Autologous Regulatory T Cells for the Treatment of Type 1 Diabetes

The immune system is tasked with defending the host from a wide array of pathogens and environmental insults. When uncontrolled, this endeavor may lead to off-target reactivity to self-tissues resulting in multiple autoimmune diseases including type 1 diabetes (T1D). This multifactorial disease process involves over 40 susceptibility genes and is influenced by poorly characterized environmental factors. While many questions regarding the pathogenesis of the disease process remain, it has become increasingly clear that the progression to disease results from a breakdown in the processes that maintain peripheral immune tolerance. The end result of this process is localized tissue inflammation, islet dysfunction, and ultimately the destruction of pancreatic β cells due to concomitant defects in innate and adaptive immune responses. A number of immunomodulatory intervention trials have now been conducted in patients at risk for or with recent onset T1D, often with the goal of restoring immune tolerance by inducing regulatory T cells (Tregs). Unfortunately, many of these trials have fallen short of inducing persistent immune regulation. This shortfall has led to additional efforts to more directly shift the balance from destructive effector T cell (Teff) responses to favor Tregs, including the use of autologous Treg cell therapy. In this review we will discuss key concepts related to the use of autologous Treg cell therapy for the treatment of T1D. Among these topics, we will discuss the notions of genetic control of Treg activity, Treg cellular plasticity, and requirements for antigen-specificity.     

Pathogenic and Regulatory T Cells in Type 1 Diabetes: Losing Self-Control,Restoring It,and How to Take the Temperature

The central role of T cells in type 1 diabetes pathogenesis is well established, but these cells continue to pose numerous challenges in understanding their dynamics and in following their modifications. Important progress has been recently made in pinpointing some novel antigens targeted by pathogenic T cells and the epitope sequences recognized. Studies on the interplay between effector T cells, their regulatory counterparts, and cells of the innate immune system have unraveled novel pathways and may inspire new therapeutic approaches. At the same time, the appreciation of the plasticity of regulatory T cells has raised important caveats on their use for cell-based therapies. Continuous development of T-cell assays exploring both pathogenic and regulatory players will be critical to “take the temperature” of undergoing disease progression and reversal.     

Functional Alterations of Proinflammatory Monocytes by T Regulatory Cells: Implications for the Prevention and Reversal of Type 1 Diabetes

The onset and development of type 1 diabetes (T1D) occurs in genetically predisposed individuals, and is attributed to autoimmune destruction of pancreatic β-cells involving a multitude of immune mechanisms. Defects in immune regulation may play a central role in T1D, involving impaired function and communication of both myeloid and lymphoid cells of the innate and adaptive immune compartments. Dendritic cells and regulatory T (Treg) cells are part of this network, which seem to be hampered in their quest to control and regulate tissue-destructive autoimmunity. Recent studies have shown that in vivo activated CD16- blood monocytes exhibiting proinflammatory features are present in diabetic subjects. These monocytes may govern T cell-mediated immune responses towards the development of tissue-destructive Th1 and Th17 subtypes, and give rise to inflammatory macrophages in tissues. Differential effects of cytokines IFN-γ and IL-4 in the development of inflammatory macrophages, and the distinct developmental pathways of proinflammatory or tissue-repair-associated monocytes suggest that controlling the activity of these monocytes could be part of an immune intervention strategy to prevent T1D. Similarly, strategies to target autoantigens to immature, steady-state dendritic cells could guide the immune response away from Th1 and Th17 immune effectors. This review examines potential approaches to this goal by manipulation of myeloid and lymphoid cell regulatory networks in T1D.     

调节性T细胞在动脉粥样硬化中的研究新进展

CD4+CD25+调节性T细胞是一个具有独特免疫调节功能的T细胞亚群,它能够抑制自身免疫性疾病的发生,维持机体内环境的稳定.动脉粥样硬化作为一种慢性炎症反应,有相关的免疫机制参与其发生发展过程,那么调节性T细胞在动脉粥样硬化发挥怎样的作用,其机制如何,现就这一方面作一综述.     

Evaluation of Exhausted Regulatory T Cells in Preeclampsia

Background: The development of a maternal immune response to fetal antigens and deficiency in regulatory T-cells (Tregs) may lead to preeclampsia. A plausible explanation for the reduced Treg cell function in women with preeclampsia is the presence of exhausted Treg cells which express CD279 or programmed cell death receptor-1 (PD-1), a negative regulatory molecule associated with limited proliferative capacity and reduced immune suppression. Objective: To assess the number of Treg CD4+ CD25high and exhausted Treg CD4+ CD25high CD279+ cells in women with preeclampsia (PE group) and healthy pregnant women (HP group) during the third trimester of pregnancy. Methods: Three-color flow cytometry was used to determine the proportion of Treg and exhausted Treg cells in 40 women in the PE group and 37 women in the HP group. Participants’ blood samples were placed in EDTA blood collection tubes. Peripheral mononuclear cells were separated from the samples and stained with flurochrome-conjugated antibodies against human CD4, CD25 and CD279 markers, and subsequently analyzed by flow cytometry. Results: The PE group had fewer Tregs compared to the HP group (p=0.011). There was a significant increase in the percentage of exhausted PD-1+(CD279) Tregs (p=0.035) in the PE group comparisons with the HP group. Conclusion: The increased number of PD-1 (CD279) molecules on the Treg cells may play a role in preeclampsia, hence it recommendation as a therapeutic target for the disease.     

Genetic Analysis of Type 1 Diabetes: Embryonic Stem Cells as New Tools to Unlock Biological Mechanisms in Type 1 Diabetes

The nonobese diabetic (NOD) mouse has provided an important animal model for studying the mechanism and genetics of type 1 diabetes over the past 30 years. Arguably, the bio-breeding (BB) rat model may be an even closer phenotypic mimic of the typical human disease. A large number of distinct genetic traits which influence diabetes development have been defined through an extraordinary effort, most conspicuously in the mouse model. However, in both NOD and BB models the lack of availability of robust means for experimental genetic manipulation has restricted our understanding of the mechanisms underlying this spontaneous autoimmune disease. Recent developments in the derivation of embryonic stem (ES) cells have the potential to transform this picture. We argue here that targeting of NOD strain ES cells can bring much needed certainty to our present understanding of the genetics of type 1 diabetes in the NOD mouse. In addition, ES cells can play important roles in the future, in both the NOD mouse and BB rat models, through the generation of new tools to investigate the mechanisms by which genetic variation acts to promote diabetes.     

Type 1 Diabetes Therapy Beyond T Cell Targeting: Monocytes,B Cells,and Innate Lymphocytes

Recent clinical trials, investigating type 1 diabetes (T1D), have focused mainly on newly diagnosed individuals who have developed diabetes. We need to continue our efforts to understand disease processes and to rationally design interventions that will be safe and specific for disease, but at the same time not induce undesirable immunosuppression. T cells are clearly involved in the pathogenesis of T1D, and have been a major focus for both antigen-specific and non-antigen-specific therapy, but thus far no single strategy has emerged as superior. As T1D is a multifactorial disease, in which multiple cell types are involved, some of these pathogenic and regulatory cell pathways may be important to consider. In this review, we examine evidence for whether monocytes, B cells, and innate lymphocytes, including natural killer cells, may be suitable targets for intervention.     

Regulatory T Cells in children with intestinal parasite infection

Chronic intestinal parasite infection can induce both persistent immune activation and defective responsiveness of T cells. This study aimed to assess the number and function of T regulatory (Treg) cells in children with intestinal parasite infection. We have studied the peripheral blood from 93 children, 53 of them parasitized with protozoa, helminths, or both; the remainder were non parasitized, healthy controls. The number and function of CD4⁺ CD25^high and CD4⁺ Foxp3⁺ cells were similar in parasitized and control children. In contrast, there was a significant increase in the levels of CD3⁺ CD69⁺, CD4⁺ CTLA-4⁺, and CD8⁺ CD28⁻ T cells in helminth infected children. Moreover, some of these patients showed a diminished response to CD3/CD28 stimulation in comparison with the control children. Our data strongly suggest that whilst Treg cells are not affected by intestinal parasite infection, CD3⁺ CD69⁺, CD4⁺ CTLA-4⁺ and CD8⁺ CD28⁻ lymphocytes may play an important, but as yet undetermined role in the diminished immune competence observed in parasitized children.     

吡喹酮治疗前后小鼠脾细胞中CD4+CD25+Foxp3+T细胞变化及其意义

目的 分析吡喹酮治疗前后小鼠脾细胞中CD4+CD25+Foxp3+T细胞的变化.探讨其与血吸虫感染后肝脏免疫病理反应的关系.方法 54只BALB/C小鼠随机分为3组,阳性感染组、吡喹酮治疗组(感染后第6周顿服吡喹酮治疗)及阴性对照组.于感染后第3、6、9周分批处死小鼠,取脾单细胞悬液,经过常规表面染色、打孔、固定、胞内染色后,用流式细胞仪检测分析CD4+CD25+Foxp3+调节性T细胞的变化.结果 感染组第3、6、9周脾细胞中CD4+CD25+Foxp3+T细胞的数量分别为(2.57 4±0.13)%、(1.77±0.21)%、(1.10±0.05)%,其含量逐步下降(P<0.05),治疗组分别为(2.61±0.12)%、(1.82±0.14)%、(1.76±0.11)%,经治疗后其含量变化差异无统计学意义(P>0.05),阴性组差异无统计学意义(P>0.05);CD4+CD25+Foxp3-T细胞和CD4+CD25-Foxp3+T细胞在各组中的含量差异均无统计学意义(P均>0.05)结论CD4+CD25+Foxp3+T细胞在日本血吸虫感染中具有免疫抑制作用,与血吸虫虫卵肉芽肿慢性病变具有相关性,吡喹酮可以通过抑制CD4+CD25+Foxp3+T降低以减缓血吸虫肉芽肿炎性病变的程度.     

The Expanding Role of Natural Killer Cells in Type 1 Diabetes and Immunotherapy

Treatments for autoimmune diseases including type 1 diabetes (T1D) are aimed at resetting the immune system, especially its adaptive arm. The innate immune system is often ignored in the design of novel immune-based therapies. There is increasing evidence for multiple natural killer (NK) subpopulations, but their role is poorly understood in autoimmunity and likely is contributing to the controversial role reported for NKs. In this review, we will summarize NK subsets and their roles in tolerance, autoimmune diabetes, and immunotherapy.     

Th17细胞／调节性T细胞平衡与自身免疫性肝病

最新研究发现了与Th1和Th2细胞亚群不同的新的活化CD4^＋T细胞亚群——调节性T细胞（Treg细胞）和Th17细胞,两者在发育和功能上互补,Th17细胞／Treg细胞平衡在自身免疫性肝病的发生、发展中发挥重要作用。本文就Th17细胞／Treg细胞平衡在自身免疫性肝病中的作用作一综述。     

The Impact of Vitamin D on Regulatory T Cells

Epidemiologic studies highlight the increasing prevalence of vitamin D deficiency and insufficiency and its association with an increased risk of autoimmune diseases and poor respiratory function, including asthma. These and additional studies have raised interest in the immunomodulatory properties of vitamin D beyond its well-established role in calcium homeostasis and bone health. Vitamin D has been shown to influence the function of cells intrinsic to innate and adaptive immunity. This review discusses recent evidence that vitamin D promotes—both directly and indirectly—regulatory or suppressor T-cell populations with the capacity to inhibit inappropriate immune responses that cause disease, suggesting that this property may in part underpin the epidemiologic findings.     

Regulatory T Cells in SLE: Biology and Use in Treatment

T regulatory cells (Tregs) represent a phenotypically and functionally heterogeneous group of lymphocytes that exert immunosuppressive activities on effector immune responses. Tregs play a key role in maintaining immune tolerance and homeostasis through diverse mechanisms which involve interactions with components of both the innate and adaptive immune systems. As in many autoimmune diseases, Tregs have been proposed to play a relevant role in the pathogenesis of systemic lupus erythematosus (SLE), an autoimmune disease characterized by a progressive breakdown of tolerance to self-antigens and the presence of concomitant hyperactive immune responses. Here, we review how Tregs dysfunction in SLE has been manipulated experimentally and preclinically in the attempt to restore, at last in part, the immune disturbances in the disease.     

Hypoglycemia in Type 1 Diabetes Mellitus

Spontaneous hypoglycemia is uncommon in the general (nondiabetic) population, but iatrogenic hypoglycemia is rife in patients with type 1 diabetes mellitus, among whom hypoglycemia constitutes a barrier to optimal glycemic control. The obligate dependence on exogenous insulin, together with the current imperfection in insulin therapies, generates degrees of blood glucose fluctuations that often exceed physiological boundaries in these patients. Downward swings in blood glucose levels, if sustained, result in hypoglycemia and significant morbidity and mortality. Hypoglycemia in type 1 diabetes indicates an imbalance between caloric supply and glucose use in response to insulin or exercise. Counterregulatory mechanisms that auto-correct iatrogenic hypoglycemia often become progressively impaired in these patients. This defective counterregulation, together with the imperfections in insulin delivery, set the stage for significant morbidity from iatrogenic hypoglycemia. Recurrent episodes of iatrogenic hypoglycemia induce a state of hypoglycemia unawareness and defective counterregulation, which defines the syndrome of hypoglycemia-associated autonomic failure (HAAF). The reduced awareness of, and counterregulatory responses to, hypoglycemia in patients with HAAF lead to worsening episodes of severe hypoglycemia. Approaches to the prevention of hypoglycemia include glucose monitoring, patient education, meal planning, and medication adjustment. In patients with HAAF, scrupulous avoidance of iatrogenic hypoglycemia may restore the symptomatic and counterregulatory responses to hypoglycemia. Behavioral training focusing on recognition of the more subtle symptoms and signs of evolving hypoglycemia may be beneficial to some patients with HAAF. A methodical search for the pattern and etiology of iatrogenic hypoglycemia is a prerequisite for the identification of the best preventive approach. With proper education, patients with type 1 diabetes and their physicians can learn to prevent or minimize the risk of hypoglycemia while pursuing excellence in glycemic control.