IL-6 in autoimmune disease and chronic inflammatory proliferative disease

Interleukin 6 (IL-6), which was originally identified as a B-cell differentiation factor, is now known to be a multifunctional cytokine that regulates the immune response, hematopoiesis, the acute phase response, and inflammation. Deregulation of IL-6 production is implicated in the pathology of several disease processes. The expression of constitutively high levels of IL-6 in transgenic mice results in fatal plasmacytosis, which has been implicated in human multiple myeloma. Increased IL-6 levels are also observed in several diseases, including rheumatoid arthritis (RA), systemic-onset juvenile chronic arthritis (JCA), osteoporosis, and psoriasis. IL-6 is critically involved in experimentally induced autoimmune disease, such as antigen-induced arthritis (AIA), and experimental allergic encephalomyelitis. All these clinical data and animal models suggest that IL-6 plays critical roles in the pathogenesis of autoimmune diseases. Here we review the evidence for the involvement of IL-6 in the pathophysiology of autoimmune diseases and chronic inflammatory proliferative diseases (CIPD) and discuss the possible molecular mechanisms of its involvement.     

Effector T cells in rheumatoid arthritis: lessons from animal models

The development of an immune response to self antigens drives naive T cells to differentiate into subsets of CD8(+) and CD4(+) effector cells including T(H)1, T(H)2, cells and the more recently described T(H)17, and regulatory T cells (T(reg)). Rheumatoid arthritis is an autoimmune disease that engages an uncontrolled influx of inflammatory cells to the joints, eventually leading to joint damage. The role that effector T cells play in the local or systemic maintenance of, or protection against, inflammation and subsequent joint damage is now becoming better understoodthrough the use of animal models. In this review, we will explore the different animal models of RA, and their contribution to elucidating the role that effector T cells play in the regulation, induction, and maintenance of inflammatory joint disease. This understanding will aid in the design of more effective therapeutic strategies for rheumatoid arthritis and other autoimmune disorders.     

Mesenchymal stem cells in the treatment of inflammatory and autoimmune diseases in experimental animal models

Multipotent mesenchymal stromal cells [also known as mesenchymal stem cells(MSCs)] are currently being studied as a cell-based treatment for inflammatory disorders. Experimental animal models of human immune-mediated diseases have been instrumental in establishing their immunosuppressive properties. In this review, we summarize recent studies examining the effectiveness of MSCs as immunotherapy in several widely-studied animal models, including type 1 diabetes, experimental autoimmune arthritis, experimental autoimmune encephalomyelitis, inflammatory bowel disease, graft-vs-host disease, and systemic lupus erythematosus. In addition, we discuss mechanisms identified by which MSCs mediate immune suppression in specific disease models, and potential sources of functional variability of MSCs between studies.     

Animal models of type I allergy using recombinant allergens

Various animal models including guinea pigs, monkeys, dogs, rats, and mice have been established in an attempt to provide insights into the complex immunological and pathophysiological mechanisms of human type I allergic diseases. The detailed knowledge of the murine genome, the various components of the murine immune system, and the generation of engineered mice has made the murine system the most attractive among all animal models. The availability of multitude technologies and reagents to characterize and manipulate immunological pathways and mediators adds to the outstanding opportunities to assess the pathology of allergic diseases and to develop novel therapeutic strategies in mice. Numerous sensitization protocols with food and aero-allergens are used to establish an allergic/asthma-like phenotype in mice. Requirements for an appropriate murine model include a close resemblance to the pathology of the disease in humans, the objective measurement of the physiologic parameters, as well as reliability and reproducibility of the experimental data. With respect to reproducible experimental conditions, it has been recognized that extract preparations from natural allergen sources can vary in their allergen-content and -composition. This might influence the degree of sensitization or the outcome of treatment strategies in dependence of the applied extract preparation. The use of recombinant allergens in experimental in vivo and in vitro systems can overcome these problems. Another aspect, that has become obvious from the experimental studies, is that allergens can differ in their immunogenicity as well as in their capacity to act as tolerogens. Therefore, it seems important that the efficacy of the different allergen-molecules to act as therapeutic agents is individually examined. In this review, examples of animal models are described, in which recombinant allergens have been used for sensitization and/or treatment of allergic responses and how they have been used to enhance our understanding of the pathology of allergic diseases.     

氧化应激及天然抗氧化剂对阿尔茨海默病的缓解作用（英文）

衰老是阿尔茨海默病（Alzheimer’s disease,AD）等神经退行性疾病的主要危险因素。氧化应激和自由基具有重要的生物学功能,氧化还原失衡导致氧化应激,与包括AD在内的许多人类疾病的病理生理有关。本文综述了活性氧（ROS）参与神经退行性疾病发病的相关机制,特别是氧化应激与AD其他关键机制的相互作用,并总结了茶多酚、L-茶氨酸、虾青素、EGb761、大豆异黄酮和烟碱在细胞和动物模型中对AD的防护作用以及在临床上对相关疾病的缓解作用。希望该综述能为AD的预防和治疗策略提供一些见解。     

Molecular targets in immune-mediated diseases: the case of tumour necrosis factor and rheumatoid arthritis

Rheumatoid arthritis is a common autoimmune condition in which, for unknown reasons, synovial joints become the target of a sustained immune response. For many years, rheumatoid arthritis was in the 'too hard basket' in terms of understanding disease mechanisms and providing rational therapy. This has changed dramatically over the last 10 years and rheumatoid arthritis is now at the forefront of biotechnology. In this review, we outline one of the most exciting recent developments, namely antagonists of the cytokine TNF. The preclinical evaluation of TNF in animal models of rheumatoid arthritis, and subsequent clinical trials of TNF inhibitors in patients, provides insight into the 'bench to bedside' paradigm. We therefore briefly review rheumatoid arthritis, animal models of rheumatoid arthritis, the biology of TNF, the pivotal clinical trials of TNF antagonists and the emerging data on side-effects. Tumour necrosis factor inhibitors in rheumatoid arthritis represent the first attempt to achieve sustained blockade of a single cytokine in a human disease. Whilst this approach has been even more successful than might have been predicted, we suggest it is only the beginning of what has become a new therapeutic era.     

Pituitary adenylate cyclase-activating polypeptide inhibits collagen-induced arthritis: an experimental immunomodulatory therapy.

Rheumatoid arthritis is a chronic, systemic, autoimmune, and inflammatory disorder that affects the synovial lining of the joints. We describe the beneficial effects of the pituitary adenylate cyclase-activating polypeptide (PACAP) in the collagen-induced arthritis experimental murine model being proposed as a novel therapeutic approach in the treatment of rheumatoid arthritis. PACAP greatly decreases arthritis frequency and severity in the studied mice by improving clinical symptoms, ameliorating joint damage, and blocking both the inflammatory and autoimmune mediators which are the main keys of the pathogenesis of this disease. With this study, PACAP emerges as a promising candidate for the treatment of a pathology with a high world incidence but currently no effective treatment.     

Murine models of human neuropathic pain

Neuropathic pain refers to pain that originates from pathology of the nervous system. Diabetes, infection (herpes zoster), nerve compression, nerve trauma, and autoimmune diseases are examples of diseases that may cause neuropathic pain. Unfortunately no satisfactory treatment is yet available for this type of pain. This consideration has led to an explosion of interest for the underlying mechanisms, accompanied by a growing number of animal models. In recent years, most of the neuropathic pain models initially developed in the rat have been translated to mice in order to exploit the resource represented by genetically modified mice. Obviously the most useful animal models of pain would be ones in which the etiology of the pain would be endogenous and not induced by the experimenters: together with the classic models based on peripheral nerve ligation, in the last years other techniques are being developed that mimic more closely clinical pain syndromes, often by attempting to induce the disease associated to neuropathic pain. Although several variables must be taken into account when using animal models for mimicking clinical neuropathic pain, the huge number of models that are now reproducible and well characterized should help to reach important goals in the comprehension of mechanisms and to discover novel therapeutic target for this disease.     

A Mouse Model for Pathogen-induced Chronic Inflammation at Local and Systemic Sites

Chronic inflammation is a major driver of pathological tissue damage and a unifying characteristic of many chronic diseases in humans including neoplastic, autoimmune, and chronic inflammatory diseases. Emerging evidence implicates pathogen-induced chronic inflammation in the development and progression of chronic diseases with a wide variety of clinical manifestations. Due to the complex and multifactorial etiology of chronic disease, designing experiments for proof of causality and the establishment of mechanistic links is nearly impossible in humans. An advantage of using animal models is that both genetic and environmental factors that may influence the course of a particular disease can be controlled. Thus, designing relevant animal models of infection represents a key step in identifying host and pathogen specific mechanisms that contribute to chronic inflammation.Here we describe a mouse model of pathogen-induced chronic inflammation at local and systemic sites following infection with the oral pathogen Porphyromonas gingivalis, a bacterium closely associated with human periodontal disease. Oral infection of specific-pathogen free mice induces a local inflammatory response resulting in destruction of tooth supporting alveolar bone, a hallmark of periodontal disease. In an established mouse model of atherosclerosis, infection with P. gingivalis accelerates inflammatory plaque deposition within the aortic sinus and innominate artery, accompanied by activation of the vascular endothelium, an increased immune cell infiltrate, and elevated expression of inflammatory mediators within lesions. We detail methodologies for the assessment of inflammation at local and systemic sites. The use of transgenic mice and defined bacterial mutants makes this model particularly suitable for identifying both host and microbial factors involved in the initiation, progression, and outcome of disease. Additionally, the model can be used to screen for novel therapeutic strategies, including vaccination and pharmacological intervention.     

Mesenchymal stem cells: Emerging mechanisms of immunomodulation and therapy

Mesenchymal stem cells (MSCs) are a pleiotropic population of cells that are self-renewing and capable of differentiating into canonical cells of the mesenchyme, including adipocytes, chondrocytes, and osteocytes. They employ multi-faceted approaches to maintain bone marrow niche homeostasis and promote wound healing during injury. Biomedical research has long sought to exploit their pleiotropic properties as a basis for cell therapy for a variety of diseases and to facilitate hematopoietic stem cell establishment and stromal reconstruction in bone marrow transplantation. Early results demonstrated their usage as safe, and there was little host response to these cells. The discovery of their immunosuppressive functions ushered in a new interest in MSCs as a promising therapeutic tool to suppress inflammation and down-regulate pathogenic immune responses in graft-versus-host and autoimmune diseases such as multiple sclerosis, autoimmune diabetes, and rheumatoid arthritis. MSCs produce a large number of soluble and membrane-bound factors, some of which inhibit immune responses. However, the full range of MSC-mediated immune-modulation remains incompletely understood, as emerging reports also reveal that MSCs can adopt an immunogenic phenotype, stimulate immune cells, and yield seemingly contradictory results in experimental animal models of inflammatory disease. The present review describes the large body of literature that has been accumulated on the fascinating biology of MSCs and their complex effects on immune responses.     

Progranulin: A conductor of receptors orchestra,a chaperone of lysosomal enzymes and a therapeutic target for multiple diseases

Progranulin (PGRN), a widely expressed glycoprotein with pleiotropic function, has been linked to a host of physiological processes and diverse pathological states. A series of contemporary preclinical disease models and clinical trials have evaluated various therapeutic strategies targeting PGRN, highlighting PGRN as a promising therapeutic target. Herein we summarize available knowledge of PGRN targeting in various kinds of diseases, including common neurological diseases, inflammatory autoimmune diseases, cancer, tissue repair, and rare lysosomal storage diseases, with a focus on the functional domain-oriented drug development strategies. In particular, we emphasize the role of extracellular PGRN as a non-conventional, extracellular matrix bound, growth factor-like conductor orchestrating multiple membrane receptors and intracellular PGRN as a chaperone/co-chaperone that mediates the folding and traffic of its various binding partners.     

Neuroprotective effect of combination therapy of glatiramer acetate and epigallocatechin-3-gallate in neuroinflammation

Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system. However, studies of MS and the animal model, experimental autoimmune encephalomyelitis (EAE), indicate that neuronal pathology is the principle cause of clinical disability. Thus, there is need to develop new therapeutic strategies that not only address immunomodulation but also neuroprotection. Here we show that the combination therapy of Glatiramer acetate (GA), an immunomodulatory MS therapeutic, and the neuroprotectant epigallocatechin-3-gallate (EGCG), the main phenol in green tea, have synergistic protective effects in vitro and in the EAE model. EGCG and GA together led to increased protection from glutamate- and TRAIL-induced neuronal cell death in vitro. EGCG combined with GA induced regeneration of hippocampal axons in an outgrowth assay. The combined application of EGCG and GA did not result in unexpected adverse events in vivo. Neuroprotective and neuroregenerative effects could be translated in the in vivo model, where combination treatment with EGCG and GA significantly delayed disease onset, strongly reduced clinical severity, even after onset of symptoms and reduced inflammatory infiltrates. These results illustrate the promise of combining neuroprotective and anti-inflammatory treatments and strengthen the prospects of EGCG as an adjunct therapy for neuroinflammatory and neurodegenerative diseases.     

Targeting VIP and PACAP receptor signalling: new therapeutic strategies in multiple sclerosis

MS (multiple sclerosis) is a chronic autoimmune and neurodegenerative pathology of the CNS (central nervous system) affecting approx. 2.5 million people worldwide. Current and emerging DMDs (disease-modifying drugs) predominantly target the immune system. These therapeutic agents slow progression and reduce severity at early stages of MS, but show little activity on the neurodegenerative component of the disease. As the latter determines permanent disability, there is a critical need to pursue alternative modalities. VIP (vasoactive intestinal peptide) and PACAP (pituitary adenylate cyclase-activating peptide) have potent anti-inflammatory and neuroprotective actions, and have shown significant activity in animal inflammatory disease models including the EAE (experimental autoimmune encephalomyelitis) MS model. Thus, their receptors have become candidate targets for inflammatory diseases. Here, we will discuss the immunomodulatory and neuroprotective actions of VIP and PACAP and their signalling pathways, and then extensively review the structure–activity relationship data and biophysical interaction studies of these peptides with their cognate receptors.     

Genetically Modified Pig Models for Human Diseases

Genetically modified animal models are important for understanding the pathogenesis of human disease and developing therapeutic strategies.Although genetically modified mice have been widely used to model human diseases,some of these mouse models do not replicate important disease symptoms or pathology.Pigs are more similar to humans than mice in anatomy,physiology,and genome. Thus,pigs are considered to be better animal models to mimic some human diseases.This review describes genetically modified pigs that have been used to model various diseases including neurological,cardiovascular,and diabetic disorders.We also discuss the development in gene modification technology that can facilitate the generation of transgenic pig models for human diseases.     

诱导型一氧化氮合酶与疾病

炎症是众多疾病如自体免疫紊乱、神经退行性病变、心血管疾病和癌症发展的病理机制,诱导型一氧化氮合酶在炎症过程中被诱导表达,产生过量的一氧化氮,引发炎症级联反应,进而导致以上多种疾病发生。抑制诱导型一氧化氮合酶表达在体内体外实验及临床使用中均体现抗炎效果和症状改善。本文综述了诱导型一氧化氮合酶在炎症过程中诱导表达及与各类重大疾病联系的最新进展,并展望了诱导型一氧化氮合酶抑制剂作为抗炎治疗策略的前景。     

Transgenic animals in inflammatory disease models

Inflammatory diseases affect a significant portion of the population worldwide and have been intensely studied for several decades. The advent of transgenic technology has allowed researchers to study individual gene contributions to the pathogenesis of these diseases. This has been done using standard inflammatory disease models in transgenic animals and by identifying novel models through the spontaneous generation of disease in the transgenic animal. Recent advances have been made in the understanding of rheumatoid arthritis, pulmonary inflammation, multiple sclerosis and inflammatory bowel disease through the use of transgenic animals in models of human inflammatory disease.     

调节性B细胞的发现和研究进展

B细胞主要通过呈递抗原和产生抗体发挥免疫调节作用.新近研究表明,一种全新的B细胞亚群--调节性B细胞(regulatory B cell,Bregs),可通过产生白细胞介素10(IL-10)或转化生长因子β1(TGF-β1)等抑制性细胞因子介导免疫耐受,抑制过度炎症反应.Bregs在一些慢性炎性疾病包括肠炎、类风湿性关节炎、实验性自身免疫脑脊髓炎、多发性硬化症、感染和肿瘤等发生、发展和转归过程起重要调节作用.Bregs的发现和作用机制的阐明,将为全面、深入了解免疫耐受的机制,寻找和开发更合理治疗慢性炎性疾病的策略提供理论依据.本文综述了Bregs的发现、生物学特征、发育调节及其参与炎性疾病发病的作用和机制.     

Biology and therapy of inherited retinal degenerative disease: insights from mouse models

Retinal neurodegeneration associated with the dysfunction or death of photoreceptors is a major cause of incurable vision loss. Tremendous progress has been made over the last two decades in discovering genes and genetic defects that lead to retinal diseases. The primary focus has now shifted to uncovering disease mechanisms and designing treatment strategies, especially inspired by the successful application of gene therapy in some forms of congenital blindness in humans. Both spontaneous and laboratory-generated mouse mutants have been valuable for providing fundamental insights into normal retinal development and for deciphering disease pathology. Here, we provide a review of mouse models of human retinal degeneration, with a primary focus on diseases affecting photoreceptor function. We also describe models associated with retinal pigment epithelium dysfunction or synaptic abnormalities. Furthermore, we highlight the crucial role of mouse models in elucidating retinal and photoreceptor biology in health and disease, and in the assessment of novel therapeutic modalities, including gene- and stem-cell-based therapies, for retinal degenerative diseases.KEY WORDS: Mouse mutants, Photoreceptor, Retinal development, Retinal disease     

Genetic Control of Spontaneous Arthritis in a Four-Way Advanced Intercross Line

Identifying the genetic basis of complex diseases, such as rheumatoid arthritis, remains a challenge that requires experimental models to reduce the genetic and environmental variability. Numerous loci for arthritis have been identified in induced animal models; however, few spontaneous models have been genetically studied. Therefore, we generated a four-way advanced intercross line (AIL) from four inbred strains, including BXD2/TyJ which spontaneously develops autoimmune arthritis. A genome-wide scan for spontaneous arthritis was performed in a cohort of 366 mice of the fourth generation (G4) of this cross. Five loci contributing to clinical phenotypes were identified in chromosomes 3, 7, 13, 18, and X. Three of the loci found in this study, confirm previously identified loci; whereas two of them are novel loci. Interesting candidate genes for the loci are highlighted. This study provides a genetic overview of spontaneous arthritis in mice and aids to solve the genetic etiology of rheumatoid arthritis and to gain a better understanding of the disease.