Discordant association of islet autoantibodies with high‐risk HLA genes in Chinese type 1 diabetes

Gu, Yong; Zhang, Mei; Chen, Heng; Wang, Zhixiao; Xing, Changying; Yang, Hui; Xu, Xinyu; Liu, Yu; Zhou, Zhiguang; Yu, Liping; Hutton, John C.; Eisenbarth, George S.; Yang, Tao

doi:10.1002/dmrr.1270

Cited by 20 publications

(19 citation statements)

References 16 publications

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“…1B and Supplementary Tables 1 and 2); 95% of patients (n = 20) in the SCT group and 86% (n = 18) in the control group had at least one predisposing allele, 62% and 52% of SCT and control group patients had at least the HLA-DR allele associated with T1D (DR9, DR4, and/or DR3) (25). Of these, 43% (n = 9) in the SCT group and 38% (n = 8) in the control group had at least one HLA-DR plus at least one HLA-A (A11 and/or A24) T1D risk alleles present (25). Only 5% (n = 1) in the SCT group and 14% (n = 3) in the control group had none of the risk alleles.…”

Section: Patient Characteristicsmentioning

confidence: 99%

Umbilical Cord Mesenchymal Stromal Cell With Autologous Bone Marrow Cell Transplantation in Established Type 1 Diabetes: A Pilot Randomized Controlled Open-Label Clinical Study to Assess Safety and Impact on Insulin Secretion

Cai

et al. 2015

Diabetes Care

142

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OBJECTIVETo determine the safety and effects on insulin secretion of umbilical cord (UC) mesenchymal stromal cells (MSCs) plus autologous bone marrow mononuclear cell (aBM-MNC) stem cell transplantation (SCT) without immunotherapy in established type 1 diabetes (T1D). RESEARCH DESIGN AND METHODSBetween January 2009 and December 2010, 42 patients with T1D were randomized (n = 21/group) to either SCT (1.1 3 10 6 /kg UC-MSC, 106.8 3 10 6 /kg aBM-MNC through supraselective pancreatic artery cannulation) or standard care (control). Patients were followed for 1 year at 3-month intervals. The primary end point was C-peptide area under the curve (AUC C-Pep ) during an oral glucose tolerance test at 1 year. Additional end points were safety and tolerability of the procedure, metabolic control, and quality of life. RESULTSThe treatment was well tolerated. At 1 year, metabolic measures improved in treated patients: AUC C-Pep increased 105.7% (6.6 6 6.1 to 13.6 6 8.1 pmol/mL/180 min, P = 0.00012) in 20 of 21 responders, whereas it decreased 7.7% in control subjects (8.4 6 6.8 to 7.7 6 4.5 pmol/mL/180 min, P = 0.013 vs. SCT); insulin area under the curve increased 49.3% (1,477.8 6 1,012.8 to 2,205.5 6 1,194.0 mmol/mL/180 min, P = 0.01), whereas it decreased 5.7% in control subjects (1,517.7 6 630.2 to 1,431.7 6 441.6 mmol/mL/180 min, P = 0.027 vs. SCT). HbA 1c decreased 12.6% (8.6 6 0.81% [70.0 6 7.1 mmol/mol] to 7.5 6 1.0% [58.0 6 8.6 mmol/mol], P < 0.01) in the treated group, whereas it increased 1.2% in the control group (8.7 6 0.9% [72.0 6 7.5 mmol/mol] to 8.8 6 0.9% [73 6 7.5 mmol/mol], P < 0.01 vs. SCT). Fasting glycemia decreased 24.4% (200.0 6 51.1 to 151.2 6 22.1 mg/dL, P < 0.002) and 4.3% in control subjects (192.4 6 35.3 to 184.2 6 34.3 mg/dL, P < 0.042). Daily insulin requirements decreased 29.2% in only the treated group (0.9 6 0.2 to 0.6 6 0.2 IU/day/kg, P = 0.001), with no change found in control subjects (0.9 6 0.2 to 0.9 6 0.2 IU/day/kg, P < 0.01 vs. SCT). CONCLUSIONSTransplantation of UC-MSC and aBM-MNC was safe and associated with moderate improvement of metabolic measures in patients with established T1D.

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Section: Patient Characteristicsmentioning

confidence: 99%

Umbilical Cord Mesenchymal Stromal Cell With Autologous Bone Marrow Cell Transplantation in Established Type 1 Diabetes: A Pilot Randomized Controlled Open-Label Clinical Study to Assess Safety and Impact on Insulin Secretion

Cai

et al. 2015

Diabetes Care

142

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“…Blood taken into the plain tubes were centrifuged at 350×g and stored frozen at 80°C. Later, RIA was used for detecting ZnT8A, GADA and IA2A as previously described (Gu et al, 2011). Briefly, human 35S-labeled recombinant antigens were produced in an in vitro-coupled transcription and translation system with SP6 (GAD, IA2) or T7 (ZnT8A) RNA polymerase and nuclease-treated rabbit reticulocyte lysate (Promega, USA).…”

Section: Laboratory Datamentioning

confidence: 99%

The heterogeneity of islet autoantibodies and the progression of islet failure in type 1 diabetic patients

Liu

Bian

et al. 2016

Sci. China Life Sci.

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Type 1 diabetes mellitus is heterogeneous in many facets. The patients suffered from type 1 diabetes present several levels of islet function as well as variable number and type of islet-specific autoantibodies. This study was to investigate prevalence and heterogeneity of the islet autoantibodies and clinical phenotypes of type 1 diabetes mellitus; and also discussed the process of islet failure and its risk factors in Chinese type 1 diabetic patients. A total of 1,291 type 1 diabetic patients were enrolled in this study. Demographic information was collected. Laboratory tests including mixed-meal tolerance test, human leukocyte antigen alleles, hemoglobinA1c, lipids, thyroid function and islet autoantibodies were conducted. The frequency of islet-specific autoantibody in newly diagnosed T1DM patients (duration shorter than half year) was 73% in East China. According to binary logistic regressions, autoantibody positivity, longer duration and lower Body Mass Index were the risk factors of islet failure. As the disease developed, autoantibodies against glutamic acid decarboxylase declined as well as the other two autoantibodies against zinc transporter 8 and islet antigen 2. The decrease of autoantibodies was positively correlated with aggressive beta cell destruction. Autoantibodies can facilitate the identification of classic T1DM from other subtypes and predict the progression of islet failure. As there were obvious heterogeneity in autoantibodies and clinical manifestation in different phenotypes of the disease, we should take more factors into consideration when identifying type 1 diabetes mellitus.autoantibodies, heterogeneity, islet failure, type 1 diabetes Citation:

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“…The C terminal dimer with one Arg325Trp mutation consisted two of C terminal, first 268-369 had Arg at position 325 and the second Trp at 325. The two C terminals were linked by the sequence encoding for a short peptide (Gu et al, 2011).…”

Section: Cloning and Expression Of Recombinant Znt8mentioning

confidence: 99%

“…Serum ZnT8A levels were analyzed by immunoprecipitated radioactivity as described earlier (Gu et al, 2011). All samples were collected with appropriate informed consent.…”

Section: Construction Of Phage Display Scfv Library From T1d Patientsmentioning

confidence: 99%

Screening and identification of human ZnT8-specific single-chain variable fragment (scFv) from type 1 diabetes phage display library

Wang

et al. 2016

Sci. China Life Sci.

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Zinc transporter 8 (ZnT8) is a major autoantigen and a predictive marker in type 1 diabetes (T1D). To investigate ZnT8-specific antibodies, a phage display library from T1D was constructed and single-chain antibodies against ZnT8 were screened and identified. Human T1D single-chain variable fragment (scFv) phage display library consists of approximately 110 8 clones. After four rounds of bio-panning, seven unique clones were positive by phage ELISA. Among them, C27 and C22, which demonstrated the highest affinity to ZnT8, were expressed in Escherichia coli Top10F' and then purified by affinity chromatography. C27 and C22 specifically bound ZnT8 N/C fusion protein and ZnT8 C terminal dimer with one Arg325Trp mutation. The specificity to human islet cells of these scFvs were further confirmed by immunohistochemistry. In conclusion, we have successfully constructed a T1D phage display antibody library and identified two ZnT8-specific scFv clones, C27 and C22. These ZnT8-specific scFvs are potential agents in immunodiagnostic and immunotherapy of T1D.Zinc transporter 8 (ZnT8), phage display, single-chain variable fragment (scFv), type 1 diabetes (T1D) Citation:Wu, Q., Wang, X., Gu, Y., Zhang, X., Qin, Y., Chen, H., Xu, X., Yang, T., and Zhang, M. (2016). Screening and identification of human ZnT8-specific single-chain variable fragment (scFv) from type 1 diabetes phage display library. Sci China Life Sci 59, 686 -693.

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Discordant association of islet autoantibodies with high‐risk HLA genes in Chinese type 1 diabetes

Abstract: The discordant association of autoantibodies with high-risk HLA gene may indicate the different immunology mechanisms of those autoantibodies. And metabolic burden resulting from overweight may accelerate apoptosis of beta cells.

Cited by 20 publications

References 16 publications

Umbilical Cord Mesenchymal Stromal Cell With Autologous Bone Marrow Cell Transplantation in Established Type 1 Diabetes: A Pilot Randomized Controlled Open-Label Clinical Study to Assess Safety and Impact on Insulin Secretion

Umbilical Cord Mesenchymal Stromal Cell With Autologous Bone Marrow Cell Transplantation in Established Type 1 Diabetes: A Pilot Randomized Controlled Open-Label Clinical Study to Assess Safety and Impact on Insulin Secretion

The heterogeneity of islet autoantibodies and the progression of islet failure in type 1 diabetic patients

Screening and identification of human ZnT8-specific single-chain variable fragment (scFv) from type 1 diabetes phage display library

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