Autologous umbilical cord blood infusion for type 1 diabetes.

OBJECTIVE: The physical, emotional, and economic costs of type 1 diabetes (T1D) mandate continued efforts to develop effective strategies to prevent or reverse the disease. Herein, we describe the scientific and therapeutic rationale underlying efforts utilizing umbilical cord blood (UCB) as a therapy for ameliorating the progression of this autoimmune disease. MATERIALS AND METHODS: We recently embarked on a pilot study to document the safety and potential efficacy of autologous UCB infusion in subjects with T1D. Under this protocol, patients recently diagnosed with the disease and for whom autologous cord blood is stored, undergo infusion. Studies are performed before infusion and every 3 to 6 months postinfusion for immunologic and metabolic assessment. To date, 15 autologous infusions have been performed. RESULTS: Preliminary observations suggest that autologous cord blood transfusion is safe and provides some slowing of the loss of endogenous insulin production in children with T1D. Mechanistic studies demonstrate that umbilical cord blood contains highly functional populations of regulatory T cells (Treg) and that increased Treg populations may be found in the peripheral blood of subjects more than 6 months after cord blood infusion. We provide the rationale for cord blood-based therapies, a summary of our initial protocol, and plans for future studies designed to explore the potential of cord blood-derived regulatory T cells to treat T1D. CONCLUSIONS: Prolonged follow-up and additional mechanistic efforts are urgently needed to determine if umbilical cord blood-derived stem cells can be used as part of safe and effective therapies for T1D.

No alterations in the frequency of FOXP3+ regulatory T-cells in type 1 diabetes.

Regulatory T-cells (Tregs) play a critical role in maintaining dominant peripheral tolerance. Previous characterizations of Tregs in type 1 diabetes have used antibodies against CD4 and alpha-chain of the interleukin-2 receptor complex (CD25). This report extends those investigations by the addition of a more lineage-specific marker for Tregs, transcription factor forkhead box P3 (FOXP3), in subjects with type 1 diabetes, their first-degree relatives, and healthy control subjects. With inclusion of this marker, two predominant populations of CD4(+)CD25(+) T-cells were identified: CD4(+)CD25(+)FOXP3(+) as well as CD4(+)FOXP3(-) T-cells expressing low levels of CD25 (CD4(+)CD25(LOW)FOXP3(-)). In all study groups, the frequency of CD4(+)CD25(+)FOXP3(+) cells was age independent, whereas CD4(+)CD25(LOW)FOXP3(-) cell frequencies strongly associated with age. In terms of additional markers for delineating cells of Treg lineage, FOXP3(+) cells were CD127(-) to CD127(LOW) whereas CD25(+) cells were less restricted in their expression of this marker, with CD127 expressed across a continuum of levels. Importantly, no differences were observed in the frequency of CD4(+)CD25(+)FOXP3(+) T-cells in individuals with or at varying degrees of risk for type 1 diabetes. These investigations suggest that altered peripheral blood frequencies of Tregs, as defined by the expression of FOXP3, are not specifically associated with type 1 diabetes and continue to highlight age as an important variable in analysis of immune regulation.

Vitamin E therapy results in a reduction in HDL function in individuals with diabetes and the haptoglobin 2-1 genotype.

OBJECTIVE: Vitamin E provides cardiovascular protection to individuals with diabetes and the haptoglobin 2-2 genotype but appears to increase cardiovascular risk in individuals with diabetes and the haptoglobin 2-1 genotype. We have previously demonstrated that the haptoglobin protein is associated with HDL and that HDL function and its oxidative modification are haptoglobin genotype dependent. We set out to test the hypothesis that the pharmacogenetic interaction between the haptoglobin genotype on cardiovascular risk might be secondary to a parallel interaction between the haptoglobin genotype and vitamin E on HDL function. RESEARCH DESIGN AND METHODS: Fifty-nine individuals with diabetes and the haptoglobin 2-1 or 2-2 genotypes were studied in a double-blind placebo controlled crossover design. Participants were treated with either vitamin E (400IU) or placebo for 3 months and crossed over for an equivalent duration. Serum was collected at baseline and after the completion of each treatment. HDL functionality as well as HDL associated markers of oxidation and inflammation were measured after each interval in HDL purified from the cohort. RESULTS: Compared to placebo, vitamin E significantly increased HDL function in haptoglobin 2-2 but significantly decreased HDL function in haptoglobin 2-1. This pharmacogenetic interaction was paralleled by similar non-significant trends in HDL associated lipid peroxides, glutathione peroxidase, and inflammatory cargo. CONCLUSION: There exists a pharmacogenetic interaction between the haptoglobin genotype and vitamin E on HDL function (clinicaltrials.gov NCT01113671).