scholarly journals T Cell Expression and Release of Kidney Injury Molecule-1 in Response to Glucose Variations Initiates Kidney Injury in Early Diabetes

2021 ◽  
Author(s):  
Josephine M. Forbes ◽  
Domenica A. McCarthy ◽  
Andrew J. Kassianos ◽  
Tracey Baskerville ◽  
Amelia J. Fotheringham ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
High Risk ◽  
Kidney Disease ◽  
Kidney Injury ◽  
Glycemic Variability ◽  
Low Risk ◽  
Kidney Injury Molecule 1

Half of the mortality in diabetes is seen in individuals <50 years of age and commonly predicted by the early onset of kidney disease (DKD). In Type 1 diabetes, increased uACR (urinary albumin-creatinine ratio) during adolescence defines this risk, but the pathological factors responsible remain unknown. We postulated that early in diabetes, glucose variations contribute to kidney injury molecule- 1 (KIM-1) release from circulating T cells, elevating uACR and DKD risk. <p>DKD risk was assigned in youth with type 1 diabetes [n=100; 20.0±2.8 yrs; M:F-54:46, HbA<sub>1C</sub>-66.1(12.3) mmol/mol; diabetes duration-10.7±5.2 yrs; BMI-24.5(5.3) kg.m<sup>-2</sup>] and 10 year historical uACR, HbA<sub>1C</sub> and random blood glucose concentrations collected retrospectively. Glucose fluctuations in the absence of diabetes were also compared to streptozotocin diabetes in <i>Apolipoprotein E-/-</i> mice. Kidney biopsies were used to examine infiltration of KIM-1 expressing T cells in DKD and compared with other chronic kidney disease.</p> <p>Individuals at high risk for DKD had persistent elevations in uACR (uACR<sub>AUC0-10yrs</sub>, 29.7±8.8 vs 4.5±0.5; <i>P</i><0.01 vs low risk) and early kidney dysfunction including ~8.3ml.min<sup>-1</sup>.1.73m<sup>-2</sup> higher estimated glomerular filtration rates (eGFR<sub>SCHWARTZ</sub>; <i>P<sub>adj</sub></i> <0.031 vs low risk) and plasma KIM-1 concentrations (~15% higher vs low risk;<i> P</i><0.034). High risk individuals had greater glycemic variability and increased peripheral blood T cell KIM-1 expression, particularly on CD8+ T cells. These findings were confirmed in a murine model of glycemic variability both in the presence and absence of diabetes. KIM-1+ T cells were also infiltrating kidney biopsies from individuals with DKD. Healthy primary human proximal tubule epithelial cells exposed to plasma from high risk youth with diabetes showed elevated collagen IV and SGLT2 expression, alleviated with KIM-1 blockade. Taken together, these studies suggest that glycemic variations confer risk for DKD in diabetes via increased CD8+ T cell production of KIM-1.<b><br> </b></p>

scholarly journals T Cell Expression and Release of Kidney Injury Molecule-1 in Response to Glucose Variations Initiates Kidney Injury in Early Diabetes

2021 ◽  
Author(s):  
Josephine M. Forbes ◽  
Domenica A. McCarthy ◽  
Andrew J. Kassianos ◽  
Tracey Baskerville ◽  
Amelia J. Fotheringham ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
High Risk ◽  
Kidney Disease ◽  
Kidney Injury ◽  
Glycemic Variability ◽  
Low Risk ◽  
Kidney Injury Molecule 1

Half of the mortality in diabetes is seen in individuals <50 years of age and commonly predicted by the early onset of kidney disease (DKD). In Type 1 diabetes, increased uACR (urinary albumin-creatinine ratio) during adolescence defines this risk, but the pathological factors responsible remain unknown. We postulated that early in diabetes, glucose variations contribute to kidney injury molecule- 1 (KIM-1) release from circulating T cells, elevating uACR and DKD risk. <p>DKD risk was assigned in youth with type 1 diabetes [n=100; 20.0±2.8 yrs; M:F-54:46, HbA<sub>1C</sub>-66.1(12.3) mmol/mol; diabetes duration-10.7±5.2 yrs; BMI-24.5(5.3) kg.m<sup>-2</sup>] and 10 year historical uACR, HbA<sub>1C</sub> and random blood glucose concentrations collected retrospectively. Glucose fluctuations in the absence of diabetes were also compared to streptozotocin diabetes in <i>Apolipoprotein E-/-</i> mice. Kidney biopsies were used to examine infiltration of KIM-1 expressing T cells in DKD and compared with other chronic kidney disease.</p> <p>Individuals at high risk for DKD had persistent elevations in uACR (uACR<sub>AUC0-10yrs</sub>, 29.7±8.8 vs 4.5±0.5; <i>P</i><0.01 vs low risk) and early kidney dysfunction including ~8.3ml.min<sup>-1</sup>.1.73m<sup>-2</sup> higher estimated glomerular filtration rates (eGFR<sub>SCHWARTZ</sub>; <i>P<sub>adj</sub></i> <0.031 vs low risk) and plasma KIM-1 concentrations (~15% higher vs low risk;<i> P</i><0.034). High risk individuals had greater glycemic variability and increased peripheral blood T cell KIM-1 expression, particularly on CD8+ T cells. These findings were confirmed in a murine model of glycemic variability both in the presence and absence of diabetes. KIM-1+ T cells were also infiltrating kidney biopsies from individuals with DKD. Healthy primary human proximal tubule epithelial cells exposed to plasma from high risk youth with diabetes showed elevated collagen IV and SGLT2 expression, alleviated with KIM-1 blockade. Taken together, these studies suggest that glycemic variations confer risk for DKD in diabetes via increased CD8+ T cell production of KIM-1.<b><br> </b></p>

scholarly journals Exocrine pancreas function is impaired in adult relatives of patients with type 1 diabetes

2021 ◽  
Author(s):  
Anna Giovenzana ◽  
Federica Vecchio ◽  
Federica Cugnata ◽  
Alessandro Nonis ◽  
Alessandra Mandelli ◽  
...  
Keyword(s):  
At Risk ◽  
Type 1 Diabetes ◽  
High Risk ◽  
Exocrine Pancreas ◽  
Pancreatic Enzyme ◽  
Low Risk ◽  
C Peptide ◽  
Hla Genotypes ◽  
Pancreas Function

Abstract Aims Alterations of the exocrine pancreas have been reported in type 1 diabetes, but their contribution to the pathogenesis of the disease is poorly understood. Here, we investigated markers of exocrine pancreas dysfunction in individuals at-risk of developing type 1 diabetes. Methods Serum P-amylase and lipase levels were assessed in samples obtained from healthy controls, patients with new onset type 1 diabetes, relatives participating to the TrialNet Pathway to Prevention who were, at blood collection, autoantibody negative or positive for a single autoantibody (low-risk individuals), and positive for multiple autoantibodies (high-risk individuals). Linear mixed models were adopted to estimate variation of pancreatic enzymes among the groups and to evaluate the influence of high-risk HLA genotypes and residual beta cell function on exocrine pancreas function. Results In adults, but not children, reduced levels of P-amylase and lipase were shown in at-risk individuals, including (for P-amylase levels only) those at low-risk, and in T1Dnew. Furthermore, while high-risk HLA genotypes negatively affected P-amylase levels in autoantibody negative adult individuals, fasting C-peptide levels did not correlate with pancreatic enzyme levels. Conclusions Exocrine pancreas dysfunction precedes the onset of type 1 diabetes in adult at-risk individuals and may be unrelated to fasting C-peptide levels.

scholarly journals Proinsulin-Reactive CD4 T Cells in the Islets of Type 1 Diabetes Organ Donors

2021 ◽  
Vol 12 ◽  
Author(s):  
Laurie G. Landry ◽  
Amanda M. Anderson ◽  
Holger A. Russ ◽  
Liping Yu ◽  
Sally C. Kent ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Cd4 T Cells ◽  
Pancreatic Beta Cells ◽  
Hot Spot ◽  
Cell Receptor ◽  
Organ Donors ◽  
Hla Dq

Proinsulin is an abundant protein that is selectively expressed by pancreatic beta cells and has been a focus for development of antigen-specific immunotherapies for type 1 diabetes (T1D). In this study, we sought to comprehensively evaluate reactivity to preproinsulin by CD4 T cells originally isolated from pancreatic islets of organ donors having T1D. We analyzed 187 T cell receptor (TCR) clonotypes expressed by CD4 T cells obtained from six T1D donors and determined their response to 99 truncated preproinsulin peptide pools, in the presence of autologous B cells. We identified 14 TCR clonotypes from four out of the six donors that responded to preproinsulin peptides. Epitopes were found across all of proinsulin (insulin B-chain, C-peptide, and A-chain) including four hot spot regions containing peptides commonly targeted by TCR clonotypes derived from multiple T1D donors. Of importance, these hot spots overlap with peptide regions to which CD4 T cell responses have previously been detected in the peripheral blood of T1D patients. The 14 TCR clonotypes recognized proinsulin peptides presented by various HLA class II molecules, but there was a trend for dominant restriction with HLA-DQ, especially T1D risk alleles DQ8, DQ2, and DQ8-trans. The characteristics of the tri-molecular complex including proinsulin peptide, HLA-DQ molecule, and TCR derived from CD4 T cells in islets, provides an essential basis for developing antigen-specific biomarkers as well as immunotherapies.

scholarly journals Increased islet antigen–specific regulatory and effector CD4+ T cells in healthy individuals with the type 1 diabetes–protective haplotype

2020 ◽  
Vol 5 (44) ◽  
pp. eaax8767 ◽  
Author(s):  
Xiaomin Wen ◽  
Junbao Yang ◽  
Eddie James ◽  
I-Ting Chow ◽  
Helena Reijonen ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Regulatory T Cells ◽  
Interleukin 4 ◽  
Specific Class ◽  
Protective Haplotype ◽  
Specific Effector ◽  
Islet Antigen

The DRB1*15:01-DQB1*06:02 (DR1501-DQ6) haplotype is linked to dominant protection from type 1 diabetes, but the cellular mechanism for this association is unclear. To address this question, we identified multiple DR1501- and DQ6-restricted glutamate decarboxylase 65 (GAD65) and islet-specific glucose-6-phosphatase catalytic subunit–related protein (IGRP)–specific T cell epitopes. Three of the DR1501/DQ6-restricted epitopes identified were previously reported to be restricted by DRB1*04:01/DRB1*03:01/DQB1*03:02. We also used specific class II tetramer reagents to assess T cell frequencies. Our results indicated that GAD65- and IGRP-specific effector and CD25+CD127−FOXP3+ regulatory CD4+ T cells were present at higher frequencies in individuals with the protective haplotype than those with susceptible or neutral haplotypes. We further confirmed higher frequencies of islet antigen–specific effector and regulatory CD4+ T cells in DR1501-DQ6 individuals through a CD154/CD137 up-regulation assay. DR1501-restricted effector T cells were capable of producing interferon-γ (IFN-γ) and interleukin-4 (IL-4) but were more likely to produce IL-10 compared with effectors from individuals with susceptible haplotypes. To evaluate their capacity for antigen-specific regulatory activity, we cloned GAD65 and IGRP epitope–specific regulatory T cells. We showed that these regulatory T cells suppressed DR1501-restricted GAD65- and IGRP-specific effectors and DQB1*03:02-restricted GAD65-specific effectors in an antigen-specific fashion. In total, these results suggest that the protective DR1501-DQ6 haplotype confers protection through increased frequencies of islet-specific IL-10–producing T effectors and CD25+CD127−FOXP3+ regulatory T cells.

Flt3 inhibition alleviates chronic kidney disease by suppressing CD103+ dendritic cell-mediated T cell activation

2018 ◽  
Vol 34 (11) ◽  
pp. 1853-1863 ◽  
Author(s):  
Ruifeng Wang ◽  
Titi Chen ◽  
Chengshi Wang ◽  
Zhiqiang Zhang ◽  
Xin Maggie Wang ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
T Cells ◽  
T Cell ◽  
Kidney Disease ◽  
T Cell Activation ◽  
Cell Activation ◽  
Kidney Injury ◽  
Public Health Problem ◽  
Global Public Health ◽  
Flt3 Inhibitor

Abstract Background Chronic kidney disease (CKD) is a global public health problem, which lacks effective treatment. Previously, we have shown that CD103+ dendritic cells (DCs) are pathogenic in adriamycin nephropathy (AN), a model of human focal segmental glomerulosclerosis (FSGS). Fms-like tyrosine kinase 3 (Flt3) is a receptor that is expressed with high specificity on tissue resident CD103+ DCs. Methods To test the effect on CD103+ DCs and kidney injury of inhibition of Flt3, we used a selective Flt3 inhibitor (AC220) to treat mice with AN. Results Human CD141+ DCs, homologous to murine CD103+ DCs, were significantly increased in patients with FSGS. The number of kidney CD103+ DCs, but not CD103− DCs or plasmacytoid DCs, was significantly decreased in AN mice after AC220 administration. Treatment with AC220 significantly improved kidney function and reduced kidney injury and fibrosis in AN mice. AC220-treated AN mice had decreased levels of inflammatory cytokines and chemokines, tumor necrosis factor-α, interleukin (IL)-1β, IL-6, CCL2 and CCL5 and reduced kidney infiltration of CD4 T cells and CD8 T cells. The protective effect of AC220 was associated with its suppression of CD103+ DCs-mediated CD8 T cell proliferation and activation in AN mice. Conclusion Flt3 inhibitor AC220 effectively reduced kidney injury in AN mice, suggesting that this inhibitor might be a useful pharmaceutical agent to treat CKD.

T Cell Reconstitution in First 200 Days Post Transplantation Predicts Long Term Survival in Allogeneic Hematopoetic Progenitor Cell Transplantation (HPCT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3224-3224 ◽  
Author(s):  
Laura Vann ◽  
Milcah Larks ◽  
Christopher Flowers ◽  
Sagar Lonial ◽  
Jonathan Kaufman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
High Risk ◽  
Immune Cells ◽  
Conditioning Regimen ◽  
Low Risk ◽  
Myeloablative Conditioning ◽  
Post Transplant ◽  
Risk Patients ◽  
Study Population

Abstract Background: Successful reconstitution of cellular immunity following allogeneic HPCT reduces the risk of relapse and confers protection against opportunistic infections. We performed an IRB-approved retrospective analysis of patients who underwent allogeneic HPCT and in whom the content of immune cells were measured in the graft and in post-transplant blood samples. Methods: The study population consisted of 122 patients with hematologic disorders (71 acute leukemia; 14 chronic leukemia; 18 lymphoma, 12 MDS; 3 aplastic anemia; and 4 other) who underwent HPCT with a non-T cell depleted graft from an HLA matched related (73) or unrelated (49) donor. 47 patients had low risk disease (AA, ALL CR1, AML CR1, CML CP1), while 75 had high risk disease (all others). The conditioning regimen was non-myeloablative in 38 (31%), included ATG in 18 (15%), and included TBI in 54 (44%). Peripheral blood was drawn at a median of 101 days post-HPCT and analyzed for T-cell subsets, B-cells, NK cells, and dendritic cells. Subjects were divided into three strata based upon the maximal value for the content of each cell subset in the blood. Univariate and multi-variable stepwise logistic regression analyses were performed to test the association of pre-transplant clinical factors, the cells in the graft, and the numbers of immune cells in the blood post-transplant with overall survival. Results: The estimated three-year survival for all subjects was 53%, with death in 49/122 patients (40%) due to progressive disease (37%), infection (29%), GVHD (20%), and other causes (14%). Univariate factors associated with death included high risk, age, the use of reduced intensity conditioning regimen, the use of TBI, the use of ATG during conditioning and the measurement of lower numbers of total T-cells, CD4+ T-cells, CD8+ T-cells, γδ T-cells, DC1 and DC2 in the peripheral blood during the first 200 days post-transplant. A multi-variable Cox model identified non-myeloablative conditioning (HR 2.2, 95% CI 1.2–3.9), TBI (HR 1.9, 95% CI 1.1–3.3), transplant risk strata (HR 1.9, 95% CI 1.0–3.6), and a blood CD3+ T-cell count of less than 600 cells/mcL (HR 1.8, 95% CI 1.2–2.5) as independent risk factors for post-transplant death. The presence of acute GVHD (all grades) or graft constituents was not significantly associated with survival. Limiting the study population to those subjects who survived at least 100 days showed that blood CD3+ T-cells, non-myeloablative conditioning, the use of TBI remained significantly associated with survival. Conclusions: Higher CD3+ counts in the early post-transplant period predict better survival. Patients who fail to achieve a blood CD3+ T-cell count of >600/mcL in the first 200 days post-transplant may be appropriate subjects for adoptive cellular immunotherapy. Low Risk Patients Low Risk Patients High Risk Patients High Risk Patients

scholarly journals Analyses of regulatory CD 4 + CD 25 + FOXP 3 + T cells and observations from peripheral T cell subpopulation markers during the development of type 1 diabetes in children

2016 ◽  
Vol 83 (4) ◽  
pp. 279-287 ◽  
Author(s):  
S. Hamari ◽  
T. Kirveskoski ◽  
V. Glumoff ◽  
P. Kulmala ◽  
O. Simell ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Cell Subpopulation

scholarly journals Targeting transcriptional coregulator OCA-B/Pou2af1 blocks activated autoreactive T cells in the pancreas and type-1 diabetes

2020 ◽  
Author(s):  
Heejoo Kim ◽  
Jelena Perovanovic ◽  
Arvind Shakya ◽  
Zuolian Shen ◽  
Cody N. German ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Target Genes ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Cell Receptor ◽  
Glucose Levels ◽  
Transcriptional Coregulator

AbstractThe transcriptional coregulator OCA-B promotes expression of T cell target genes in cases of repeated antigen exposure, a necessary feature of autoimmunity. We hypothesized that T cell-specific OCA-B deletion and pharmacologic OCA-B inhibition would protect mice from autoimmune diabetes. We developed an Ocab conditional allele and backcrossed it onto a diabetes-prone NOD/ShiLtJ strain background. T cell-specific OCA-B loss protected mice from spontaneous disease. Protection was associated with large reductions in islet CD8+ T cell receptor specificities associated with diabetes pathogenesis. CD4+ clones associated with diabetes were present, but associated with anergic phenotypes. The protective effect of OCA-B loss was recapitulated using autoantigen-specific NY8.3 mice, but diminished in monoclonal models specific to artificial or neoantigens. Rationally-designed membrane-penetrating OCA-B peptide inhibitors normalized glucose levels, and reduced T cell infiltration and proinflammatory cytokine expression in newly-diabetic NOD mice. Together, the results indicate that OCA-B is a potent autoimmune regulator and a promising target for pharmacologic inhibition.~40-word summary statement for the online JEM table of contents and alertsKim and colleagues show that OCA-B in T cells is essential for the generation of type-1 diabetes. OCA-B loss leaves the pancreatic lymph nodes largely undisturbed, but associates autoreactive CD4+ T cells in the pancreas with anergy while deleting potentially autoreactive CD8+ T cells.SummaryKim et al. show that loss or inhibition of OCA-B in T cells protects mice from type-1 diabetes.

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