain the downhill gradient that results in movement of glucose into cells through the facilitative glucose transporters. GLUT4 and hexokinase (HK) II are the major transporter and hexokinase isoforms in skeletal muscle, heart, and adipose tissue, ...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.44.12.1426
更新日期:1995-12-01 00:00:00
abstract::We used hepatic balance and tracer ([3H]glucose) techniques to examine the impact of "breakfast" on hepatic glucose metabolism later in the same day. From 0-240 min, 2 groups of conscious dogs (n = 9 dogs/group) received a duodenal infusion of glucose (GLC) or saline (SAL), then were fasted from 240-360 min. Three dog...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db16-1308
更新日期:2017-05-01 00:00:00
abstract::Type 2 diabetes in humans is not a single gene disorder but a multifactorial disease caused by the interaction of multiple genes and environmental factors. Recombinant inbred (RI) strains are a powerful tool for analyzing not only single genetic traits but also multifactorial genetic traits. By using the SMXA RI mice,...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.52.1.180
更新日期:2003-01-01 00:00:00
abstract::Antibodies to islet cell proteins detected as 37,000 and 40,000 M(r), tryptic fragments (37- and 40-kDa antigens) are strongly associated with progression to IDDM. The 40-kDa antigen has recently been identified as the tyrosine phosphatase-like protein IA-2 (ICA512) whereas the 37-kDa antigen has been suggested to be ...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.45.9.1187
更新日期:1996-09-01 00:00:00
abstract::In an ongoing investigation of the effects of age on G protein-coupled receptor signaling in human atrial tissue, we have found that the density of atrial muscarinic acetylcholine receptor (mAChR) increases with age but reaches statistical significance only in patients with diabetes. Moreover, we find that in elderly ...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.53.9.2392
更新日期:2004-09-01 00:00:00
abstract:OBJECTIVE:Phosphoinositide 3-kinase enhancer A (PIKE-A) is a proto-oncogene that promotes tumor growth and transformation by enhancing Akt activity. However, the physiological functions of PIKE-A in peripheral tissues are unknown. Here, we describe the effect of PIKE deletion in mice and explore the role of PIKE-A in o...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db09-1404
更新日期:2010-04-01 00:00:00
abstract::Dietary methionine restriction (MR) produces a rapid and persistent remodeling of white adipose tissue (WAT), an increase in energy expenditure (EE), and enhancement of insulin sensitivity. Recent work established that hepatic expression of FGF21 is robustly increased by MR. Fgf21-/- mice were used to test whether FGF...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/db16-1212
更新日期:2017-04-01 00:00:00
abstract::Little information is available on cholesterol absorption and synthesis in human type 1 diabetes. We studied these variables using serum cholesterol precursor sterol ratios to cholesterol as surrogate markers of cholesterol synthesis and those of cholestanol and plant sterols to reflect cholesterol absorption in seven...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diabetes.53.9.2217
更新日期:2004-09-01 00:00:00
abstract::Near normal glucoregulation was maintained in 10 patients with insulin-dependent (type I) diabetes mellitus for 6 wk with preprogrammed continuous subcutaneous insulin infusion using a portable battery-powered infusion pump (CSII). This form of therapy resulted in a statistically significant increase in motor nerve co...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.29.8.668
更新日期:1980-08-01 00:00:00
abstract::Ambulatory blood pressure (AMBP) measurements were obtained at 20-min intervals for 24 h in 25 subjects with insulin-dependent (type I) diabetes mellitus and 21 control subjects. The diabetic patients had normal kidney function (glomerular filtration rate 112.1 +/- 7.2 ml.min-1.1.73 m-2, renal plasma flow 459.0 +/- 23...
journal_title:Diabetes
pub_type: 杂志文章
doi:10.2337/diab.39.12.1556
更新日期:1990-12-01 00:00:00