Magnetic resonance imaging (MRI) has detected changes in pancreas volume and other characteristic... more Magnetic resonance imaging (MRI) has detected changes in pancreas volume and other characteristics in type 1 and type 2 diabetes. However, differences in MRI technology and approaches across locations currently limit the incorporation of pancreas imaging into multisite trials. The purpose of this study was to develop a standardized MRI protocol for pancreas imaging and to define the reproducibility of these measurements. Calibrated phantoms with known MRI properties were imaged at five sites with differing MRI hardware and software to develop a harmonized MRI imaging protocol. Subsequently, five healthy volunteers underwent MRI at four sites using the harmonized protocol to assess pancreas size, shape, apparent diffusion coefficient (ADC), longitudinal relaxation time (T1), magnetization transfer ratio (MTR), and pancreas and hepatic fat fraction. Following harmonization, pancreas size, surface area to volume ratio, diffusion, and longitudinal relaxation time were reproducible, with coefficients of variation less than 10%. In contrast, non-standardized image processing led to greater variation in MRI measurements. By using a standardized MRI image acquisition and processing protocol, quantitative MRI of the pancreas performed at multiple locations can be incorporated into clinical trials comparing pancreas imaging measures and metabolic state in individuals with type 1 or type 2 diabetes.
Innate immune signals foster adaptive immunity through activation of antigen presenting cells. Re... more Innate immune signals foster adaptive immunity through activation of antigen presenting cells. Recent in vitro evidence suggests that innate signaling may also contribute to immunity by countering the effects of regulatory T cells (T-regs), counter-regulation. We present in vivo evidence using a transgenic skin allograft model that the function of T-regs is lost in the setting of acute skin transplantation but remains intact when grafts were transplanted one month prior to allow surgery-induced inflammation to abate. Our findings identify T-reg counter-regulation as a naturally occurring process that accompanies transplantation and an important barrier to T-reg mediated tolerance. Our finding further highlights the central role of regulatory cell deactivation in the initiation of the immune response.
Involvement of Treg in transplant tolerance has been demonstrated in multiple models. During the ... more Involvement of Treg in transplant tolerance has been demonstrated in multiple models. During the active process of graft rejection, these regulatory cells are themselves regulated and inactivated, a process termed counter-regulation. We hypothesize that ligation of the costimulatory molecule glucocorticoid-induced TNF receptor-related protein (GITR) on Treg inhibits their ability to promote graft survival, and by blocking GITR ligation graft survival can be prolonged. To this aim, we have designed a soluble GITR fusion protein (GITR-Fc), which binds GITR ligand and inhibits activation of GITR. Here, we show that GITR-Fc prolonged mouse skin graft survival, and this prolongation is dependent on Treg. In a full MHC-mismatched skin graft setting, GITR-Fc significantly improved graft survival when used in combination with MR1, anti-CD40L, while GITR-Fc alone did not demonstrate graft prolongation. These results demonstrate that disruption of binding of GITR with GITR ligand may be an important strategy in prolonging allograft survival.
Archivum Immunologiae Et Therapiae Experimentalis, May 30, 2008
Introduction: The relative contributions of CD4 + and CD8 + T cells to transplant rejection remai... more Introduction: The relative contributions of CD4 + and CD8 + T cells to transplant rejection remain unknown. The authors integrated a previous model of CD4-mediated graft rejection with a complementary model of CD8-mediated rejection to directly compare the function of graft-reactive CD4 + and CD8 + lymphocytes in vivo in a model where rejection requires transgenic T cells. These studies allow direct comparison of CD4 and CD8 T cell responses to the same antigen without the confounding effects of T cell depletion or homeostatic proliferation. Materials and Methods: Clone 4 and TS1 mice possess MHC class I-and II-restricted CD8 + and CD4 + T cells, respectively, which express transgenic T cell receptors that recognize the influenza hemagglutinin antigen (HA). We compared the in vivo response of CFSE-labeled, HA-specific transgenic CD8 + and CD4 + T cells after adoptive transfer into syngeneic BALB/c mice grafted with HA-expressing skin. Results: As in the authors' CD4 + model, HA104 skin was consistently rejected by both Clone 4 mice (n=9, MST: 14.2) and by 5×10 5 Clone 4 lymphocytes transferred to naive BALB/c hosts that do not otherwise reject HA + grafts. Rejection correlated with extensive proliferation of either graft-reactive T cell subset in the draining lymph nodes, and antigen-specific CD4 + and CD8 + cells acquired effector function and proliferated with similar kinetics. Conclusions: These data extend the authors' unique transgenic transplantation model to the investigation of CD8 T cell function. The initial results confirm fundamental functional similarity between the CD4 and CD8 T cell subsets and provide insight into the considerable redundancy underlying T cell mechanisms mediating allograft rejection.
BACKGROUND-Many models of transplant tolerance have been found to depend upon the induction of re... more BACKGROUND-Many models of transplant tolerance have been found to depend upon the induction of regulatory T cells (T-regs). Innate immune signals are known to down-regulate T-regs thereby augmenting immunity by abrogating regulatory T cell function. Such signals may also provide a barrier to transplantation tolerance mediated by T-regs. A number of cell surface molecules expressed by T-regs have been found to inhibit T-reg activity, the best characterized of which is the glucocorticoid-induced TNF receptor-related protein (GITR). METHODS-Using an adoptive transfer model of allograft rejection we can study the effects of inflammation and antigen-specific T-regs on graft survival. Inflammation resulting from the transplant procedure counter-regulates the suppressor activity of T-regs. To assess whether T-reg activity could be enhanced by blocking GITR signaling we compared the capacity of T-regs to prolong the survival of grafts in the presence or absence of AITRL-Fc, a novel construct that binds GITR. RESULTS-We report that interruption of GITR-GITRL binding by AITRL-Fc resulted in longterm T-reg-dependent acceptance of skin grafts in the setting of innate immune signals that otherwise interfere with T-reg activity. CONCLUSIONS-Inflammation and other innate immune signals may activate antigen presenting cells (APC) to upregulate GITRL. GITR-GITRL interaction is one pathway by which APCs may
Pancreas size, as measured by MRI, is smaller at the onset of T1D and in individuals at risk for ... more Pancreas size, as measured by MRI, is smaller at the onset of T1D and in individuals at risk for T1D. To determine whether pancreas MRI predicts T1D progression, we measured pancreas size and shape longitudinally in Type 1 Diabetes TrialNet Pathway to Prevention study participants. To increase enrollment and expand this study across multiple TrialNet sites, we established the Multicenter Assessment of the Pancreas in T1D (MAP-T1D) group to develop harmonized MRI acquisition and image processing protocols and ensure the consistency of imaging results across sites. Using this standardized protocol (PMID: 34428220) , we performed longitudinal pancreas MRI in 41 multiple autoantibody-positive individuals (mean age y.o., range 8 - 45 y.o., 49% female) at three TrialNet Clinical Centers. Average time between study entry and diabetes diagnosis for individuals who progressed to Stage 3 was 54 months while non-progressors were followed for a median time of 63 months. Five study participants who developed Stage 3 T1D during follow up had a smaller pancreas (29.5 ± 9.0 ml vs. 54.8 ± 22.5 ml, p = 0.02) and smaller pancreas volume normalized by body weight (0.61 ± 0.18 ml/kg vs. 0.85 ± 0.23 ml, p = 0.03) at study entry compared with those who did not progress to Stage 3. We found that pancreas volume was stable over time, with no significant increase or decrease up to four years after the initial MRI (total of 123 MRIs) . There was no significant change in pancreas size in the five individuals who progressed to Stage 3 T1D. The shape of the pancreas at study onset was also different in the five individuals who progressed to Stage 3 T1D compared with non-progressors, with larger surface area to volume ratio (p = 0.02) , and shorter principal axes (p = 0.05, shortest axis; p = 0.02, second shortest axis) . These data suggest that small pancreas size and altered shape predicts progression from Stage 2 to Stage 3 T1D. Disclosure J.Virostko: None. L.H.Philipson: Advisory Panel; Nevro Corp., Research Support; Dompé, Novo Nordisk, provention BIo. T.Kay: None. H.E.Thomas: Research Support; Captix Biomedical, CSL Limited, Pandion Therapeutics, Procyon Technologies. S.W.Greeley: None. A.Steck: None. A.C.Powers: None. D.J.Moore: None. J.J.Wright: None. J.M.Williams: None. M.A.Hilmes: None. T.M.Triolo: None. H.C.Broncucia: None. L.Du: None. H.Kang: None. W.E.Russell: None. Funding NIDDK (R03DK129979, U24DK097771, UC4 DK106993, DK020593) ; JDRF International (3-SRA-2015-102-M-B, 3-SRA-2019-759-M-B) ; Thomas J. Beatson, Jr. Foundation (2021-003)
To determine the mechanism of reduced pancreas size in type 1 diabetes and the significance of is... more To determine the mechanism of reduced pancreas size in type 1 diabetes and the significance of islet-derived insulin in pancreatic growth. RESEARCH DESIGN AND METHODS Using a validated and standardized MRI protocol, we measured pancreas volume and shape in a family with an autosomal-dominant insulin gene mutation that results in insulin deficiency similar in severity to that of type 1 diabetes but without autoimmunity. DNA sequencing confirmed the mutation in all four affected individuals and none of the four control family members. Insulin secretory capacity was determined by measuring postprandial urinary C-peptide. RESULTS Family members with this form of monogenic diabetes had a markedly smaller pancreas and a severely impaired postprandial C-peptide level than family members without diabetes.
Individuals with new-onset type 1 diabetes (T1D) and those at risk for T1D have a smaller pancrea... more Individuals with new-onset type 1 diabetes (T1D) and those at risk for T1D have a smaller pancreas. The reason for the reduced pancreas size and acinar cell number in T1D is not known, with possible explanations being a direct effect of insulin deficiency, acinar cell-directed autoimmunity, or cytokine-mediated inflammation. To test the hypothesis that insulin deficiency leads to reduced pancreas size, we measured pancreas volume in a family with monogenic diabetes due to an INS-gene mutation using a standardized MRI protocol developed as part of the Multicenter Assessment of the Pancreas in Type 1 Diabetes program (MAP-T1D, www.map-t1d.com, PMID: 34428220) . Pancreas volume was normalized to body weight to calculate pancreas volume index (PVI) . The family, carrying a heterozygous c.94G>C (p.Gly32Arg) INS mutation, was identified as part of the Monogenic Diabetes Registry at the University of Chicago. All family members with diabetes, including the father, diagnosed at age 22, a...
Pancreas volume is reduced in individuals with diabetes and in autoantibody positive individuals ... more Pancreas volume is reduced in individuals with diabetes and in autoantibody positive individuals at high risk for developing type 1 diabetes (T1D). Studies investigating pancreas volume are underway to assess pancreas volume in large clinical databases and studies, but manual pancreas annotation is time-consuming and subjective, preventing extension to large studies and databases. This study develops deep learning for automated pancreas volume measurement in individuals with diabetes. A convolutional neural network was trained using manual pancreas annotation on 160 abdominal magnetic resonance imaging (MRI) scans from individuals with T1D, controls, or a combination thereof. Models trained using each cohort were then tested on scans of 25 individuals with T1D. Deep learning and manual segmentations of the pancreas displayed high overlap (Dice coefficient = 0.81) and excellent correlation of pancreas volume measurements (R2 = 0.94). Correlation was highest when training data include...
OBJECTIVE We compared the uptake of telemedicine for diabetes care across multiple demographic gr... more OBJECTIVE We compared the uptake of telemedicine for diabetes care across multiple demographic groups during the coronavirus disease 2019 pandemic to understand the impact of telemedicine adoption on access to care. RESEARCH DESIGN AND METHODS The study analyzed demographic information of patients with type 1 diabetes seen between 1 January 2018 and 30 June 2020 at a single center. We compared the odds of completing a visit via telemedicine across multiple demographic characteristics. RESULTS Among 28,977 patient visits, the odds of completing a visit via telemedicine were lower among non-English-speaking (1.7% vs. 2.7%; adjusted odds ratio [aOR] 0.45, 95% CI 0.26–0.79) and Medicaid-insured (32.0% vs. 35.9%; aOR 0.83, 95% CI 0.72–0.95) pediatric patients. No clinically significant differences were observed for other demographic factors. CONCLUSIONS Rapid transition to telemedicine did not significantly impact access to diabetes care for most demographic groups. However, disparities ...
There are variable reports of risk of concordance for progression to islet autoantibodies (Ab+) a... more There are variable reports of risk of concordance for progression to islet autoantibodies (Ab+) and type 1 diabetes in identical twins (IT) after one twin is diagnosed. We examined development of Ab+ and type 1 diabetes and the effects of genetic factors and common environment on Ab+ in IT, nonidentical twins (NT), and full siblings (FS). Subjects from the TrialNet Pathway to Prevention Study ( = 48,026) were screened from 2004 to 2015 for Ab+ (GAD antibody [GADA], insulinoma-associated antigen 2 [IA-2A], and autoantibodies against insulin [IAA]). Of these, 17,226 (157 IT, 283 NT, and 16,786 FS) were followed for Ab+ or type 1 diabetes for a median of 2.1 years. At screening, IT were more likely to have positive GADA, IA-2A, and IAA than NT or FS (all < 0.0001). Younger age, male sex, and genetic factors were significant factors for expression of IA-2A, IAA, one or more Ab+, and two or more Ab+ (all ≤ 0.03). Initially, Ab+ IT had a 69% risk of diabetes by 3 years compared with 1....
Only 21 % of adolescents with type 1 diabetes (T1D) meet glycemic goals set forth by the American... more Only 21 % of adolescents with type 1 diabetes (T1D) meet glycemic goals set forth by the American Diabetes Association. Adherence to therapy is a particular concern in this population, and the association between poor adherence and worsening glycemic control indicates that there is a critical need to improve adherence to therapy in adolescents with T1D. In this article, we review barriers to adherence in adolescents with T1D and discuss interventions aimed at improving adherence to therapy and glycemic control. Interventions include technology-based applications, family-based therapies, motivational interviewing, and others. Notably, less than 10 % of the interventions reviewed are provider-led, clinic-based interventions, and few have focused on regimen-related aspects of adherence. This article also outlines the importance of provider communication and the role of providers in facilitating adherence behaviors in adolescents with T1D. Finally, we suggest future directions of research to improve adherence to therapy in adolescents with T1D.
B lymphocytes are required for diabetogenesis in nonobese diabetic (NOD) mice. The complement com... more B lymphocytes are required for diabetogenesis in nonobese diabetic (NOD) mice. The complement component of the innate immune system regulates B cell activation and tolerance through complement receptors CR1/CR2. Thus, it is important to assess the contribution of complement receptors to autoimmune diabetes in NOD mice. Examination of the lymphoid compartments of NOD mice revealed striking expansion of a splenic B cell subset with high cell surface expression of CR1/CR2. This subset of B cells exhibited an enhanced C3 binding ability. Importantly, longterm in vivo blockade of C3 binding to CR1/CR2 prevented the emergence of the CR1/CR2 hi B cells and afforded resistance to autoimmune diabetes in NOD mice. These findings implicate complement as an important regulatory element in controlling the T cellmediated attack on islet  cells of NOD mice.
OBJECTIVE To determine the mechanism of reduced pancreas size in type 1 diabetes and the signific... more OBJECTIVE To determine the mechanism of reduced pancreas size in type 1 diabetes and the significance of islet-derived insulin in pancreatic growth. RESEARCH DESIGN AND METHODS Using a validated and standardized MRI protocol, we measured pancreas volume and shape in a family with an autosomal-dominant insulin gene mutation that results in insulin deficiency similar in severity to that of type 1 diabetes but without autoimmunity. DNA sequencing confirmed the mutation in all four affected individuals and none of the four control family members. Insulin secretory capacity was determined by measuring postprandial urinary C-peptide. RESULTS Family members with this form of monogenic diabetes had a markedly smaller pancreas and a severely impaired postprandial C-peptide level than family members without diabetes. CONCLUSIONS These results suggest that severe insulin deficiency, rather than islet-directed autoimmunity, leads to reduced pancreas size in type 1 diabetes and that insulin is a...
OBJECTIVE Although mortality from coronavirus disease 2019 (COVID-19) among youth with type 1 dia... more OBJECTIVE Although mortality from coronavirus disease 2019 (COVID-19) among youth with type 1 diabetes is rare, severe acute respiratory syndrome coronavirus 2 is associated with increased pediatric hospitalizations for diabetic ketoacidosis (DKA). To clarify whether the relationship between COVID-19 and DKA is coincidental or causal, we compared tissue glucose disposal (TGD) during standardized treatment for DKA between pediatric patients with COVID-19 and those without COVID-19. RESEARCH DESIGN AND METHODS We retrospectively compared TGD during standardized therapy for DKA in all children with preexisting type 1 diabetes with or without COVID-19. Cases were assessed beginning with the first case of COVID-19–positive DKA on 19 June 2020 through 2 February 2022. RESULTS We identified 93 COVID-19–negative patients and 15 COVID-19–positive patients who were treated for DKA, with similar baseline characteristics between groups. Median TGD was 46% lower among patients who had COVID-19 c...
Insulin resistance is an underappreciated facet of type 1 diabetes that occurs with remarkable co... more Insulin resistance is an underappreciated facet of type 1 diabetes that occurs with remarkable consistency and considerable magnitude. Although therapeutic innovations are continuing to normalize dysglycemia, a sizable body of data suggests a second metabolic abnormality—iatrogenic hyperinsulinemia—principally drives insulin resistance and its consequences in this population and has not been addressed. We review this evidence to show that injecting insulin into the peripheral circulation bypasses first-pass hepatic insulin clearance, which leads to the unintended metabolic consequence of whole-body insulin resistance. We propose restructuring insulin therapy to restore the physiological insulin balance between the hepatic portal and peripheral circulations and thereby avoid the complications of life-long insulin resistance. As technology rapidly advances and our ability to ensure euglycemia improves, iatrogenic insulin resistance will become the final barrier to overcome to restore ...
Reduced pancreas volume, as measured by non-contrast magnetic resonance imaging (MRI), is observe... more Reduced pancreas volume, as measured by non-contrast magnetic resonance imaging (MRI), is observed in individuals with newly-diagnosed type 1 diabetes (T1D) and declines over the first year after diagnosis. In this study, we determined the repeatability and inter-reader reproducibility of pancreas volume measurements by MRI. Test-retest scans in individuals with or without T1D (n = 16) had an intraclass correlation coefficient (ICC) of 0.985 (95% CI 0.961 to 0.995) for pancreas volume. Independent pancreas outlines by two board-certified radiologists (n = 30) yielded an ICC of 0.945 (95% CI 0.889 to 0.973). The mean Dice coefficient, a measurement of the degree of overlap between pancreas regions of interest between the two readers, was 0.77. Prandial state did not influence pancreatic measurements, as stomach volume did not correlate with pancreas volume. These data demonstrate that MRI measurements of pancreas volume between two readers are repeatable and reproducible with ICCs th...
Although insulin resistance consistently occurs with type 1 diabetes, its predominant driver is u... more Although insulin resistance consistently occurs with type 1 diabetes, its predominant driver is uncertain. We therefore determined the relative contributions of hyperglycemia and iatrogenic hyperinsulinemia to insulin resistance using hyperinsulinemic-euglycemic clamps in three participant groups (n = 10/group) with differing insulinemia and glycemia: healthy control subjects (euinsulinemia and euglycemia), glucokinase–maturity-onset diabetes of the young (GCK-MODY; euinsulinemia and hyperglycemia), and type 1 diabetes (hyperinsulinemia and hyperglycemia matching GCK-MODY). We assessed the contribution of hyperglycemia by comparing insulin sensitivity in control and GCK-MODY and the contribution of hyperinsulinemia by comparing GCK-MODY and type 1 diabetes. Hemoglobin A1c was normal in control subjects and similarly elevated for type 1 diabetes and GCK-MODY. Basal insulin levels in control subjects and GCK-MODY were nearly equal but were 2.5-fold higher in type 1 diabetes. Low-dose ...
Overcoming the immune response to establish durable immune tolerance in type 1 diabetes remains a... more Overcoming the immune response to establish durable immune tolerance in type 1 diabetes remains a substantial challenge. The ongoing effector immune response involves numerous immune cell types but is ultimately orchestrated and sustained by the hematopoietic stem cell (HSC) niche. We therefore hypothesized that tolerance induction also requires these pluripotent precursors. In this study, we determined that the tolerance-inducing agent anti-CD45RB induces HSC mobilization in nonautoimmune B6 mice but not in diabetes-prone NOD mice. Ablation of HSCs impaired tolerance to allogeneic islet transplants in B6 recipients. Mobilization of HSCs resulted in part from decreasing osteoblast expression of HSC retention factors. Furthermore, HSC mobilization required a functioning sympathetic nervous system; sympathectomy prevented HSC mobilization and completely abrogated tolerance induction. NOD HSCs were held in their niche by excess expression of CXCR4, which, when blocked, led to HSC mobil...
Magnetic resonance imaging (MRI) has detected changes in pancreas volume and other characteristic... more Magnetic resonance imaging (MRI) has detected changes in pancreas volume and other characteristics in type 1 and type 2 diabetes. However, differences in MRI technology and approaches across locations currently limit the incorporation of pancreas imaging into multisite trials. The purpose of this study was to develop a standardized MRI protocol for pancreas imaging and to define the reproducibility of these measurements. Calibrated phantoms with known MRI properties were imaged at five sites with differing MRI hardware and software to develop a harmonized MRI imaging protocol. Subsequently, five healthy volunteers underwent MRI at four sites using the harmonized protocol to assess pancreas size, shape, apparent diffusion coefficient (ADC), longitudinal relaxation time (T1), magnetization transfer ratio (MTR), and pancreas and hepatic fat fraction. Following harmonization, pancreas size, surface area to volume ratio, diffusion, and longitudinal relaxation time were reproducible, with coefficients of variation less than 10%. In contrast, non-standardized image processing led to greater variation in MRI measurements. By using a standardized MRI image acquisition and processing protocol, quantitative MRI of the pancreas performed at multiple locations can be incorporated into clinical trials comparing pancreas imaging measures and metabolic state in individuals with type 1 or type 2 diabetes.
Innate immune signals foster adaptive immunity through activation of antigen presenting cells. Re... more Innate immune signals foster adaptive immunity through activation of antigen presenting cells. Recent in vitro evidence suggests that innate signaling may also contribute to immunity by countering the effects of regulatory T cells (T-regs), counter-regulation. We present in vivo evidence using a transgenic skin allograft model that the function of T-regs is lost in the setting of acute skin transplantation but remains intact when grafts were transplanted one month prior to allow surgery-induced inflammation to abate. Our findings identify T-reg counter-regulation as a naturally occurring process that accompanies transplantation and an important barrier to T-reg mediated tolerance. Our finding further highlights the central role of regulatory cell deactivation in the initiation of the immune response.
Involvement of Treg in transplant tolerance has been demonstrated in multiple models. During the ... more Involvement of Treg in transplant tolerance has been demonstrated in multiple models. During the active process of graft rejection, these regulatory cells are themselves regulated and inactivated, a process termed counter-regulation. We hypothesize that ligation of the costimulatory molecule glucocorticoid-induced TNF receptor-related protein (GITR) on Treg inhibits their ability to promote graft survival, and by blocking GITR ligation graft survival can be prolonged. To this aim, we have designed a soluble GITR fusion protein (GITR-Fc), which binds GITR ligand and inhibits activation of GITR. Here, we show that GITR-Fc prolonged mouse skin graft survival, and this prolongation is dependent on Treg. In a full MHC-mismatched skin graft setting, GITR-Fc significantly improved graft survival when used in combination with MR1, anti-CD40L, while GITR-Fc alone did not demonstrate graft prolongation. These results demonstrate that disruption of binding of GITR with GITR ligand may be an important strategy in prolonging allograft survival.
Archivum Immunologiae Et Therapiae Experimentalis, May 30, 2008
Introduction: The relative contributions of CD4 + and CD8 + T cells to transplant rejection remai... more Introduction: The relative contributions of CD4 + and CD8 + T cells to transplant rejection remain unknown. The authors integrated a previous model of CD4-mediated graft rejection with a complementary model of CD8-mediated rejection to directly compare the function of graft-reactive CD4 + and CD8 + lymphocytes in vivo in a model where rejection requires transgenic T cells. These studies allow direct comparison of CD4 and CD8 T cell responses to the same antigen without the confounding effects of T cell depletion or homeostatic proliferation. Materials and Methods: Clone 4 and TS1 mice possess MHC class I-and II-restricted CD8 + and CD4 + T cells, respectively, which express transgenic T cell receptors that recognize the influenza hemagglutinin antigen (HA). We compared the in vivo response of CFSE-labeled, HA-specific transgenic CD8 + and CD4 + T cells after adoptive transfer into syngeneic BALB/c mice grafted with HA-expressing skin. Results: As in the authors' CD4 + model, HA104 skin was consistently rejected by both Clone 4 mice (n=9, MST: 14.2) and by 5×10 5 Clone 4 lymphocytes transferred to naive BALB/c hosts that do not otherwise reject HA + grafts. Rejection correlated with extensive proliferation of either graft-reactive T cell subset in the draining lymph nodes, and antigen-specific CD4 + and CD8 + cells acquired effector function and proliferated with similar kinetics. Conclusions: These data extend the authors' unique transgenic transplantation model to the investigation of CD8 T cell function. The initial results confirm fundamental functional similarity between the CD4 and CD8 T cell subsets and provide insight into the considerable redundancy underlying T cell mechanisms mediating allograft rejection.
BACKGROUND-Many models of transplant tolerance have been found to depend upon the induction of re... more BACKGROUND-Many models of transplant tolerance have been found to depend upon the induction of regulatory T cells (T-regs). Innate immune signals are known to down-regulate T-regs thereby augmenting immunity by abrogating regulatory T cell function. Such signals may also provide a barrier to transplantation tolerance mediated by T-regs. A number of cell surface molecules expressed by T-regs have been found to inhibit T-reg activity, the best characterized of which is the glucocorticoid-induced TNF receptor-related protein (GITR). METHODS-Using an adoptive transfer model of allograft rejection we can study the effects of inflammation and antigen-specific T-regs on graft survival. Inflammation resulting from the transplant procedure counter-regulates the suppressor activity of T-regs. To assess whether T-reg activity could be enhanced by blocking GITR signaling we compared the capacity of T-regs to prolong the survival of grafts in the presence or absence of AITRL-Fc, a novel construct that binds GITR. RESULTS-We report that interruption of GITR-GITRL binding by AITRL-Fc resulted in longterm T-reg-dependent acceptance of skin grafts in the setting of innate immune signals that otherwise interfere with T-reg activity. CONCLUSIONS-Inflammation and other innate immune signals may activate antigen presenting cells (APC) to upregulate GITRL. GITR-GITRL interaction is one pathway by which APCs may
Pancreas size, as measured by MRI, is smaller at the onset of T1D and in individuals at risk for ... more Pancreas size, as measured by MRI, is smaller at the onset of T1D and in individuals at risk for T1D. To determine whether pancreas MRI predicts T1D progression, we measured pancreas size and shape longitudinally in Type 1 Diabetes TrialNet Pathway to Prevention study participants. To increase enrollment and expand this study across multiple TrialNet sites, we established the Multicenter Assessment of the Pancreas in T1D (MAP-T1D) group to develop harmonized MRI acquisition and image processing protocols and ensure the consistency of imaging results across sites. Using this standardized protocol (PMID: 34428220) , we performed longitudinal pancreas MRI in 41 multiple autoantibody-positive individuals (mean age y.o., range 8 - 45 y.o., 49% female) at three TrialNet Clinical Centers. Average time between study entry and diabetes diagnosis for individuals who progressed to Stage 3 was 54 months while non-progressors were followed for a median time of 63 months. Five study participants who developed Stage 3 T1D during follow up had a smaller pancreas (29.5 ± 9.0 ml vs. 54.8 ± 22.5 ml, p = 0.02) and smaller pancreas volume normalized by body weight (0.61 ± 0.18 ml/kg vs. 0.85 ± 0.23 ml, p = 0.03) at study entry compared with those who did not progress to Stage 3. We found that pancreas volume was stable over time, with no significant increase or decrease up to four years after the initial MRI (total of 123 MRIs) . There was no significant change in pancreas size in the five individuals who progressed to Stage 3 T1D. The shape of the pancreas at study onset was also different in the five individuals who progressed to Stage 3 T1D compared with non-progressors, with larger surface area to volume ratio (p = 0.02) , and shorter principal axes (p = 0.05, shortest axis; p = 0.02, second shortest axis) . These data suggest that small pancreas size and altered shape predicts progression from Stage 2 to Stage 3 T1D. Disclosure J.Virostko: None. L.H.Philipson: Advisory Panel; Nevro Corp., Research Support; Dompé, Novo Nordisk, provention BIo. T.Kay: None. H.E.Thomas: Research Support; Captix Biomedical, CSL Limited, Pandion Therapeutics, Procyon Technologies. S.W.Greeley: None. A.Steck: None. A.C.Powers: None. D.J.Moore: None. J.J.Wright: None. J.M.Williams: None. M.A.Hilmes: None. T.M.Triolo: None. H.C.Broncucia: None. L.Du: None. H.Kang: None. W.E.Russell: None. Funding NIDDK (R03DK129979, U24DK097771, UC4 DK106993, DK020593) ; JDRF International (3-SRA-2015-102-M-B, 3-SRA-2019-759-M-B) ; Thomas J. Beatson, Jr. Foundation (2021-003)
To determine the mechanism of reduced pancreas size in type 1 diabetes and the significance of is... more To determine the mechanism of reduced pancreas size in type 1 diabetes and the significance of islet-derived insulin in pancreatic growth. RESEARCH DESIGN AND METHODS Using a validated and standardized MRI protocol, we measured pancreas volume and shape in a family with an autosomal-dominant insulin gene mutation that results in insulin deficiency similar in severity to that of type 1 diabetes but without autoimmunity. DNA sequencing confirmed the mutation in all four affected individuals and none of the four control family members. Insulin secretory capacity was determined by measuring postprandial urinary C-peptide. RESULTS Family members with this form of monogenic diabetes had a markedly smaller pancreas and a severely impaired postprandial C-peptide level than family members without diabetes.
Individuals with new-onset type 1 diabetes (T1D) and those at risk for T1D have a smaller pancrea... more Individuals with new-onset type 1 diabetes (T1D) and those at risk for T1D have a smaller pancreas. The reason for the reduced pancreas size and acinar cell number in T1D is not known, with possible explanations being a direct effect of insulin deficiency, acinar cell-directed autoimmunity, or cytokine-mediated inflammation. To test the hypothesis that insulin deficiency leads to reduced pancreas size, we measured pancreas volume in a family with monogenic diabetes due to an INS-gene mutation using a standardized MRI protocol developed as part of the Multicenter Assessment of the Pancreas in Type 1 Diabetes program (MAP-T1D, www.map-t1d.com, PMID: 34428220) . Pancreas volume was normalized to body weight to calculate pancreas volume index (PVI) . The family, carrying a heterozygous c.94G>C (p.Gly32Arg) INS mutation, was identified as part of the Monogenic Diabetes Registry at the University of Chicago. All family members with diabetes, including the father, diagnosed at age 22, a...
Pancreas volume is reduced in individuals with diabetes and in autoantibody positive individuals ... more Pancreas volume is reduced in individuals with diabetes and in autoantibody positive individuals at high risk for developing type 1 diabetes (T1D). Studies investigating pancreas volume are underway to assess pancreas volume in large clinical databases and studies, but manual pancreas annotation is time-consuming and subjective, preventing extension to large studies and databases. This study develops deep learning for automated pancreas volume measurement in individuals with diabetes. A convolutional neural network was trained using manual pancreas annotation on 160 abdominal magnetic resonance imaging (MRI) scans from individuals with T1D, controls, or a combination thereof. Models trained using each cohort were then tested on scans of 25 individuals with T1D. Deep learning and manual segmentations of the pancreas displayed high overlap (Dice coefficient = 0.81) and excellent correlation of pancreas volume measurements (R2 = 0.94). Correlation was highest when training data include...
OBJECTIVE We compared the uptake of telemedicine for diabetes care across multiple demographic gr... more OBJECTIVE We compared the uptake of telemedicine for diabetes care across multiple demographic groups during the coronavirus disease 2019 pandemic to understand the impact of telemedicine adoption on access to care. RESEARCH DESIGN AND METHODS The study analyzed demographic information of patients with type 1 diabetes seen between 1 January 2018 and 30 June 2020 at a single center. We compared the odds of completing a visit via telemedicine across multiple demographic characteristics. RESULTS Among 28,977 patient visits, the odds of completing a visit via telemedicine were lower among non-English-speaking (1.7% vs. 2.7%; adjusted odds ratio [aOR] 0.45, 95% CI 0.26–0.79) and Medicaid-insured (32.0% vs. 35.9%; aOR 0.83, 95% CI 0.72–0.95) pediatric patients. No clinically significant differences were observed for other demographic factors. CONCLUSIONS Rapid transition to telemedicine did not significantly impact access to diabetes care for most demographic groups. However, disparities ...
There are variable reports of risk of concordance for progression to islet autoantibodies (Ab+) a... more There are variable reports of risk of concordance for progression to islet autoantibodies (Ab+) and type 1 diabetes in identical twins (IT) after one twin is diagnosed. We examined development of Ab+ and type 1 diabetes and the effects of genetic factors and common environment on Ab+ in IT, nonidentical twins (NT), and full siblings (FS). Subjects from the TrialNet Pathway to Prevention Study ( = 48,026) were screened from 2004 to 2015 for Ab+ (GAD antibody [GADA], insulinoma-associated antigen 2 [IA-2A], and autoantibodies against insulin [IAA]). Of these, 17,226 (157 IT, 283 NT, and 16,786 FS) were followed for Ab+ or type 1 diabetes for a median of 2.1 years. At screening, IT were more likely to have positive GADA, IA-2A, and IAA than NT or FS (all < 0.0001). Younger age, male sex, and genetic factors were significant factors for expression of IA-2A, IAA, one or more Ab+, and two or more Ab+ (all ≤ 0.03). Initially, Ab+ IT had a 69% risk of diabetes by 3 years compared with 1....
Only 21 % of adolescents with type 1 diabetes (T1D) meet glycemic goals set forth by the American... more Only 21 % of adolescents with type 1 diabetes (T1D) meet glycemic goals set forth by the American Diabetes Association. Adherence to therapy is a particular concern in this population, and the association between poor adherence and worsening glycemic control indicates that there is a critical need to improve adherence to therapy in adolescents with T1D. In this article, we review barriers to adherence in adolescents with T1D and discuss interventions aimed at improving adherence to therapy and glycemic control. Interventions include technology-based applications, family-based therapies, motivational interviewing, and others. Notably, less than 10 % of the interventions reviewed are provider-led, clinic-based interventions, and few have focused on regimen-related aspects of adherence. This article also outlines the importance of provider communication and the role of providers in facilitating adherence behaviors in adolescents with T1D. Finally, we suggest future directions of research to improve adherence to therapy in adolescents with T1D.
B lymphocytes are required for diabetogenesis in nonobese diabetic (NOD) mice. The complement com... more B lymphocytes are required for diabetogenesis in nonobese diabetic (NOD) mice. The complement component of the innate immune system regulates B cell activation and tolerance through complement receptors CR1/CR2. Thus, it is important to assess the contribution of complement receptors to autoimmune diabetes in NOD mice. Examination of the lymphoid compartments of NOD mice revealed striking expansion of a splenic B cell subset with high cell surface expression of CR1/CR2. This subset of B cells exhibited an enhanced C3 binding ability. Importantly, longterm in vivo blockade of C3 binding to CR1/CR2 prevented the emergence of the CR1/CR2 hi B cells and afforded resistance to autoimmune diabetes in NOD mice. These findings implicate complement as an important regulatory element in controlling the T cellmediated attack on islet  cells of NOD mice.
OBJECTIVE To determine the mechanism of reduced pancreas size in type 1 diabetes and the signific... more OBJECTIVE To determine the mechanism of reduced pancreas size in type 1 diabetes and the significance of islet-derived insulin in pancreatic growth. RESEARCH DESIGN AND METHODS Using a validated and standardized MRI protocol, we measured pancreas volume and shape in a family with an autosomal-dominant insulin gene mutation that results in insulin deficiency similar in severity to that of type 1 diabetes but without autoimmunity. DNA sequencing confirmed the mutation in all four affected individuals and none of the four control family members. Insulin secretory capacity was determined by measuring postprandial urinary C-peptide. RESULTS Family members with this form of monogenic diabetes had a markedly smaller pancreas and a severely impaired postprandial C-peptide level than family members without diabetes. CONCLUSIONS These results suggest that severe insulin deficiency, rather than islet-directed autoimmunity, leads to reduced pancreas size in type 1 diabetes and that insulin is a...
OBJECTIVE Although mortality from coronavirus disease 2019 (COVID-19) among youth with type 1 dia... more OBJECTIVE Although mortality from coronavirus disease 2019 (COVID-19) among youth with type 1 diabetes is rare, severe acute respiratory syndrome coronavirus 2 is associated with increased pediatric hospitalizations for diabetic ketoacidosis (DKA). To clarify whether the relationship between COVID-19 and DKA is coincidental or causal, we compared tissue glucose disposal (TGD) during standardized treatment for DKA between pediatric patients with COVID-19 and those without COVID-19. RESEARCH DESIGN AND METHODS We retrospectively compared TGD during standardized therapy for DKA in all children with preexisting type 1 diabetes with or without COVID-19. Cases were assessed beginning with the first case of COVID-19–positive DKA on 19 June 2020 through 2 February 2022. RESULTS We identified 93 COVID-19–negative patients and 15 COVID-19–positive patients who were treated for DKA, with similar baseline characteristics between groups. Median TGD was 46% lower among patients who had COVID-19 c...
Insulin resistance is an underappreciated facet of type 1 diabetes that occurs with remarkable co... more Insulin resistance is an underappreciated facet of type 1 diabetes that occurs with remarkable consistency and considerable magnitude. Although therapeutic innovations are continuing to normalize dysglycemia, a sizable body of data suggests a second metabolic abnormality—iatrogenic hyperinsulinemia—principally drives insulin resistance and its consequences in this population and has not been addressed. We review this evidence to show that injecting insulin into the peripheral circulation bypasses first-pass hepatic insulin clearance, which leads to the unintended metabolic consequence of whole-body insulin resistance. We propose restructuring insulin therapy to restore the physiological insulin balance between the hepatic portal and peripheral circulations and thereby avoid the complications of life-long insulin resistance. As technology rapidly advances and our ability to ensure euglycemia improves, iatrogenic insulin resistance will become the final barrier to overcome to restore ...
Reduced pancreas volume, as measured by non-contrast magnetic resonance imaging (MRI), is observe... more Reduced pancreas volume, as measured by non-contrast magnetic resonance imaging (MRI), is observed in individuals with newly-diagnosed type 1 diabetes (T1D) and declines over the first year after diagnosis. In this study, we determined the repeatability and inter-reader reproducibility of pancreas volume measurements by MRI. Test-retest scans in individuals with or without T1D (n = 16) had an intraclass correlation coefficient (ICC) of 0.985 (95% CI 0.961 to 0.995) for pancreas volume. Independent pancreas outlines by two board-certified radiologists (n = 30) yielded an ICC of 0.945 (95% CI 0.889 to 0.973). The mean Dice coefficient, a measurement of the degree of overlap between pancreas regions of interest between the two readers, was 0.77. Prandial state did not influence pancreatic measurements, as stomach volume did not correlate with pancreas volume. These data demonstrate that MRI measurements of pancreas volume between two readers are repeatable and reproducible with ICCs th...
Although insulin resistance consistently occurs with type 1 diabetes, its predominant driver is u... more Although insulin resistance consistently occurs with type 1 diabetes, its predominant driver is uncertain. We therefore determined the relative contributions of hyperglycemia and iatrogenic hyperinsulinemia to insulin resistance using hyperinsulinemic-euglycemic clamps in three participant groups (n = 10/group) with differing insulinemia and glycemia: healthy control subjects (euinsulinemia and euglycemia), glucokinase–maturity-onset diabetes of the young (GCK-MODY; euinsulinemia and hyperglycemia), and type 1 diabetes (hyperinsulinemia and hyperglycemia matching GCK-MODY). We assessed the contribution of hyperglycemia by comparing insulin sensitivity in control and GCK-MODY and the contribution of hyperinsulinemia by comparing GCK-MODY and type 1 diabetes. Hemoglobin A1c was normal in control subjects and similarly elevated for type 1 diabetes and GCK-MODY. Basal insulin levels in control subjects and GCK-MODY were nearly equal but were 2.5-fold higher in type 1 diabetes. Low-dose ...
Overcoming the immune response to establish durable immune tolerance in type 1 diabetes remains a... more Overcoming the immune response to establish durable immune tolerance in type 1 diabetes remains a substantial challenge. The ongoing effector immune response involves numerous immune cell types but is ultimately orchestrated and sustained by the hematopoietic stem cell (HSC) niche. We therefore hypothesized that tolerance induction also requires these pluripotent precursors. In this study, we determined that the tolerance-inducing agent anti-CD45RB induces HSC mobilization in nonautoimmune B6 mice but not in diabetes-prone NOD mice. Ablation of HSCs impaired tolerance to allogeneic islet transplants in B6 recipients. Mobilization of HSCs resulted in part from decreasing osteoblast expression of HSC retention factors. Furthermore, HSC mobilization required a functioning sympathetic nervous system; sympathectomy prevented HSC mobilization and completely abrogated tolerance induction. NOD HSCs were held in their niche by excess expression of CXCR4, which, when blocked, led to HSC mobil...
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Papers by Daniel Moore