IL-12 and IL-18 synergize to promote TH1 responses and have been implicated as accelerators of au... more IL-12 and IL-18 synergize to promote TH1 responses and have been implicated as accelerators of autoimmune pathogenesis in type 1 diabetes (T1D). We investigated the influence of these cytokines on immune cells involved in human T1D progression: natural killer (NK) cells, regulatory T cells (Tregs), and cytotoxic T lymphocytes (CTL). NK cells from T1D patients exhibited higher surface CD226 versus controls and lower CD25 compared to first-degree relatives and controls. Changes in NK cell phenotype towards terminal differentiation were associated with cytomegalovirus (CMV) seropositivity, while possession of IL18RAP, IFIH1, and IL2RA T1D-risk variants impacted NK cell activation as evaluated by immuno-expression quantitative trait loci (eQTL) analyses. IL-12 and IL-18 stimulated NK cells from healthy donors exhibited enhanced specific killing of myelogenous K562 target cells. Moreover, activated NK cell increased expression of NKG2A, NKG2D, CD226, TIGIT and CD25, which enabled competition for IL-2 upon co-culture with Tregs, resulting in Treg downregulation of FOXP3, production of IFNγ, and loss of suppressive function. We generated islet-autoreactive CTL “avatars”, which upon exposure to IL-12 and IL-18, upregulated IFNγ and Granzyme-B leading to increased lymphocytotoxicity of a human β-cell line in vitro. These results support a model for T1D pathogenesis wherein IL-12 and IL-18 synergistically enhance CTL and NK cell cytotoxic activity and disrupt immunoregulation by Tregs.Working Model Summarizing the Hypothesized Contributions of Elevated IL-12 and IL-18 Levels Toward Failure in Immunoregulation and T1D Pathogenesis. In immune homeostasis (left), regulatory T cells (Treg) suppress activation and function of CD8+T cells, CD4+T cells and NK cells via various mechanisms including competition for IL-2. In settings of increased genetic risk for T1D, exposure to some environmental trigger(s) compound genetic defects to induce a break in tolerance (right), during which time IL-12 and IL-18 levels are elevated and NK cells upregulate CD25. This allows for direct competition with Tregs for IL-2, resulting in decreased Treg IL-2 signaling, STAT5 phosphorylation (pSTAT5), and FOXP3 expression, ultimately abrogating suppression. We hypothesize that this, together with enhanced production of cytokines and cytolytic proteins by CD4+conventional T cells and CD8+cytotoxic T cells, leads to augmented lysis of β-cells (right).
Interest in adoptive T-cell therapies has been ignited by the recent clinical success of genetica... more Interest in adoptive T-cell therapies has been ignited by the recent clinical success of genetically-modified T cells in the cancer immunotherapy space. In addition to immune targeting for malignancies, this approach is now being explored for the establishment of immune tolerance with regulatory T cells (Tregs). Herein, we will summarize the basic science and clinical results emanating from trials directed at inducing durable immune regulation through administration of Tregs. We will discuss some of the current challenges facing the field in terms of maximizing cell purity, stability and expansion capacity, while also achieving feasibility and GMP production. Indeed, recent advances in methodologies for Treg isolation, expansion, and optimal source materials represent important strides toward these considerations. Finally, we will review the emerging genetic and biomaterial-based approaches on the horizon for directing Treg specificity to augment tissue-targeting and regenerative medicine.
Autoantibodies (AAb) against beta cell antigens are useful biomarkers for type 1 diabetes (T1D) p... more Autoantibodies (AAb) against beta cell antigens are useful biomarkers for type 1 diabetes (T1D) prediction; however, staging of pre-T1D requires lengthy and invasive glucose tolerance testing. A need exists for additional serum biomarkers reflective of metabolic and immunologic dysregulation to test concurrently with AAb. The insulin-like growth factor (IGF) family, consisting of IGF1 and IGF2, has been shown to promote insulin action and possess immunoregulatory properties. Their activity is regulated by at least seven IGF binding proteins (IGFBPs). We hypothesized that IGF1 and IGF2 levels or bioavailability are reduced during T1D development. Total serum IGF1, IGF2, and IGFBP1-7 levels were measured in an age-matched (12.0 ± 3.7 years), cross-sectional cohort of AAb negative (AAb-) controls (CTRL) (n=74); AAb- first-degree relatives (AAb- FDR, n=55); FDR positive (AAb+ FDR) for one (n=23) or multiple (n=26) of GAD65, IA-2, or ZnT8 AAbs; new onset (NO) T1D patients (n=63, duration 1.0 ± 0.7 months); and established T1D patients (n=68, duration 4.4 ± 3.7 years). IGF1 and IGF2 levels were significantly lower in AAb+ FDR compared to AAb- FDR (204 ± 117 vs. 346 ± 160 ng/mL, p<0.001; 701 ± 496 vs. 1054 ± 721 ng/mL, p<0.01). Lower IGF1 levels were noted in single AAb+ FDR (183 ± 112 ng/mL, p<0.0001), while lower IGF2 levels remained significant in multiple AAb+ FDR only (686 ± 535 ng/mL, p<0.05). IGFBP1 levels were increased in AAb+ FDR compared to AAb- FDR (3.6 ± 3.2 vs. 1.8 ± 1.7 ng/mL, p<0.01), and this was apparent in single AAb+ FDR (4.5 ± 4.0 ng/mL, p<0.001). IGFBP7 levels were significantly lower in multiple AAb+ FDR as compared to AAb- FDR (79 ± 21 vs. 95 ± 22 ng/mL, p<0.05). Additionally, we established a multiple logistic regression model evaluating age, IGFs, and IGFBPs (IGFBP1, -3, and -7), which could effectively discriminate AAb+ FDR from CTRL (AUC = 0.84). These data suggest a dysregulated IGF axis is present prior to symptomatic T1D and may provide new biomarkers to improve disease prediction. Disclosure M. Shapiro: None. C. Wasserfall: None. A.R. Schultz: None. S.M. McGrail: None. M.J. Haller: None. D. Schatz: None. M.A. Atkinson: Other Relationship; Self; Patent Issued. T.M. Brusko: Stock/Shareholder; Self; OneVax, LLC. Advisory Panel; Self; Caladrius Biosciences, Inc.. Consultant; Self; Merck & Co., Inc., Sanofi-Aventis.
e14629 Background: We have previously shown that the soluble form of the alpha-subunit of the IL-... more e14629 Background: We have previously shown that the soluble form of the alpha-subunit of the IL-2 receptor (sCD25) is significantly elevated in a small series of HCC patients compared to controls. These preliminary studies showed a significant correlation with tumor stage and a novel immuno-inhibitory function for sCD25. AIM To determine the correlation of serum levels of sCD25 with the presence and extent of HCC using a large well characterized series of HCC patients and controls with cirrhosis. METHODS Serum samples were collected from 87 patients with HCC and 30 patients with compensated cirrhosis without HCC. The levels of sCD25 were quantified using ELISA. We then performed descriptive statistics, ROC analysis and correlation analysis. RESULTS The level of sCD25 in the serum of HCC patients was significantly higher (mean + SE: 12,799 + 2,030 pg/mL) than in the control group having cirrhosis without HCC (3,585 + 293 pg/mL; p.0.00002). We found a significant positive correlation between the level of sCD25 in the serum of HCC patients and the tumor stage of patients with HCC (R=0.4; p=0.0001). The ROC curve analysis showed that at a cut-off of >5,150 pg/mL the serum level of sCD25 had a sensitivity of 62.1% and a specificity of 83.3% (AUC=0.740, p< 0.0001. A significant negative correlation was found between serum level of sCD25 and survival of HCC patients (R=-0.3, p<0.01). CONCLUSIONS Peripheral levels of sCD25 show early promise as a novel immune biomarker for HCC with the potential to predict presence of more aggressive HCC and poor outcome.
The treatment of chronic inflammation with systemically administered anti-inflammatory treatments... more The treatment of chronic inflammation with systemically administered anti-inflammatory treatments is associated with moderate-to-severe side effects, and the efficacy of locally administered drugs is short-lived. Here we show that inflammation can be locally suppressed by a fusion protein of the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO) and galectin-3 (Gal3). Gal3 anchors IDO to tissue, limiting the diffusion of IDO-Gal3 away from the injection site. In rodent models of endotoxin-induced inflammation, psoriasis, periodontal disease and osteoarthritis, the fusion protein remained in the inflamed tissues and joints for about 1 week after injection, and the amelioration of local inflammation, disease progression and inflammatory pain in the animals were concomitant with homoeostatic preservation of the tissues and with the absence of global immune suppression. IDO-Gal3 may serve as an immunomodulatory enzyme for the control of focal inflammation in other inflammatory...
Aims/hypothesis TCF7L2 variants are the strongest genetic risk factor for type 2 diabetes. In ind... more Aims/hypothesis TCF7L2 variants are the strongest genetic risk factor for type 2 diabetes. In individuals with type 1 diabetes, these variants are associated with a higher C-peptide AUC, a lower glucose AUC during an OGTT, single autoantibody positivity near diagnosis, particularly in individuals older than 12 years of age, and a lower frequency of type 1 diabetes-associated HLA genotypes. Based on initial observations from clinical cohorts, we tested the hypothesis that type 2 diabetes-predisposing TCF7L2 genetic variants are associated with a higher percentage of residual insulin-containing cells (ICI%) in pancreases of donors with type 1 diabetes, by examining genomic data and pancreatic tissue samples from the Network for Pancreatic Organ donors with Diabetes (nPOD) programme. Methods We analysed nPOD donors with type 1 diabetes (n=110; mean±SD age at type 1 diabetes onset 12.2±7.9 years, mean±SD diabetes duration 15.3±13.7 years, 53% male, 80% non-Hispanic White, 12.7% African ...
OBJECTIVE Biomarkers predicting risk of type 1 diabetes (stage 3) among children with islet autoa... more OBJECTIVE Biomarkers predicting risk of type 1 diabetes (stage 3) among children with islet autoantibodies are greatly needed to prevent diabetic ketoacidosis and facilitate prevention therapies. RESEARCH DESIGN AND METHODS Children in the prospective The Environmental Determinants of Diabetes in the Young (TEDDY) study (n = 707) with confirmed diabetes-associated autoantibodies (GAD antibody, IA-2A, and/or insulin autoantibody) and two or more HbA1c measurements were followed to diabetes or median age 11.1 years. Once confirmed autoantibody positive, HbA1c was measured quarterly. Cox models and receiver operative characteristic curve analyses revealed the prognostic utility for risk of stage 3 on a relative HbA1c increase from the baseline visit or an oral glucose tolerance test (OGTT) 2-h plasma glucose (2-hPG). This HbA1c approach was then validated in the Type 1 Diabetes TrialNet Pathway to Prevention Study (TrialNet) (n = 1,190). RESULTS A 10% relative HbA1c increase from basel...
Background High gluten intake is associated with increased risk of celiac disease (CD) in childre... more Background High gluten intake is associated with increased risk of celiac disease (CD) in children at genetic risk. Objectives We aimed to investigate if different dietary gluten sources up to age 2 y confer different risks of celiac disease autoimmunity (CDA) and CD in children at genetic risk. Methods Three-day food records were collected at ages 6, 9, 12, 18, and 24 mo from 2088 Swedish genetically at-risk children participating in a 15-y follow-up cohort study on type 1 diabetes and CD. Screening for CD was performed with tissue transglutaminase autoantibodies (tTGA). The primary outcome was CDA, defined as persistent tTGA positivity. The secondary outcome was CD, defined as having a biopsy specimen showing Marsh score ≥ 2 or an averaged tTGA level ≥ 100 Units. Cox regression adjusted for total gluten intake estimated HRs with 95% CIs for daily intake of gluten sources. Results During follow-up, 487 (23.3%) children developed CDA and 242 (11.6%) developed CD. Daily intake of ≤15...
Cytometric immunophenotyping is a powerful tool to discover and implement T‐cell biomarkers of ty... more Cytometric immunophenotyping is a powerful tool to discover and implement T‐cell biomarkers of type 1 diabetes (T1D) progression and response to clinical therapy. Although many discovery‐based T‐cell biomarkers have been described, to date, no such markers have been widely adopted in standard practice. The heterogeneous nature of T1D and lack of standardized assays and experimental design across studies is a major barrier to the broader adoption of T‐cell immunophenotyping assays. There is an unmet need to harmonize the design of immunophenotyping assays, including those that measure antigen‐agnostic cell populations, such that data collected from different clinical trial sites and T1D cohorts are comparable, yet account for cohort‐specific features and different drug mechanisms of action. In these Guidelines, we aim to provide expert advice on how to unify aspects of study design and practice. We provide recommendations for defining cohorts, method implementation, as well as tools for data analysis and reporting by highlighting and building on selected successes. Harmonization of cytometry‐based T‐cell assays will allow researchers to better integrate findings across trials, ultimately enabling the identification and validation of biomarkers of disease progression and treatment response in T1D.
Type 1 diabetes (T1D) is a disease that arises due to complex immunogenetic mechanisms. Key cell-... more Type 1 diabetes (T1D) is a disease that arises due to complex immunogenetic mechanisms. Key cell-cell interactions involved in the pathogenesis of T1D are activation of autoreactive T cells by dendritic cells (DC), migration of T cells across endothelial cells (EC) lining capillary walls into the islets of Langerhans, interaction of T cells with macrophages in the islets, and killing of β-cells by autoreactive CD8+ T cells. Overall, pathogenic cell-cell interactions are likely regulated by the individual’s collection of genetic T1D-risk variants. To accurately model the role of genetics, it is essential to build systems to interrogate single candidate genes in isolation during the interactions of cells that are essential for disease development. However, obtaining single-donor matched cells relevant to T1D is a challenge. Sourcing these genetic variants from human induced pluripotent stem cells (iPSC) avoids this limitation. Herein, we have differentiated iPSC from one donor into DC...
Previously, we demonstrated low-dose antithymocyte globulin (ATG) and granulocyte colony-stimulat... more Previously, we demonstrated low-dose antithymocyte globulin (ATG) and granulocyte colony-stimulating factor (GCSF) immunotherapy preserved C-peptide for 2 years in a pilot study of patients with established type 1 diabetes (n = 25). Here, we evaluated the long-term outcomes of ATG/GCSF in study participants with 5 years of available follow-up data (n = 15). The primary end point was area under the curve (AUC) C-peptide during a 2-h mixed-meal tolerance test. After 5 years, there were no statistically significant differences in AUC C-peptide when comparing those who received ATG/GCSF versus placebo (P = 0.41). A modeling framework based on mean trajectories in C-peptide AUC over 5 years, accounting for differing trends between groups, was applied to recategorize responders (n = 9) and nonresponders (n = 7). ATG/GCSF reponders demonstrated nearly unchanged HbA1c over 5 years (mean [95% CI] adjusted change 0.29% [–0.69%, 1.27%]), but the study was not powered for comparisons against no...
1.This paper reviews efforts across 16 international consortia to construct human anatomical stru... more 1.This paper reviews efforts across 16 international consortia to construct human anatomical structures, cell types, and biomarkers (ASCT+B) tables and three-dimensional reference organs in support of a Human Reference Atlas. We detail the ontological descriptions and spatial three-dimensional anatomical representations together with user interfaces that support the registration and exploration of human tissue data. Four use cases are presented to demonstrate the utility of ASCT+B tables for advancing biomedical research and improving health.
IL-12 and IL-18 synergize to promote TH1 responses and have been implicated as accelerators of au... more IL-12 and IL-18 synergize to promote TH1 responses and have been implicated as accelerators of autoimmune pathogenesis in type 1 diabetes (T1D). We investigated the influence of these cytokines on immune cells involved in human T1D progression: natural killer (NK) cells, regulatory T cells (Tregs), and cytotoxic T lymphocytes (CTL). NK cells from T1D patients exhibited higher surface CD226 versus controls and lower CD25 compared to first-degree relatives and controls. Changes in NK cell phenotype towards terminal differentiation were associated with cytomegalovirus (CMV) seropositivity, while possession of IL18RAP, IFIH1, and IL2RA T1D-risk variants impacted NK cell activation as evaluated by immuno-expression quantitative trait loci (eQTL) analyses. IL-12 and IL-18 stimulated NK cells from healthy donors exhibited enhanced specific killing of myelogenous K562 target cells. Moreover, activated NK cell increased expression of NKG2A, NKG2D, CD226, TIGIT and CD25, which enabled competition for IL-2 upon co-culture with Tregs, resulting in Treg downregulation of FOXP3, production of IFNγ, and loss of suppressive function. We generated islet-autoreactive CTL “avatars”, which upon exposure to IL-12 and IL-18, upregulated IFNγ and Granzyme-B leading to increased lymphocytotoxicity of a human β-cell line in vitro. These results support a model for T1D pathogenesis wherein IL-12 and IL-18 synergistically enhance CTL and NK cell cytotoxic activity and disrupt immunoregulation by Tregs.Working Model Summarizing the Hypothesized Contributions of Elevated IL-12 and IL-18 Levels Toward Failure in Immunoregulation and T1D Pathogenesis. In immune homeostasis (left), regulatory T cells (Treg) suppress activation and function of CD8+T cells, CD4+T cells and NK cells via various mechanisms including competition for IL-2. In settings of increased genetic risk for T1D, exposure to some environmental trigger(s) compound genetic defects to induce a break in tolerance (right), during which time IL-12 and IL-18 levels are elevated and NK cells upregulate CD25. This allows for direct competition with Tregs for IL-2, resulting in decreased Treg IL-2 signaling, STAT5 phosphorylation (pSTAT5), and FOXP3 expression, ultimately abrogating suppression. We hypothesize that this, together with enhanced production of cytokines and cytolytic proteins by CD4+conventional T cells and CD8+cytotoxic T cells, leads to augmented lysis of β-cells (right).
Interest in adoptive T-cell therapies has been ignited by the recent clinical success of genetica... more Interest in adoptive T-cell therapies has been ignited by the recent clinical success of genetically-modified T cells in the cancer immunotherapy space. In addition to immune targeting for malignancies, this approach is now being explored for the establishment of immune tolerance with regulatory T cells (Tregs). Herein, we will summarize the basic science and clinical results emanating from trials directed at inducing durable immune regulation through administration of Tregs. We will discuss some of the current challenges facing the field in terms of maximizing cell purity, stability and expansion capacity, while also achieving feasibility and GMP production. Indeed, recent advances in methodologies for Treg isolation, expansion, and optimal source materials represent important strides toward these considerations. Finally, we will review the emerging genetic and biomaterial-based approaches on the horizon for directing Treg specificity to augment tissue-targeting and regenerative medicine.
Autoantibodies (AAb) against beta cell antigens are useful biomarkers for type 1 diabetes (T1D) p... more Autoantibodies (AAb) against beta cell antigens are useful biomarkers for type 1 diabetes (T1D) prediction; however, staging of pre-T1D requires lengthy and invasive glucose tolerance testing. A need exists for additional serum biomarkers reflective of metabolic and immunologic dysregulation to test concurrently with AAb. The insulin-like growth factor (IGF) family, consisting of IGF1 and IGF2, has been shown to promote insulin action and possess immunoregulatory properties. Their activity is regulated by at least seven IGF binding proteins (IGFBPs). We hypothesized that IGF1 and IGF2 levels or bioavailability are reduced during T1D development. Total serum IGF1, IGF2, and IGFBP1-7 levels were measured in an age-matched (12.0 ± 3.7 years), cross-sectional cohort of AAb negative (AAb-) controls (CTRL) (n=74); AAb- first-degree relatives (AAb- FDR, n=55); FDR positive (AAb+ FDR) for one (n=23) or multiple (n=26) of GAD65, IA-2, or ZnT8 AAbs; new onset (NO) T1D patients (n=63, duration 1.0 ± 0.7 months); and established T1D patients (n=68, duration 4.4 ± 3.7 years). IGF1 and IGF2 levels were significantly lower in AAb+ FDR compared to AAb- FDR (204 ± 117 vs. 346 ± 160 ng/mL, p&amp;amp;lt;0.001; 701 ± 496 vs. 1054 ± 721 ng/mL, p&amp;amp;lt;0.01). Lower IGF1 levels were noted in single AAb+ FDR (183 ± 112 ng/mL, p&amp;amp;lt;0.0001), while lower IGF2 levels remained significant in multiple AAb+ FDR only (686 ± 535 ng/mL, p&amp;amp;lt;0.05). IGFBP1 levels were increased in AAb+ FDR compared to AAb- FDR (3.6 ± 3.2 vs. 1.8 ± 1.7 ng/mL, p&amp;amp;lt;0.01), and this was apparent in single AAb+ FDR (4.5 ± 4.0 ng/mL, p&amp;amp;lt;0.001). IGFBP7 levels were significantly lower in multiple AAb+ FDR as compared to AAb- FDR (79 ± 21 vs. 95 ± 22 ng/mL, p&amp;amp;lt;0.05). Additionally, we established a multiple logistic regression model evaluating age, IGFs, and IGFBPs (IGFBP1, -3, and -7), which could effectively discriminate AAb+ FDR from CTRL (AUC = 0.84). These data suggest a dysregulated IGF axis is present prior to symptomatic T1D and may provide new biomarkers to improve disease prediction. Disclosure M. Shapiro: None. C. Wasserfall: None. A.R. Schultz: None. S.M. McGrail: None. M.J. Haller: None. D. Schatz: None. M.A. Atkinson: Other Relationship; Self; Patent Issued. T.M. Brusko: Stock/Shareholder; Self; OneVax, LLC. Advisory Panel; Self; Caladrius Biosciences, Inc.. Consultant; Self; Merck &amp;amp;amp; Co., Inc., Sanofi-Aventis.
e14629 Background: We have previously shown that the soluble form of the alpha-subunit of the IL-... more e14629 Background: We have previously shown that the soluble form of the alpha-subunit of the IL-2 receptor (sCD25) is significantly elevated in a small series of HCC patients compared to controls. These preliminary studies showed a significant correlation with tumor stage and a novel immuno-inhibitory function for sCD25. AIM To determine the correlation of serum levels of sCD25 with the presence and extent of HCC using a large well characterized series of HCC patients and controls with cirrhosis. METHODS Serum samples were collected from 87 patients with HCC and 30 patients with compensated cirrhosis without HCC. The levels of sCD25 were quantified using ELISA. We then performed descriptive statistics, ROC analysis and correlation analysis. RESULTS The level of sCD25 in the serum of HCC patients was significantly higher (mean + SE: 12,799 + 2,030 pg/mL) than in the control group having cirrhosis without HCC (3,585 + 293 pg/mL; p.0.00002). We found a significant positive correlation between the level of sCD25 in the serum of HCC patients and the tumor stage of patients with HCC (R=0.4; p=0.0001). The ROC curve analysis showed that at a cut-off of >5,150 pg/mL the serum level of sCD25 had a sensitivity of 62.1% and a specificity of 83.3% (AUC=0.740, p< 0.0001. A significant negative correlation was found between serum level of sCD25 and survival of HCC patients (R=-0.3, p<0.01). CONCLUSIONS Peripheral levels of sCD25 show early promise as a novel immune biomarker for HCC with the potential to predict presence of more aggressive HCC and poor outcome.
The treatment of chronic inflammation with systemically administered anti-inflammatory treatments... more The treatment of chronic inflammation with systemically administered anti-inflammatory treatments is associated with moderate-to-severe side effects, and the efficacy of locally administered drugs is short-lived. Here we show that inflammation can be locally suppressed by a fusion protein of the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO) and galectin-3 (Gal3). Gal3 anchors IDO to tissue, limiting the diffusion of IDO-Gal3 away from the injection site. In rodent models of endotoxin-induced inflammation, psoriasis, periodontal disease and osteoarthritis, the fusion protein remained in the inflamed tissues and joints for about 1 week after injection, and the amelioration of local inflammation, disease progression and inflammatory pain in the animals were concomitant with homoeostatic preservation of the tissues and with the absence of global immune suppression. IDO-Gal3 may serve as an immunomodulatory enzyme for the control of focal inflammation in other inflammatory...
Aims/hypothesis TCF7L2 variants are the strongest genetic risk factor for type 2 diabetes. In ind... more Aims/hypothesis TCF7L2 variants are the strongest genetic risk factor for type 2 diabetes. In individuals with type 1 diabetes, these variants are associated with a higher C-peptide AUC, a lower glucose AUC during an OGTT, single autoantibody positivity near diagnosis, particularly in individuals older than 12 years of age, and a lower frequency of type 1 diabetes-associated HLA genotypes. Based on initial observations from clinical cohorts, we tested the hypothesis that type 2 diabetes-predisposing TCF7L2 genetic variants are associated with a higher percentage of residual insulin-containing cells (ICI%) in pancreases of donors with type 1 diabetes, by examining genomic data and pancreatic tissue samples from the Network for Pancreatic Organ donors with Diabetes (nPOD) programme. Methods We analysed nPOD donors with type 1 diabetes (n=110; mean±SD age at type 1 diabetes onset 12.2±7.9 years, mean±SD diabetes duration 15.3±13.7 years, 53% male, 80% non-Hispanic White, 12.7% African ...
OBJECTIVE Biomarkers predicting risk of type 1 diabetes (stage 3) among children with islet autoa... more OBJECTIVE Biomarkers predicting risk of type 1 diabetes (stage 3) among children with islet autoantibodies are greatly needed to prevent diabetic ketoacidosis and facilitate prevention therapies. RESEARCH DESIGN AND METHODS Children in the prospective The Environmental Determinants of Diabetes in the Young (TEDDY) study (n = 707) with confirmed diabetes-associated autoantibodies (GAD antibody, IA-2A, and/or insulin autoantibody) and two or more HbA1c measurements were followed to diabetes or median age 11.1 years. Once confirmed autoantibody positive, HbA1c was measured quarterly. Cox models and receiver operative characteristic curve analyses revealed the prognostic utility for risk of stage 3 on a relative HbA1c increase from the baseline visit or an oral glucose tolerance test (OGTT) 2-h plasma glucose (2-hPG). This HbA1c approach was then validated in the Type 1 Diabetes TrialNet Pathway to Prevention Study (TrialNet) (n = 1,190). RESULTS A 10% relative HbA1c increase from basel...
Background High gluten intake is associated with increased risk of celiac disease (CD) in childre... more Background High gluten intake is associated with increased risk of celiac disease (CD) in children at genetic risk. Objectives We aimed to investigate if different dietary gluten sources up to age 2 y confer different risks of celiac disease autoimmunity (CDA) and CD in children at genetic risk. Methods Three-day food records were collected at ages 6, 9, 12, 18, and 24 mo from 2088 Swedish genetically at-risk children participating in a 15-y follow-up cohort study on type 1 diabetes and CD. Screening for CD was performed with tissue transglutaminase autoantibodies (tTGA). The primary outcome was CDA, defined as persistent tTGA positivity. The secondary outcome was CD, defined as having a biopsy specimen showing Marsh score ≥ 2 or an averaged tTGA level ≥ 100 Units. Cox regression adjusted for total gluten intake estimated HRs with 95% CIs for daily intake of gluten sources. Results During follow-up, 487 (23.3%) children developed CDA and 242 (11.6%) developed CD. Daily intake of ≤15...
Cytometric immunophenotyping is a powerful tool to discover and implement T‐cell biomarkers of ty... more Cytometric immunophenotyping is a powerful tool to discover and implement T‐cell biomarkers of type 1 diabetes (T1D) progression and response to clinical therapy. Although many discovery‐based T‐cell biomarkers have been described, to date, no such markers have been widely adopted in standard practice. The heterogeneous nature of T1D and lack of standardized assays and experimental design across studies is a major barrier to the broader adoption of T‐cell immunophenotyping assays. There is an unmet need to harmonize the design of immunophenotyping assays, including those that measure antigen‐agnostic cell populations, such that data collected from different clinical trial sites and T1D cohorts are comparable, yet account for cohort‐specific features and different drug mechanisms of action. In these Guidelines, we aim to provide expert advice on how to unify aspects of study design and practice. We provide recommendations for defining cohorts, method implementation, as well as tools for data analysis and reporting by highlighting and building on selected successes. Harmonization of cytometry‐based T‐cell assays will allow researchers to better integrate findings across trials, ultimately enabling the identification and validation of biomarkers of disease progression and treatment response in T1D.
Type 1 diabetes (T1D) is a disease that arises due to complex immunogenetic mechanisms. Key cell-... more Type 1 diabetes (T1D) is a disease that arises due to complex immunogenetic mechanisms. Key cell-cell interactions involved in the pathogenesis of T1D are activation of autoreactive T cells by dendritic cells (DC), migration of T cells across endothelial cells (EC) lining capillary walls into the islets of Langerhans, interaction of T cells with macrophages in the islets, and killing of β-cells by autoreactive CD8+ T cells. Overall, pathogenic cell-cell interactions are likely regulated by the individual’s collection of genetic T1D-risk variants. To accurately model the role of genetics, it is essential to build systems to interrogate single candidate genes in isolation during the interactions of cells that are essential for disease development. However, obtaining single-donor matched cells relevant to T1D is a challenge. Sourcing these genetic variants from human induced pluripotent stem cells (iPSC) avoids this limitation. Herein, we have differentiated iPSC from one donor into DC...
Previously, we demonstrated low-dose antithymocyte globulin (ATG) and granulocyte colony-stimulat... more Previously, we demonstrated low-dose antithymocyte globulin (ATG) and granulocyte colony-stimulating factor (GCSF) immunotherapy preserved C-peptide for 2 years in a pilot study of patients with established type 1 diabetes (n = 25). Here, we evaluated the long-term outcomes of ATG/GCSF in study participants with 5 years of available follow-up data (n = 15). The primary end point was area under the curve (AUC) C-peptide during a 2-h mixed-meal tolerance test. After 5 years, there were no statistically significant differences in AUC C-peptide when comparing those who received ATG/GCSF versus placebo (P = 0.41). A modeling framework based on mean trajectories in C-peptide AUC over 5 years, accounting for differing trends between groups, was applied to recategorize responders (n = 9) and nonresponders (n = 7). ATG/GCSF reponders demonstrated nearly unchanged HbA1c over 5 years (mean [95% CI] adjusted change 0.29% [–0.69%, 1.27%]), but the study was not powered for comparisons against no...
1.This paper reviews efforts across 16 international consortia to construct human anatomical stru... more 1.This paper reviews efforts across 16 international consortia to construct human anatomical structures, cell types, and biomarkers (ASCT+B) tables and three-dimensional reference organs in support of a Human Reference Atlas. We detail the ontological descriptions and spatial three-dimensional anatomical representations together with user interfaces that support the registration and exploration of human tissue data. Four use cases are presented to demonstrate the utility of ASCT+B tables for advancing biomedical research and improving health.
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Papers by Todd Brusko