Focus has also shifted towards the potential benefits of synergistic combinatorial approaches, both in terms of efficacy and the potential for reduced side effects

Focus has also shifted towards the potential benefits of synergistic combinatorial approaches, both in terms of efficacy and the potential for reduced side effects. lower doseAntigen based therapy: oral insulin long term induction of regulatory, non-inflammatory T-cell responsesPre-POINT*46Increased Tregs in those who received a higher dose of oral insulin (62.5 mg)Combination therapyusing various immune agents have been carried out in new onset T1D patients. Marek-Trzonkowska et al. carried out autologous infusion of expanded Tregs in children with T1D (n=10, 8C16 years old, disease duration of 2 months) and compared to children who did not receive the Treg infusions.39 Two of the treated children were in remission 5 months after the infusion and 8 children required 0.5 U/kg/day of insulin. The C-peptide in the treatment group was also significantly higher compared to the non-treated group (p=0.01). Recently, Bluestone et al. have focused on the functionality of expanded Tregs. He and his co-workers successfully carried out an open label, phase I trial where Tregs from T1D patients (n=14, disease duration 3926 weeks) were harvested, expanded using anti-CD3, anti-CD28, and IL-2 (sepsis secondary to the high dose of the immunosuppressive agents. Haller et al. subsequently developed a protocol in which cyclophosphamide was eliminated to avoid serious toxicity and a lower dose of ATG (2.5 mg/kg) was used along with an extended course of G-CSF (6 mg peglylated G-CSF q 2 weeks x 6 doses) (Table 1).54 This randomised, single-blind, placebo-controlled, phase II study was carried out in subjects 12C45 years old (T1D duration 4 months to 2 S1RA years). Mean AUC C-peptide (4-hour MMTT) at 12 months post therapy, was significantly higher in the study group compared to placebo group (p=0.017). The majority of the subjects in the treatment group showed no decline in -cell function even after 12 months. A significantly higher number of Tregs were also observed in the study group at 2 weeks and 12 months post treatment. Unlike high-dose ATG, the low dose ATG and G-CSF combination not only favoured the induction of Tregs, but also led to less severe T-cell depletion and allowed faster T-cell recovery. Only transient and fully reversible side effects such as cytokine release syndrome and serum sickness were reported in the study group. As the sample size was small, a phase IIb, clinical study of the efficacy of ATG and G-CSF in new onset T1D ( 3 months post diagnosis) patients is currently being conducted by TrialNet.55 Ongoing follow up of the original ATG/G-CSF pilot study subjects will help to determine Rabbit Polyclonal to ABCD1 if and when re-dosing with ATG/G-CSF or other immunotherapeutics is required to achieve long term preservation of -cell function. In addition, Haller et al. have proposed the use of ATG/G-CSF and oral insulin as a potential option for utilising this combination approach in an effort to delay or prevent T1D in high risk subjects. Conclusion Although the last 20 years have seen major advances in the treatment of T1D associated with the development of insulin analogues, insulin pumps, and continuous glucose sensing, T1D is still associated with significant morbidity, mortality, and socioeconomic burden. Similarly, the search for an effective strategy to prevent and reverse T1D remains elusive. Significant but short term beneficial metabolic S1RA outcomes from past trials in new onset T1D patients have not always translated into complete independence from exogenous insulin, and it is questionable if this goal is pragmatic for those who already have clinical disease. Moreover, it is uncertain if the lack of success S1RA with immunotherapeutics is related to the relatively late phase of disease in which most trials have been performed, or the most appropriate combination of agents has yet to be studied, or the specific type of patient cohort most likely to benefit from these approaches has yet to be identified. An important aspect that should be contemplated in view of the recent finding of a more aggressive disease state in younger children with less residual -cell function at diagnosis, is whether preventive interventions in high risk young children, will be more logical and efficacious.