Natural and induced regulatory T cells: targets for immunotherapy of autoimmune disease and allergy

Recent advances in immunology have greatly increased our understanding of immunological tolerance. In particular, there has been a resurgence of interest in mechanisms of immune regulation. Immune regulation refers to the phenomenon, previously known as immune suppression, by which excessive responses to infectious agents and hypersensitivities to otherwise innocuous antigens such as self antigens and allergens are avoided. We now appreciate that various distinct cell types mediate immune suppression and that some of these may be induced by appropriate administration of antigens, synthetic peptides and drugs of various types. The induction of antigen specific immunotherapy for treatment of autoimmune and allergic diseases remains the 'holy grail' for treatment of these diseases. This goal comes ever closer as understanding of the mechanisms of immune suppression and in particular antigen specific immunotherapy increases. Here we review evidence that immune suppression is mediated by various different subsets of CD4 T cells.     

调节性T细胞在骨破坏中的作用

代谢性骨破坏疾病如关节炎、骨质疏松,临床主要表现为骨骼的功能障碍,由于其机制目前仍未完全阐明,临床缺乏有效的治疗方法。调节性T细胞(Tregs)是一群具有免疫抑制功能的T细胞亚群,在免疫系统中起重要作用,体外实验证实Tregs抑制破骨细胞(OC)的分化和功能。在动物模型中,进一步证实Tregs通过抑制破骨细胞的发生而阻断骨质破坏的发生。该文对有关Tregs在骨破坏中的作用最新进展作一综述,以增进对Tregs生物学功能和病理作用的了解。     

Arachidonic acid signaling in pathogenesis of allergy: therapeutic implications

In recent years, significant progress has been made in understanding the involvement of pro-inflammatory lipidic mediators in the pathogenesis of allergic diseases. The most relevant lipidic mediator is arachidonic acid and its metabolites. Arachidonic acid is the precursor for biosynthesis of eicosanoids, potent mediators of inflammation that have been implicated in the pathogenesis of diverse disease processes. Eicosanoids are mainly synthesized by the action of cyclo-oxygenase (prostaglandin endoperoxide synthase) that generates prostaglandins and thromboxane, and 5-lipoxygenase, which leads to the production of leukotrienes. In addition, 12- and 15-lipoxygenase are found in mammalian systems. The activity of these enzymes results in the formation of different hydroxyeicosatetraenoic acids, but their functions in vivo have not been clearly established in normal or pathological states. Since several arachidonic acid metabolites clearly play an important role in allergic response, a substantial effort has been directed to understanding the cellular and molecular aspects of these pathways and their pharmacological modulation. This review summarizes some of these aspects based on our current knowledge of the involvement of arachidonic metabolism in the pathogenesis of allergic diseases and outlines the potential therapeutic opportunities that can result from the modulation of these metabolites.     

The therapeutic potential of regulatory T cells for the treatment of autoimmune disease

Introduction: Immune tolerance remains the holy grail of therapeutic immunology in the fields of organ and tissue transplant rejection, autoimmune diseases, and allergy and asthma. We have learned that FoxP3⁺CD4⁺ regulatory T cells play a vital role in both the induction and maintenance of self-tolerance.

Areas covered: In this opinion piece, we highlight regulatory T cells (Treg) cell biology and novel immune treatments to take advantage of these cells as potent therapeutics. We discuss the potential to utilize Treg and Treg-friendly therapies to replace current general immunosuppressives and induce tolerance as a path towards a drug-free existence without associated toxicities.

Expert opinion: Finally, we opine on the fact that biomedicine sits on the cusp of a new revolution: the use of human cells as versatile therapeutic engines. We highlight the challenges and opportunities associated with the development of a foundational cellular engineering science that provides a systematic framework for safely and predictably regulating cellular behaviors. Although Treg therapy has become a legitimate clinical treatment, development of the therapy will require a better understanding of the underlying Treg biology, manufacturing advances to promote cost effectiveness and combinations with other drugs to alter the pathogenicity/regulatory balance.     

Role of cytokines in psychopathology: therapeutic implications

Cytokines can influence physiological functions such as sleep and food intake; they also interact with a number of neurotransmitters and second messengers in the brain. Cytokines are involved in a number of infectious, inflammatory, neoplastic, metabolic and degenerative illnesses. They also have been implicated in some psychiatric disorders, including 1) depressive and anxiety disorders; 2) schizophrenic disorders (chronic and acute); 3) autistic disorder; 4) eating disorders; and 5) obsessive-compulsive disorder. Alterations in cytokine peptide/receptor production or function in major psychiatric disorders are of special interest to researchers in the field. Exogenous administration of cytokines may be of therapeutic value in disorders in which the cytokine system may be disturbed. In some brain disorders of defined neuropathology, some cytokines have been found clinically useful. Such a development has yet to occur in the treatment of psychiatric disorders; however, some limited and very preliminary observations suggest that manipulation of the cytokine network may be of potential value in the treatment of some psychiatric disorders. Considering the human and economic costs of major psychiatric disorders, alteration of the cytokine network as a potential therapeutic tool is worthy of consideration and investigation.     

Taming regulatory T cells by autologous T cell immunization: A potential new strategy for cancer immune therapy

Regulatory T cells (Tregs) play important roles in the maintenance of immune homeostasis, and is also involved in tumor immune tolerance. Dampening or elimination of Treg functions has been shown to lead to enhanced immune responses against tumors, and thus inhibition of tumor growth. Recently, we have developed a new immunization scheme, referred to as irradiated mitogen-activated autologous T cell vaccination (ATCV), and shown that such immunization could significantly enhance anti-tumor immunity in vivo. Mechanistically, the enhanced anti-tumor response appears to be due to reduced Treg functions and inhibition of activation-induced cell death (AICD) in effector T cells. Thus, ATCV may constitute a novel strategy in cancer immune therapy.     

Role of MMPs in metastatic dissemination: implications for therapeutic advances

Matrix metalloproteinases (MMPs) have been implicated in both normal and pathologic processes. In cancer in particular, in vitro and animal studies showed an involvement of MMPs in many stages of cancer progression. This led to the development of MMP inhibitors that in most cases failed in clinical trials. In this review we go over the role of MMPs in the different stages of cancer progression and try to understand why the early generation of MMP inhibitors failed. The analysis of the lessons from this first experience, plus the review of the current knowledge that shows that MMPs may be pro-or anti-tumorigenic may set the stage for a future success for this therapeutic strategy in cancer.     

CD4+CD25+ regulatory T cells: a therapeutic target for liver diseases

Background: Regulatory T cells (T_regs) have been shown to play an important role in maintaining peripheral immune homeostasis by suppressing autoreactive and allergen-specific T cells and turning off the immune response after the pathogen has been cleared. However, in certain situations T_regs can impair effective immunity to some pathogens and tumour cells. Objective: To review the role of T_regs in liver pathology and to assess the potential to enhance or inhibit their function as applied to the treatment of liver disease. Methods: The literature was reviewed using standard indexing terms and incorporating publications up to and including those published in 2007. Results/conclusions: T_regs are therapeutic targets for modulation in autoimmune disease and may provide new opportunities for application to human liver conditions.     

供体特异性调节性T细胞在肝移植免疫耐受中的意义

免疫耐受是器官移植的终极目标。尽管目前对于移植术后免疫耐受的探索很多,但大多处于试验阶段,应用于临床的方案甚少。对调节性 T细胞诱导免疫耐受的研究较为透彻,但供体特异性调节性 T细胞因其比例较低、制备困难,在移植免疫中的研究相对较少。本文从调节性 T细胞的共性、供体特异性调节性 T细胞的抑制功能、体外培养技术、胸腺移植等方面出发,总结供体特异性调节性 T 细胞在近年的研究热点,以期为临床研究提供新思路。     

Modulation of regulatory T cells by intranasal allergen immunotherapy in an experimental rat model of airway allergy

Allergic airway diseases such as asthma and allergic rhinitis are increasing in prevalence worldwide. The theory of an altered Th1/Th2 balance in allergic diathesis has recently been termed a “procrustean paradigm” as it failed to explain many preclinical findings. Regulatory T cells (Treg) have now been shown to be critical in T-cell homeostasis and in the maintenance of peripheral tolerance to allergens. Allergen specific immunotherapy (SIT) has been shown to induce regulatory T cells in allergic patients. Among various types of SIT, intranasal immunotherapy had not been studied in detail for the treatment of allergic airway diseases. So, there was a need to study the contribution of regulatory T cells and their mechanistic pathways following intranasal immunotherapy in-vivo. It had been previously shown that intranasal allergen immunotherapy using Alstonia scholaris pollen extract abrogates allergic airway inflammation with decline in IgE and Th2 cytokine levels. The present study for the first time offers a multi-targeted approach towards attenuation of airway allergy by the generation of CD4 + CD25 + Foxp3 + T cells and other subsets of Treg cells like Tr1 cells, Th3 cells, CTLA4 + Treg cells, and also modulation of various Treg cell surface molecules like GITR, OX40, CD39 and CD73 by intranasal immunotherapy in the same animal model. This animal experiment will thus help to chart out newer molecular targets for treating allergic asthma or rhinitis.     

Targeting regulatory T cells for anticancer therapy

Regulatory T-cells (Tregs) comprise a group of either thymically derived or peripherally induced suppressor CD4+ cells involved in the control of effector T-cells against both self- and foreign-antigens. They are found increased in tumor tissues and are thought to be involved in pathogenesis of cancer by providing tumors with a mechanism to evade immune detection and destruction. Despite the fact that mechanisms of Tregs regulation are still in progress, efforts are made aiming to develop approaches to deplete or inhibit tumor-associated Tregs function. This could lead to restore antitumor immunity and emerging strategies for therapeutic vaccination, and immunotherapeutic targeting of Tregs with specific drugs are underway.     

Role of regulatory T cells in the induction of atopic dermatitis by immunosuppressive chemicals

Immunosuppressive environmental chemicals may exacerbate allergic diseases, including atopic dermatitis (AD). We examined the effects of the immunosuppressive environmental chemicals methoxychlor, parathion, piperonyl butoxide, dexamethasone, and cyclophosphamide on picryl-chloride-induced AD in NC/Nga mice. Mice were orally exposed (age, 5 weeks) to these chemicals; during their sensitization and challenge (age, 8-12 weeks) with picryl chloride, we measured ear thickness and scored skin dryness, erythema, edema, and wounding. After the challenge, we analyzed dermatitis severity and cytokine gene expression in the pinna, serum levels of IgE and IgG2a, T- and B-cell numbers and cytokine production in auricular lymph nodes, and counted splenic regulatory T cells. Exposure to environmental immunosuppressive chemicals markedly increased dermatitis severity and gene expression in the pinna; serum IgE and IgG2a levels; and numbers of helper T cells and IgE-positive B cells, production of Th1 and Th2 cytokines, and production of IgE in auricular lymph-node cells and markedly decreased the numbers of splenic regulatory T cells. Prior exposure to immunosuppressive environmental chemicals aggravates AD; a decrease in the numbers of regulatory T cells may influence this process.     

Role of free radicals in the neurodegenerative diseases: therapeutic implications for antioxidant treatment

Free radicals and other so-called 'reactive species' are constantly produced in the brain in vivo. Some arise by 'accidents of chemistry', an example of which may be the leakage of electrons from the mitochondrial electron transport chain to generate superoxide radical (O2*-). Others are generated for useful purposes, such as the role of nitric oxide in neurotransmission and the production of O2*- by activated microglia. Because of its high ATP demand, the brain consumes O2 rapidly, and is thus susceptible to interference with mitochondrial function, which can in turn lead to increased O2*- formation. The brain contains multiple antioxidant defences, of which the mitochondrial manganese-containing superoxide dismutase and reduced glutathione seem especially important. Iron is a powerful promoter of free radical damage, able to catalyse generation of highly reactive hydroxyl, alkoxyl and peroxyl radicals from hydrogen peroxide and lipid peroxides, respectively. Although most iron in the brain is stored in ferritin, 'catalytic' iron is readily mobilised from injured brain tissue. Increased levels of oxidative damage to DNA, lipids and proteins have been detected by a range of assays in post-mortem tissues from patients with Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis, and at least some of these changes may occur early in disease progression. The accumulation and precipitation of proteins that occur in these diseases may be aggravated by oxidative damage, and may in turn cause more oxidative damage by interfering with the function of the proteasome. Indeed, it has been shown that proteasomal inhibition increases levels of oxidative damage not only to proteins but also to other biomolecules. Hence, there are many attempts to develop antioxidants that can cross the blood-brain barrier and decrease oxidative damage. Natural antioxidants such as vitamin E (tocopherol), carotenoids and flavonoids do not readily enter the brain in the adult, and the lazaroid antioxidant tirilazad (U-74006F) appears to localise in the blood-brain barrier. Other antioxidants under development include modified spin traps and low molecular mass scavengers of O2*-. One possible source of lead compounds is the use of traditional remedies claimed to improve brain function. Little is known about the impact of dietary antioxidants upon the development and progression of neurodegenerative diseases, especially Alzheimer's disease. Several agents already in therapeutic use might exert some of their effects by antioxidant action, including selegiline (deprenyl), apomorphine and nitecapone.     

Garp as a therapeutic target for modulation of T regulatory cell function

Introduction: Foxp3⁺ T regulatory cells (Tregs) play critical roles in immune homeostasis primarily by suppressing many aspects of the immune response. Tregs uniquely express GARP on their cell surface and GARP functions as a delivery system for latent TGF-β. As Treg-derived TGF-β may mediate the suppressive functions of Tregs, GARP may represent a target to inhibit Treg suppression in cancer or augment suppression in autoimmunity.

Areas covered: This article will focus on 1) the role of Treg-derived TGF-β in the suppressive activity of Treg, 2) the cellular and molecular regulation of expression of GARP on mouse and human Tregs, 3) the role of integrins in the activation of latent-TGF-β/GARP complex, 4) an overview of our present understanding of the function of the latent-TGF-β/GARP complex.

Expert opinion: Two approaches are outlined for targeting the L-TGF-β1/GARP complex for therapeutic purposes. Tregs play a major role in suppressive effector T cell responses to tumors and TGF-β1 may be a major contributor to this process. One approach is to specifically block the production of active TGF-β1 from Tregs as an adjunct to tumor immunotherapy. The second approach in autoimmunity is to selectively enhance the production of TGF-β by Tregs at sites of chronic inflammation.     

Pre-differentiated Th1 and Th17 effector T cells in autoimmune gastritis: Ag-specific regulatory T cells are more potent suppressors than polyclonal regulatory T cells

Naïve antigen-specific CD4⁺ T cells (TxA23) induce autoimmune gastritis when transferred into BALB/c nu/nu mice. Transfer of in vitro pre-differentiated Th1 or Th17 TxA23 effector T cells into BALB/c nu/nu recipients induces distinct histological patterns of disease. We have previously shown that co-transfer of polyclonal naturally occurring Treg (nTreg) suppressed development of Th1-, but not Th17-mediated disease. Therefore, we analysed the suppressive capacity of different types of Treg to suppress Th1- and Th17-mediated autoimmune gastritis. We compared nTreg with polyclonal TGFβ-induced WT Treg (iTreg) or TGFβ-induced antigen-specific TxA23 iTreg in co-transfer experiments with Th1 or Th17 TxA23 effector T cells. 6 weeks after transfer in vitro pre-differentiated TxA23 Th1 and Th17 effector cells induced destructive gastritis. Th1-mediated disease was prevented by co-transfer of nTreg and also antigen-specific iTreg, whereas WT iTreg did not show an effect. However, Th17-mediated disease was only suppressed by antigen-specific iTreg. Pre-activation of nTreg in vitro prior to transfer did not increase their suppressive activity in Th17-mediated gastritis. Thus, antigen-specific iTreg are potent suppressors of autoimmune gastritis induced by both, fully differentiated Th1 and Th17 effector cells.     

HIV-1-induced depletion of CD4+ T cells in the gut: mechanism and therapeutic implications

The mechanism of CD4+ T cell depletion remains a central unresolved issue in AIDS research. Recent studies have examined the massive depletion of CD4+ T cells observed in macaque models of acute HIV infection. A key question is whether the observed CD4+ T cell death is due to direct consequences of viral infection and to indirect mechanisms including increased expression of mediators of T-cell apoptosis. The therapeutic implications of the early CD4+ T cell loss are discussed.