Glucocorticoid hormone differentially modulates the in vitro expansion and cytokine profile of thymic and splenic Treg cells

Objective

Functional disturbances in regulatory T cells (Treg) have been described in autoimmune diseases, and their potential therapeutic use is intensively studied. Our goal was to investigate the influence of glucocorticoid hormone on the in vitro differentiation of Treg cells from thymic and splenic CD4⁺ T cells under different conditions to establish methods for generating stable and functionally suppressive iTregs for future use in adoptive transfer experiments.

Peripherally induced regulatory T cells contribute to the control of autoimmune diabetes in the NOD mouse model

Type 1 diabetes (T1D) results from the autoimmune destruction of pancreatic beta cells and is partly caused by deficiencies in the Foxp3⁺ regulatory T‐cell (Treg) compartment. Conversely, therapies that increase Treg function can prevent autoimmune diabetes in animal models. The majority of Tregs develop in the thymus (tTregs), but a proportion of Foxp3⁺ Tregs is generated in the periphery (pTregs) from Foxp3^?CD4⁺ T‐cell precursors. Whether pTregs play a distinct role in T1D has not yet been explored. We report here that pTregs are a key modifier of disease in the nonobese diabetic (NOD) mouse model for T1D. We generated NOD mice deficient for the Foxp3 enhancer CNS1 involved in pTreg induction. We show that CNS1 knockout decreased the frequency of pTregs and increased the risk of diabetes. Our results show that pTregs fulfill an important non‐redundant function in the prevention of beta cell autoimmunity that causes T1D.     

Asthma Prevention by Lactobacillus Rhamnosus in a Mouse Model is Associated With CD4+CD25+Foxp3+ T Cells

Purpose

Probiotic bacteria can induce immune regulation or immune tolerance in allergic diseases. The underlying mechanisms have been recently investigated, but are still unclear. The aim of this study was to evaluate the protective effects of the probiotic Lactobacillus rhamnosus (Lcr35) in a mouse model of asthma and to identify its mechanism of action.

Methods

Lcr35 was administered daily by the oral route at a dosage of 1×10⁹ CFU/mouse in BALB/c mice for 7 days before the first sensitization. Clinical parameters and regulatory T (Treg) cells were examined. The role of CD4⁺CD25⁺Foxp3⁺ Treg cells was analyzed using a Treg cell-depleting anti-CD25 monoclonal antibody (mAb).

Results

Airway hyperresponsiveness, total IgE production, pulmonary eosinophilic inflammation, and splenic lymphocyte proliferation were suppressed after Lcr35 treatment. Th1 (IFN-γ) and Th2 (IL-4, IL-5, and IL-13) cytokines in the serum were suppressed, and the percentage of CD4⁺CD25⁺Foxp3⁺ Treg cells in the spleen was significantly increased in the Lcr35 treatment group. Anti-CD25 mAb administration abolished the protective effects of Lcr35, indicating that CD4⁺ CD25⁺Foxp3⁺ Treg cells are essential in mediating the activity of Lcr35.

Conclusions

Oral administration of Lcr35 attenuated the features of allergic asthma in a mouse model and induced immune regulation by a CD4⁺CD25⁺Foxp3⁺ Treg cell-mediated mechanism.     

Vimentin immunohistochemical expression as a prognostic factor in gastric cancer: A meta-analysis

Objective

The prognostic value of vimentin expression in Gastric Cancer (GC) has been assessed for years while the results are still in dispute. Thus, we performed a meta-analysis to determine the effect of vimentin immunohistochemical (IHC) expression on the prognosis of GC.

Differentiation of human dendritic cell subsets for immune tolerance induction

Objectives

Since no further progress was achieved, in order to improve the long-term organ transplantation outcome, the immune tolerance appears as an interesting therapeutic goal. Dendritic cells (DCs) are specialized cells participating in the homeostasis of the immune response. Moreover, subsets of DCs, identified in humans, appear to have their respective competences in immune response modulation. Our objective is to purify from PBMC or to differentiate DC subsets from monocytes using several strategies and evaluate their IL10 secretion.

Influenza A virus-induced thymus atrophy differentially affects dynamics of conventional and regulatory T-cell development in mice

Foxp3⁺ Treg cells, which are crucial for maintenance of self-tolerance, mainly develop within the thymus, where they arise from CD25⁺Foxp3^– or CD25^–Foxp3⁺ Treg cell precursors. Although it is known that infections can cause transient thymic involution, the impact of infection-induced thymus atrophy on thymic Treg (tTreg) cell development is unknown. Here, we infected mice with influenza A virus (IAV) and studied thymocyte population dynamics post infection. IAV infection caused a massive, but transient thymic involution, dominated by a loss of CD4⁺CD8⁺ double-positive (DP) thymocytes, which was accompanied by a significant increase in the frequency of CD25⁺Foxp3⁺ tTreg cells. Differential apoptosis susceptibility could be experimentally excluded as a reason for the relative tTreg cell increase, and mathematical modeling suggested that enhanced tTreg cell generation cannot explain the increased frequency of tTreg cells. Yet, an increased death of DP thymocytes and augmented exit of single-positive (SP) thymocytes was suggested to be causative. Interestingly, IAV-induced thymus atrophy resulted in a significantly reduced T-cell receptor (TCR) repertoire diversity of newly produced tTreg cells. Taken together, IAV-induced thymus atrophy is substantially altering the dynamics of major thymocyte populations, finally resulting in a relative increase of tTreg cells with an altered TCR repertoire.     

LncRNA TP73-AS1 accelerates tumor progression in gastric cancer through regulating miR-194-5p/SDAD1 axis

Background

Long noncoding RNAs (lncRNAs) have been considered as significant regulators in many cancer progression, such as proliferation, invasion and other path of evolution. Nevertheless, we have not had a grasp of the role of lncRNA TP73-AS1 in gastric cancer (GC).

Induced and thymus‐derived Foxp3+ regulatory T cells share a common niche

Foxp3⁺ regulatory T (Treg) cells, which play a central role for the maintenance of immune homeostasis and self‐tolerance, are known to be both generated in the thymus (thymus‐derived, tTreg cells) and in the periphery, where they are converted from conventional CD4⁺ T cells (induced Treg (iTreg) cells). Recent data suggest a division of labor between these two Treg‐cell subsets since their combined action was shown to be essential for protection in inflammatory disease models. Here, using the transfer colitis model, we examined whether tTreg cells and iTreg cells fill different niches within the CD4⁺ T‐cell compartment. When naive T cells were co‐transferred with either pure tTreg cells or with a mixture of tTreg cells and iTreg cells, induction of Foxp3⁺ Treg cells from naive T cells was not hampered by preoccupation of the Treg‐cell niche. Using neuropilin‐1 (Nrp1) as a surface marker to separate tTreg cells and iTreg cells, we demonstrate that tTreg cells and iTreg cells alone can completely fill the Treg‐cell niche and display comparable TCR repertoires. However, when transferred together Nrp1⁺ tTreg cells outcompeted Nrp1^? iTreg cells and dominated the Treg‐cell compartment. Taken together, our data suggest that tTreg cells and iTreg cells share a common peripheral niche.     

Expression of IL-7 receptor in human peripheral regulatory T cells

Introduction

Regulatory T cells (Tregs, CD4 + CD25^high Foxp3⁺) play a crucial role in allergy and other inflammatory diseases. However, the isolation of viable Tregs on the basis of intracellular expression of specific Forkhead Box Protein P3 (Foxp3) is difficult. In this study we checked if the expression of IL-7 receptor (CD127) on the Tregs could be a useful marker for isolation of viable Treg Foxp3⁺ cells.

Material and methods

Twenty-five patients sensitized to grass pollen with allergic rhinitis (AR) and ten healthy subjects were included. We compared Foxp3 expression in different CD4⁺ T cell subsets by flow cytometry and we assessed the relationship between the expression of Foxp3 and CD127 within regulatory T cells.

Results

Within the CD⁴+ lymphocytes 3.68 ±2.0% showed expression of Foxp3, 51.82 ±8.03% of CD4⁺CD25^high were Foxp3 positive (Foxp3⁺), whereas 82.12 ±5.4% of CD4⁺CD25^highCD127^low were Foxp3⁺. High intracellular expression of Foxp3 correlated with low superficial CD127 expression (r = 0.42, p = 0.017). There were no significant differences regarding the analysed markers between AR patients and healthy controls.

Conclusions

Regulatory T cells may be purified from the fresh peripheral blood as viable regulatory Foxp3 bright cells using CD4, high expression of CD25 and low expression of CD127 antigen.     

Recirculating IL-1R2+ Tregs fine-tune intrathymic Treg development under inflammatory conditions

The vast majority of Foxp3⁺ regulatory T cells (Tregs) are generated in the thymus, and several factors, such as cytokines and unique thymic antigen-presenting cells, are known to contribute to the development of these thymus-derived Tregs (tTregs). Here, we report the existence of a specific subset of Foxp3⁺ Tregs within the thymus that is characterized by the expression of IL-1R2, which is a decoy receptor for the inflammatory cytokine IL-1. Detailed flow cytometric analysis of the thymocytes from Foxp3^hCD2xRAG1^GFP reporter mice revealed that the IL-1R2⁺ Tregs are mainly RAG1^GFP– and CCR6⁺CCR7^–, demonstrating that these Tregs are recirculating cells entering the thymus from the periphery and that they have an activated phenotype. In the spleen, the majority of IL-1R2⁺ Tregs express neuropilin-1 (Nrp-1) and Helios, suggesting a thymic origin for these Tregs. Interestingly, among all tissues studied, the highest frequency of IL-1R2⁺ Tregs was observed in the thymus, indicating preferential recruitment of this Treg subset by the thymus. Using fetal thymic organ cultures (FTOCs), we demonstrated that increased concentrations of exogenous IL-1β blocked intrathymic Treg development, resulting in a decreased frequency of CD25⁺Foxp3⁺ tTregs and an accumulation of CD25⁺Foxp3⁻ Treg precursors. Interestingly, the addition of IL-1R2⁺ Tregs, but not IL-1R2⁻ Tregs, to reaggregated thymic organ cultures (RTOCs) abrogated the IL-1β-mediated blockade, demonstrating that these recirculating IL-1R2⁺ Tregs can quench IL-1 signaling in the thymus and thereby maintain thymic Treg development even under inflammatory conditions.     

Exploring beliefs on diabetes treatment adherence among Dutch type 2 diabetes patients and healthcare providers

Objective

Despite well-known beneficial effects, adherence to core elements of diabetes treatment is suboptimal. This study, conducted in the Netherlands, aimed to explore if and how treatment adherence success factors are applied in diabetes consultations, and to explore salient personal beliefs about type 2 diabetes treatment including both healthy lifestyle adaptations and pharmacotherapy.

Clinicopathological and prognostic significance of C/EBP homologous protein (CHOP) in advanced gastric cancer

Background

Few studies have reported the clinical and prognostic significance of C/EBP homologous protein (CHOP) in advanced gastric cancer (GC). Therefore, the present study investigated the expression of CHOP in advanced GC patients to determine its potential prognostic role.

Daratumumab: Therapeutic asset,biological trap!

Objectives

Recently, daratumumab has been included in the therapeutic strategies for myeloma patients. This molecule is an antibody directed against CD38, strongly expressed on plasma cells. Nevertheless, as CD38 is also present on erythrocyte membrane, daratumumab interferes with immunohaematological tests, complicating the selection of compatible blood.

Creating a synergy effect: A cluster randomized controlled trial testing the effect of a tailored multimedia intervention on patient outcomes

Objective

Improving adherence is a challenge and multiple barriers are likely to explain non-adherence. These barriers differ per patient and over course of the regimen. Hence, personalized interventions tailored to the specific barriers are needed. In a theoretical and evidence-based Tailored Multimedia Intervention, technology (online preparatory assessment, text messaging) was used as an add-on to a tailored counseling session (learned during a communication skills training), with the expectation of synergistic effects.