Experimental animal models resembling rheumatoid arthritis

Summary The experimental animal models of arthritis which in certain aspects share similarities to human rheumatoid arthritis are reviewed. Various methods have been applied to induce in animals experimental models of arthritis which would provide important insights into the aetiopathogenetic mechanisms of human RA. Immunological methods and infectious agents induced the most interesting models. The histology of the synovial tissue, regardless of the inducing mechanisms, is similar to the lesions of RA. Yet, none of these experimental models of arthritis reflects all the articular and systemic features, the immunological profile and the genetic factors which characterize the human disease. The animal models of arthritis reported here and the development of new ones may ultimately offer the information necessary for the understanding of the mechanisms involved in the aetiopathogenesis of human rheumatoid disease.     

Advances in research on animal models of rheumatoid arthritis

At present, rheumatoid arthritis (RA) is considered a type of autoimmune disease. Its pathology is not certain, and effective drugs with less toxicity have not been established. The establishment and application of animal models are effective methods for RA research, especially using animal models similar to humans. Arthritis is more heterogeneous, and this is an important starting point when discussing animal models for arthritis. Animal models are instrumental in understanding the etiology and pathogenetic mechanisms of RA. Appropriate animal models should be selected according to experiments because they have different traits. Various methods have been applied to induce arthritis in animal experimental models, which have provided important insights into the etiopathogenetic mechanisms of human RA. This review was written to give a broad introduction of the current stage of RA model and hope to offer beneficial help for RA-related research.     

New therapeutics in rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic disorder characterized predominately by a chronic inflammatory polyarthritis, with frequent progression to joint destruction and disability. Radiographic joint damage develops in as many as 75% of patients within the first 2 years of disease. For this reason, current RA treatment approaches have focused on early intensive therapy with multiple disease-modifying antirheumatic drugs. The approval of new drugs for this indication has expanded the number of therapeutic options that can potentially allow for tight control of the inflammatory process.     

Gene therapy works in animal models of rheumatoid arthritis so what!

Rheumatoid arthritis (RA) is a systemic disease with polyarticular manifestation of chronic inflammation in the knees and small joints of hand and feet. The current systemic anti-tumor necrosis factor (TNF)-α therapies with biologics ameliorate disease in 60% to 70% of RA patients. However, biologics must be given systemically in relatively high dosages to achieve constant therapeutic levels in the joints, and side effects have been reported. To this end, local gene delivery can provide an alternative approach to achieve high, long-term expression of biologics, optimizing the therapeutic efficacy and minimizing systemic exposure. Evidence from animal models convincingly supports the application of local gene therapy in rheumatoid arthritis, but preclinical studies remain necessary to evaluate the merge of cell-specific targeting, viral vector development, and disease-regulated transgene expression to optimize efficacy and safety.     

Animal models of rheumatoid arthritis

Experimental animal models of arthritis, including type II collagen-induced arthritis, proteoglycan-induced arthritis, adjuvant arthritis, pristane-induced arthritis, and streptococcal cell wall-induced arthritis have contributed to recent advances in the understanding of the immunopathology of arthritis. The dissection of the T-cell populations regulating the autoimmune response is currently the most active area of investigation. Research into the mechanism underlying the association of specific class II major histocompatibility complex antigens with arthritis has focused attention on the interaction of particular V beta T-cell subsets with antigens presented in context of permissive major histocompatibility complex antigens. Several models indicate that both the structure of the major histocompatibility complex antigen and the T-cell receptor may be critical in the development of autoimmunity, while the MIs antigen system appears to regulate the availability of T cells with self-reactivity specificities. Studies on the role of heat-shock proteins in experimental arthritis have prompted research into the role of gamma/delta T cells in joint disease, while the availability of recombinant cytokines has permitted the direct analysis of soluble factors. In addition to providing basic insights into autoimmune disease, animal models continue to provide the means to test novel experimental approaches to the treatment of rheumatoid arthritis.     

Cartilage autoimmunity in experimental models for rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a disease characterized by a chronic and erosive inflammation of cartilaginous joints without evidence for persisting infectious agents. The association with HLA class II genes, autoimmune responses to cartilage proteins and the arthritogenicity of cartilage proteins in experimental animals suggest that cartilage autoimmunity plays an important role in the disease process. In the present review T cell recognition of type II collagen (CII) and its consequences for development of collagen-induced arthritis (CIA) is discussed. Susceptibility to disease is associated with major histocompatibility complex (MHC) genes; the important gene in the H-2^q haplotype has been shown to be coding for the A^q molecule. An immunodominant peptide from CII located at position 256–270 has been defined and recognition of the A^q/CII256–270 peptide complex is essential for the development of arthritis. Interestingly, the structures recognized by T cells are mainly post-translational modifications of lysine at position 264 (K264). The majority of the CII-reactive T cells recognize a β-galactose O-linked to K264. In addition, it has recently been shown that the MHC class II molecules associated with RA, i.e. HLA-DR4 (DRB1*0401/DRA) and the HLA-DR1, possess peptide binding pockets with a very similar structures to the A^q molecule. Consequently DR1 and DR4 transgenic mice are highly susceptible to CIA and bind peptides derived from the same region of CII. The most interesting area for further investigation will be to understand how the recognition of this immunodominant CII peptide will normally induce tolerance in the immune system and how this tolerance is modulated or broken to allow the development of arthritis. Since the same structural interactions most likely occur also in humans, these questions have high relevance for solving the RA enigma.     

Cartilage autoimmunity in experimental models for rheumatoid arthritis

Rheumatoid arthritis (RA) is a disease characterized by a chronic and erosive inflammation of cartilaginous joints without evidence for persisting infectious agents. The association with HLA class II genes, autoimmune responses to cartilage proteins and the arthritogenicity of cartilage proteins in experimental animals suggest that cartilage autoimmunity plays an important role in the disease process. In the present review T cell recognition of type II collagen (CII) and its consequences for development of collagen-induced arthritis (CIA) is discussed. Susceptibility to disease is associated with major histocompatibility complex (MHC) genes; the important gene in theH-2 ^q haplotype has been shown to be coding for the A ^q molecule. An immunodominant peptide from CII located at position 256–270 has been defined and recognition of the A ^q /CII256–270 peptide complex is essential for the development of arthritis. Interestingly, the structures recognized by T cells are mainly post-translational modifications of lysine at position 264 (K264). The majority of the CII-reactive T cells recognize a β-galactoseO-linked to K264. In addition, it has recently been shown that the MHC class II molecules associated with RA, i.e. HLA-DR4 (DRB1^*0401/DRA) and the HLA-DR1, possess peptide binding pockets with a very similar structures to the A ^q molecule. Consequently DR1 and DR4 transgenic mice are highly susceptible to CIA and bind peptides derived from the same region of CII. The most interesting area for further investigation will be to understand how the recognition of this immunodominant CII peptide will normally induce tolerance in the immune system and how this tolerance is modulated or broken to allow the development of arthritis. Since the same structural interactions most likely occur also in humans, these questions have high relevance for solving the RA enigma.     

Lessons from animal models of arthritis

There is increasing thought that autoantibodies to systemic self-antigens may provide a principal effector mechanism for the initiation and propagation of joint inflammation. The recent identification of arthritis transfer with antibodies to the self-antigen glucose-6-phosphate isomerase has boosted this interest. Fc receptor involvement in arthritis has been evaluated, identifying pro-inflammatory and inhibitory Fc gamma receptor subtypes, and demonstrating a link between Fc gamma receptor expression, cytokine production, cartilage destruction, and mouse strain susceptibility to immune complex arthritis. Further proof of a key role of interleukin (IL)-1 in arthritis was provided by the occurrence of spontaneous arthritis in IL-1 receptor antagonist knockout mice and elicitation of full-blown arthritis in tumor necrosis factor (TNF)-deficient mice. IL-18 (part of the IL-1 family) is a crucial upstream cytokine that, with IL-12, induces IL-1 and TNF and promotes arthritis and T-cell differentiation. IL-18 neutralization improved arthritis outcome, but its central role in host defense against bacterial infections may complicate therapeutic IL-18 targeting. T helper 1 (Th1) cells may aggravate arthritis and joint destruction through the production of IL-17, which shows joint destructive potential independent of IL-1. Studies have also focused on the control of receptor activator of nuclear factor kappaB ligand, modulation with IL-4, and regulation of downstream mediators in tissue destruction. Gene therapeutic approaches proved efficacious and will provide future ways to control arthritis.     

人类风湿关节炎滑膜成纤维细胞-软骨-重度联合免疫缺陷鼠模型的研制

目的 建立人类风湿关节炎(RA)滑膜成纤维细胞(SFs)-软骨-重度联合免疫缺陷(SCID)小鼠模型,以骨关节炎滑膜成纤维细胞(OASFs)作对照,探讨RASFs在RA发病中的作用及机制.方法 将培养传代至第4代的RASFs/OASFs经5-溴脱氧尿嘧啶核苷体(5-Brdu)标记后注入可吸收明胶海绵,与人的正常软骨一起移植入SCID小鼠背部皮下,第30天处死模型,剪取移植物和鼠双膝关节作组织学观察,免疫组织化学检测5-Brdu和Vimentin阳性细胞,酶联免疫吸附试验(ELISA)检测血清中人基质金属蛋白酶(MMP)-3和人白细胞介素(IL)-6含量.统计学方法采用两独立样本秩和检验.结果 ①2组血清中均可检测出人MMP-3,仅在RASFs组检测到1例IL-6.②RASFs组移植的软骨侵蚀程度(0.6±0.7与0.3±0.5)和软骨降解程度(2.3±0.8与1.7±1.0)较OASFs组有增高趋势,但差异均无统计学意义(P＞0.05).③RASFs组鼠膝关节的滑膜增生程度(3.1±0.8与1.7±1.0,P＜0.01)和软骨侵蚀程度(1.6±1.7与0.6±1.4,P＜0.05)均显著高于OASFs组.④在SCID鼠皮下、移植软骨处、鼠膝关节滑膜及骨髓中检测出5-Brdu及Vimentin阳性的SFs.结论 传代培养的RASFs在SCID鼠皮下存活并保持其侵袭性生长的特点,且能迁移至远处关节中诱发关节炎症.     

Alcoholic liver disease: Utility of animal models

Alcoholic liver disease(ALD) is a major cause of acute and chronic liver injury. Extensive evidence has been accumulated on the pathological process of ALD during the past decades. However, effective treatment options for ALD are very limited due to the lack of suitable in vivo models that recapitulate the full spectrum of ALD. Experimental animal models of ALD, particularly rodents, have been used extensively to mimic human ALD. An ideal animal model should recapitulate all aspects of the ALD process, including significant steatosis, hepatic neutrophil infiltration, and liver injury. A better strategy against ALD depends on clear diagnostic biomarkers, accurate predictor(s) of its progression and new therapeutic approaches to modulate stop or even reverse the disease. Numerous models employing rodent animals have been established in the last decades to investigate the effects of acute and chronic alcohol exposure on the initiation and progression of ALD. Although significant progress has been made in gaining better knowledge on the mechanisms and pathology of ALD, many features of ALD are unknown, and require further investigation, ideally with improved animal models that more effectively mimic human ALD. Although differences in the degree and stages of alcoholic liver injury inevitably exist between animal models and human ALD, the acquisition and translational relevance will be greatly enhanced with the development of new and improved animal models of ALD.     

冠状病毒动物模型研究进展及2019-nCoV可能的易感小动物模型

建立高致病性冠状病毒动物模型对疫苗、抗体、药物、病毒致病机制研究意义重大。非人灵长类、雪貂、叙利亚仓鼠等动物均可用于建立冠状病毒的感染和疾病动物模型。不同动物模型能从不同层面模拟重现临床感染症状。然而,从适用性、经济性、易于获取等角度综合考虑,建立冠状病毒易感的小鼠模型,并快速提供数量充足的动物,对于冠状病毒疫情防控更有现实意义。本文简述了MERS-CoV、SARS-CoV以及新型冠状病毒(2019-nCoV)3种高致病性冠状病毒小鼠模型的研究进展。基于近日发表在Nature的研究成果,即SARS-CoV和2019-nCoV均利用hACE2受体感染宿主细胞推测,我们于2018年构建的hACE2-KI/NIFDC人源化小鼠模型有望用于2019-nCoV的相关研究。     

Clues provided by animal models of arthritis

All the findings discussed support the premise that animal experimentation is a pertinent endeavor for understanding chronic inflammatory synovitis in humans. Whether any of these data actually identify processes operative in RA or can be used to predict outcomes in the human disease is currently unclear. The review closes with an illustration of an area of controversy existing, in part, because of an absence of animal model research. The rationale for the use of gamma-interferon (IFN) in RA has been aptly described by S. H. Pincus as "curious". Evidence of deficient gamma-IFN production within the rheumatoid synovium has been acquired by several laboratories, suggesting that administration of this lymphokine might be helpful. This conclusion has been supported by news of short-term success in uncontrolled pilot trials. However, gamma-IFN is perhaps the most vigorous of the interleukins in terms of diversely activating the immune system. Thus, it would seem logical to envision that gamma-IFN would accelerate any process attributable to autoimmunity. The use of animal models to probe this dilemma, and others arising in the future, could provide a more convincing scientific cornerstone for clinical trials in RA. One caveat, however--animal models provide only clues or potential insights, not final answers, for human disease.     

Genistein: the potential for efficacy in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that may affect many tissues and organs. Without treatment, inflammation leads to cartilage damage, bone erosions, joint destruction, and impaired movement. Because of the limited success of disease-modifying anti-rheumatic drugs, the exploration of new anti-rheumatic drugs with high efficacy and less toxicity is eagerly needed. Genistein, the major active compound from soybean, has received much attention due to its potential beneficial effects on some of the degenerative diseases. It has been found that genistein has anti-inflammatory, antiangiogenesis, antiproliferative, antioxidant, immunomodulatory, pain relief, and joint protection properties. Hence, significant advances have been made, both by in vitro and in vivo studies showing that genistein is a promising agent for RA treatment.     

Animal models of rheumatoid arthritis and related inflammation

The major, extensively studied, experimentally-induced rat and mouse models of arthritis with features resembling rheumatoid arthritis are reviewed here. Etiopathogenetic studies that were recently published are emphasized. In summary, multiple triggering stimuli can induce disease in genetically-prone strains of inbred rats and mice. Multiple genetic loci, including both MHC and non-MHC, regulate disease expression in these animals. By comparison with other models of autoimmune disease, clustering of regulatory loci within and among species is increasingly becoming evident. At the cellular level, both innate and acquired immune systems are involved in the disease manifestations. At the molecular level, unbalanced chronic production of tumor necrosis factor-a (TNF-a), interleukin (IL)-1, IL-6 and IL-12, as opposed to IL-4 and IL-10, is correlated with arthritis disease susceptibility and severity.     

The potential roles for novel biomarkers in rheumatoid arthritis assessment

Comprehensive management of rheumatoid arthritis (RA) requires regular monitoring of disease activity, functional status, and structural damage to facilitate optimal patient outcomes. Tight control strategies have been successfully used in other diseases including diabetes and hypertension. Tight control requires frequent disease activity measurements in order to tailor treatment for individual patients, resulting in improved patient outcomes. Current monitoring measures used in clinical practice are largely driven by subjective evaluation of signs and symptoms, which are critical but limited by assessor variability and may not reflect true biological change in a timely manner. Research suggests that novel biomarkers may provide quantitative, objective assessments of disease activity and structural damage risk in RA, which are not captured by current measures. The simultaneous use of multiple biomarkers in a single test algorithm may provide a more comprehensive quantitative representation of the overall complex heterogeneous biology of RA. This article reviews the current management strategies for monitoring RA and the potential impact that multi-biomarker assays may have on RA assessment, which may further improve clinical outcomes.     

Glycosaminoglycans are a potential cause of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic, systemic, and inflammatory disease of connective tissue with unknown etiology. We investigated whether aberrant immune responses to glycosaminoglycans (GAGs), a major component of joint cartilage, joint fluid, and other soft connective tissue, causes this disease. Here we show that injection of GAGs such as hyaluronic acid, heparin, and chondroitin sulfates A, B, and C induce arthritis, tendosynovitis, dermatitis, and other pathological conditions in mice. We developed a technique by staining tissue specimens with fluorochrome- or biotin-labeled GAGs to visualize the direct binding between cells and GAGs. We discovered that inflammatory infiltrates from the affected tissue are dominated by a distinct phenotype of GAG-binding cells, a significant portion of which are CD4(+) T cells. GAG-binding cells seem to be expanded in bone marrow of GAG-immunized mice. Furthermore, we identified GAG-binding cells in inflamed synovial tissue of human patients with RA. Our findings suggest that carbohydrate self-antigenic GAGs provoke autoimmune dysfunctions that involve the expansion of GAG-binding cells which migrate to anatomical sites rich in GAGs. These GAG-binding cells might, in turn, promote the inflammation and pathology seen both in our murine model and in human RA.