PD-1 Receptor (+) T cells are associated with the efficacy of the combined treatment with regulatory t cells and rituximab in type 1 diabetes children via regulatory t cells suppressive activity amelioration.

An imbalance between exaggerated autoaggressive T cell responses, primarily CD8 + T cells, and impaired tolerogenic mechanisms underlie the development of type 1 diabetes mellitus. Disease-modifying strategies, particularly immunotherapy focusing on FoxP3 + T regulatory cells (Treg), and B cells facilitating antigen presentation for T cells, show promise. Selective depletion of B cells may be achieved with an anti-CD20 monoclonal antibody (mAb). In a 2-year-long flow cytometry follow-up, involving 32 peripheral blood T and B cell markers across three trial arms (Treg + rituximab N = 12, Treg + placebo N = 13, control N = 11), we observed significant changes. PD-1 receptor (+) CD4 + Treg, CD4 + effector T cells (Teffs), and CD8 + T cell percentages increased in the combined regimen group by the end of follow-up. Conversely, the control group exhibited a notable reduction in PD-1 receptor (+) CD4 + Teff percentages. Considering clinical endpoints, higher PD-1 receptor (+) expression on T cells correlated with positive responses, including a higher mixed meal tolerance test AUC, and reduced daily insulin dosage. PD-1 receptor (+) T cells emerged as a potential therapy outcome biomarker. In vitro validation confirmed that successful Teff suppression was associated with elevated PD-1 receptor (+) Treg levels. These findings support PD-1 receptor (+) T cells as a reliable indicator of treatment with combined immunotherapy consisting of Tregs and anti-CD20 mAb efficacy in type 1 diabetes mellitus.

Combined therapy with CD4+ CD25highCD127- T regulatory cells and anti-CD20 antibody in recent-onset type 1 diabetes is superior to monotherapy: Randomized phase I/II trial.

AIMS: Monotherapy with autologous expanded CD4+ CD25high CD127- T regulatory cells (Tregs) or rituximab has been documented to slow disease progression in patients with recent-onset type 1 diabetes mellitus (T1DM). Whether a combined therapy including both drugs would further benefit this patient population is unknown. MATERIALS AND METHODS: We conducted a three-arms clinical trial to explore the efficacy and safety of the combined treatment with Tregs and rituximab in paediatric patients with T1DM. The patients were allocated to three groups: Tregs only (n = 13), Tregs + rituximab (n = 12) and control (n = 11). The key primary efficacy analyses were C-peptide levels (mixed meal tolerance test) and the proportion of patients in remission at 12 and 24 months. RESULTS: At month 24, as compared with the control, both treatment groups remained superior in the area under the curve of C-peptide mixed meal tolerance test, whereas in the analysis of all visits only the combined therapy improved area under the curve at 12 and 24 months. The proportion of patients in remission was significantly higher in the combined group than in the control group at 3, 6, 9 and 21 months but not at 18 and 24 months. There was no significant difference between the Tregs only group and control group. Adverse events occurred in 80% patients, mostly in the combined group and Tregs only group. No adverse events led to the withdrawal of the intervention or death. All comparisons were performed with alpha level of 5%. CONCLUSIONS: Over 2 years, combined therapy with Tregs and rituximab was consistently superior to monotherapy in delaying T1DM progression in terms of C-peptide levels and the maintenance of remission.

Proinsulin-specific T regulatory cells may control immune responses in type 1 diabetes: implications for adoptive therapy.

OBJECTIVE: Here we looked for possible mechanisms regulating the progression of type 1 diabetes mellitus (T1DM). In this disease, autoaggressive T cells (T conventional cells, Tconvs) not properly controlled by T regulatory cells (Tregs) destroy pancreatic islets. RESEARCH DESIGN AND METHODS: We compared the T-cell compartment of patients with newly diagnosed T1DM (NDT1DM) with long-duration T1DM (LDT1DM) ones. The third group consisted of patients with LDT1DM treated previously with polyclonal Tregs (LDT1DM with Tregs). We have also looked if the differences might be dependent on the antigen specificity of Tregs expanded for clinical use and autologous sentinel Tconvs. RESULTS: Patients with LDT1DM were characterized by T-cell immunosenescence-like changes and expansion of similar vß/T-cell receptor (TCR) clones in Tconvs and Tregs. The treatment with Tregs was associated with some inhibition of these effects. Patients with LDT1DM possessed an increased percentage of various proinsulin-specific T cells but not GAD65-specific ones. The percentages of all antigen-specific subsets were higher in the expansion cultures than in the peripheral blood. The proliferation was more intense in proinsulin-specific Tconvs than in specific Tregs but the levels of some proinsulin-specific Tregs were exceptionally high at baseline and remained higher in the expanded clinical product than the levels of respective Tconvs in sentinel cultures. CONCLUSIONS: T1DM is associated with immunosenescence-like changes and reduced diversity of T-cell clones. Preferential expansion of the same TCR families in both Tconvs and Tregs suggests a common trigger/autoantigen responsible. Interestingly, the therapy with polyclonal Tregs was associated with some inhibition of these effects. Proinsulin-specific Tregs appeared to be dominant in the immune responses in patients with T1DM and probably associated with better control over respective autoimmune Tconvs. TRIAL REGISTRATION NUMBER: EudraCT 2014-004319-35.

Assessing the knowledge of the consequences of uncontrolled diabetesin pregnancy and its effects on fetal development, among femaleadolescents with type 1 diabetes.

INTRODUCTION: Two forms of diabetes can be distinguished during pregnancy: gestational diabetes and pregestational diabetes, which exists prior to pregnancy. In young women, the most common form of pregestational diabetes is type 1 diabetes (T1D). Regarding the decreasing age of sexual initiation and health risks for the mother and child related to hyperglycemia, it is essential that adolescents with T1D possess proper knowledge of pregnancy planning and diabetes management in case of pregnancy. Preconception counseling in adolescent patients with T1D remains a challenge for the whole therapeutic team. AIM OF THE STUDY: Assessing the awareness of consequences of uncontrolled diabetes on the course of pregnancy and fetal development among patients with T1D. MATERIAL AND METHODS: The study was carried out in the group of 70 patients with T1D, aaged 15-18 years. The survey was consisted of 25 questions regarding health status, lifestyle, the knowledge of self-management of diabetes and the impact of diabetes on pregnancy and fetal development. Respondents were asked to indicate the sources of information from which they had gianed knowledge about the aforesaid issues. The data obtained were statistically analyzed. RESULTS: 20% (n=14) of respondents declared sexual activity. In the group of sexually active patients, in 50% (n=7) last HbA1c level, reported by subjects, was between 7.5-9%, and in 21.4% (n=3) >9%. The patients were aware of the consequences of uncontrolled diabetes on fetal development, however their knowledge was unsatisfactory. Surveyed adolescents indicated metabolic disorders (61.4 %, n=43), central nervous system malformations (55.7%, n=39) and heart defects (47.1%, n=33) as the most frequent complications. The respondents gathered knowledge mainly from a diabetologist (40%, n=28) and the Internet (40%, n=28). The majority of patients stated that preconception care should be provided by a diabetologist (88.6%, n=62) or a gynecologist (70%, n=49). CONCLUSION: In spite of continuous diabetes care, adolescents with T1D do not possess sufficient knowledge regarding the consequences of hyperglycemia during pregnancy. This study has emphasized the need for including reproductive health issues in diabetes education addressed to adolescent patients.

Factors affecting long-term efficacy of T regulatory cell-based therapy in type 1 diabetes.

BACKGROUND: Recent studies suggest that immunotherapy using T regulatory cells (Tregs) prolongs remission in type 1 diabetes (T1DM). Here, we report factors that possibly affect the efficacy of this treatment. METHODS: The metabolic and immune background of 12 children with recently diagnosed T1DM, as well as that of untreated subjects, during a 2-year follow-up is presented. Patients were treated with up to 30 × 106/kg b.w. of autologous expanded CD3+CD4+CD25highCD127- Tregs. RESULTS: The disease progressed and all patients were insulin-dependent 2 years after inclusion. The ß-cell function measured by c-peptide levels and the use of insulin were the best preserved in patients treated with two doses of Tregs (3/6 in remission), less so after one dose (1/6 in remission) and the worst in untreated controls (no remissions). Increased levels of Tregs could be seen in peripheral blood after their adoptive transfer together with the shift from naïve CD62L+CD45RA+ to memory CD62L+CD45RA- Tregs. Increasing serum levels of proinflammatory cytokines were found: IL6 increased in all subjects, while IL1 and TNFα increased only in untreated group. Therapeutic Tregs were dependent on IL2, and their survival could be improved by other lymphocytes. CONCLUSIONS: The disease progression was associated with changing proportions of naïve and memory Tregs and slowly increasing proinflammatory activity, which was only partially controlled by the administered Tregs. The therapeutic cells were highly dependent on IL2. We conclude that the therapy should be administered at the earliest to protect the highest possible mass of islets and also to utilize the preserved content of Tregs in the earlier phases of T1DM. Trial registration http://www.controlled-trials.com/ISRCTN06128462 ; registered retrospectively.

[Insulin secretion in the early phase of type 1 diabetes mellitus (T1DM) and new hopes for maintaining it through therapy]. / Insulinosekrecja we wczesnej fazie cukrzycy typu 1 i nowe nadzieje terapeutyczne na jej utrzymanie.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease with a progressive loss of pancreatic beta cell functional mass and subsequent impairment of insulin secretion. At present, the most important factors that help sustain insulin secretion at the early stage of the disease and have the potential to reduce the risk or even prevent long-term diabetic complications include early diagnosis, early initiation of the insulin therapy, an appropriate education of patients and immunotherapeutic interventions. In this paper, the issue of insulin secretion at the early stage of T1DM and some of the most recent research on novel therapies supporting traditional treatments are discussed.