Regulatory T-cells (Tregs) play a critical role in maintain-

OBJECTIVEWe conducted an open-label, phase I study using autologous umbilical cord blood (UCB) infusion to ameliorate type 1 diabetes (T1D). Having previously reported on the first 15 patients reaching 1 year of follow-up, herein we report on the complete cohort after 2 years of follow-up.RESEARCH DESIGN AND METHODSA total of 24 T1D patients (median age 5.1 years) received a single intravenous infusion of autologous UCB cells and underwent metabolic and immunologic assessments.RESULTSNo infusion-related adverse events were observed. β-Cell function declined after UCB infusion. Area under the curve C-peptide was 24.3% of baseline 1 year postinfusion (P < 0.001) and 2% of baseline 2 years after infusion (P < 0.001). Flow cytometry revealed increased regulatory T cells (Tregs) (P = 0.04) and naive Tregs (P = 0.001) 6 and 9 months after infusion, respectively.CONCLUSIONSAutologous UCB infusion in children with T1D is safe and induces changes in Treg frequency but fails to preserve C-peptide.

OBJECTIVEInterest continues to grow regarding the therapeutic potential for umbilical cord blood therapies to modulate autoimmune disease. We conducted an open-label phase I study using autologous umbilical cord blood infusion to ameliorate type 1 diabetes.RESEARCH DESIGN AND METHODSFifteen patients diagnosed with type 1 diabetes and for whom autologous umbilical cord blood was stored underwent a single intravenous infusion of autologous cells and completed 1 year of postinfusion follow-up. Intensive insulin regimens were used to optimize glycemic control. Metabolic and immunologic assessments were performed before infusion and at established time periods thereafter.RESULTSMedian (interquartile range [IQR]) age at infusion was 5.25 (3.1–7.3) years, with a median postdiagnosis time to infusion of 17.7 (10.9–26.5) weeks. No infusion-related adverse events were observed. Metabolic indexes 1 year postinfusion were peak C-peptide median 0.50 ng/ml (IQR 0.26–1.30), P = 0.002; A1C 7.0% (IQR 6.5–7.7), P = 0.97; and insulin dose 0.67 units · kg−1 · day−1 (IQR 0.55–0.77), P = 0.009. One year postinfusion, no changes were observed in autoantibody titers, regulatory T-cell numbers, CD4-to-CD8 ratio, or other T-cell phenotypes.CONCLUSIONSAutologous umbilical cord blood transfusion in children with type 1 diabetes is safe but has yet to demonstrate efficacy in preserving C-peptide. Larger randomized studies as well as 2-year postinfusion follow-up of this cohort are needed to determine whether autologous cord blood–based approaches can be used to slow the decline of endogenous insulin production in children with type 1 diabetes.

OBJECTIVEThe pancreas in type 1 diabetes exhibits decreased size (weight/volume) and abnormal exocrine morphology. Serum trypsinogen levels are an established marker of pancreatic exocrine function. As such, we hypothesized that trypsinogen levels may be reduced in patients with pre–type 1 diabetes and type 1 diabetes compared with healthy control subjects.RESEARCH DESIGN AND METHODSSerum trypsinogen levels were determined in 100 persons with type 1 diabetes (72 new-onset, 28 established), 99 autoantibody-positive (AAb+) subjects at varying levels of risk for developing this disease, 87 AAb-negative (AAb−) control subjects, 91 AAb− relatives with type 1 diabetes, and 18 patients with type 2 diabetes.RESULTSTrypsinogen levels increased significantly with age in control subjects (r = 0.71; P < 0.0001) and were significantly lower in patients with new-onset (mean ± SD 14.5 ± 6.1 ng/mL; P < 0.0001) and established type 1 diabetes (16.7 ± 6.9 ng/mL; P < 0.05) versus AAb− control subjects (25.3 ± 11.2 ng/mL), AAb− relatives (29.3 ± 15.0 ng/mL), AAb+ subjects (26.5 ± 12.1 ng/mL), and patients with type 2 diabetes (31.5 ± 17.3 ng/mL). Multivariate analysis revealed reduced trypsinogen in multiple-AAb+ subjects (P < 0.05) and patients with type 1 diabetes (P < 0.0001) compared with AAb− subjects (control subjects and relatives combined) and single-AAb+ (P < 0.01) subjects when considering age and BMI.CONCLUSIONSThese findings further support the interplay between pancreatic endocrine and exocrine dysfunction. Longitudinal studies are warranted to validate trypsinogen as a predictive biomarker of type 1 diabetes progression.

Recent studies, albeit controversial, have suggested that the incretin exendin-4 (Ex-4) is capable of inducing beta cell proliferation in vivo. Furthermore, this compound has been shown to enhance the ability of other agents (e.g., anti-CD3, antilymphocyte serum) to reverse type 1 diabetes (T1D) in NOD mice. However, the mechanisms underlying this beneficial action for disease reversal remain largely unclear. Herein, we tested the hypothesis that Ex-4 therapy may act as a stimulator of regulatory T cells (Tregs). We evaluated the effect of Ex-4 (Byetta; 0.2 microg/mouse/day for 30 days) treatment on the frequency and function of Tregs and changes in the cytokine profile of NOD mice with recently diagnosed T1D. In comparison to that of saline-treated control NOD mice, the frequency of Tregs was increased in Ex-4-treated mice. Suppression assays demonstrated a trend towards increased Treg suppression after administration of Ex-4, but were limited by small sample size. Lastly, Ex-4 treatment induced production of IL-10, indicating a possible shift towards a more Th2-like phenotype. Taken collectively, these data suggest that in addition to its potential effects on beta cell proliferation, Ex-4 may also act as a regulator of the immune response.