Hypertension in transgenic (mREN2)27 rats is not associated with the presence of B1 receptors

B1 receptors are inducible receptors expressed only in stressful conditions. The aim of this study was to determine if, in (mREN2)27 transgenic rats, hypertension is associated with the presence of B1 receptors in the cardiovascular system and if a heat stress inducible effect is preserved during hypertension. Age-matched (16 weeks old) heterozygous hypertensive transgenic (mREN2)27 rats (HT rats) and the normotensive control animals (homozygous Sprague-Dawley rats, NT rats) were used. The study was conducted in two parts: in the first part the responsiveness of B1 receptors was studied in rats submitted to heat stress (42 degrees C rectal temperature, 20 min) or sham anaesthesia 24 h before, by recording changes in isometric tension in aortic rings in response to [des-Arg9]-bradykinin, a B1 receptor agonist. In the second part, we studied whether B1 receptor mRNA was present in aorta, heart and kidneys, using a semi-quantitative RT-PCR technique. [des-Arg9]-Bradykinin induced a concentration-dependent relaxation of aortic rings only from animals submitted to prior heat stress. This response was significantly higher in aortic rings from heat stressed HT rats than from heat stressed NT ones. B1 receptor mRNA was undetectable in organs from rats not submitted to heat stress but they were present 5 h after heat stress in aorta, heart and kidneys from both NT and HT rats. In conclusion, arterial hypertension observed in (mREN2)27 rats is not associated with the presence of B1 receptors. However, after heat stress, we observed an increase in responsiveness from HT rat aortas compared to NT ones.     

Massive thymic deletion results in systemic autoimmunity through elimination of CD4+ CD25+ T regulatory cells

Incomplete deletion of KRN T cells that recognize the ubiquitously expressed self-antigen glucose-6-phosphate-isomerase (GPI) initiates an anti-GPI autoimmune cascade in K/BxN mice resulting in a humorally mediated arthritis. Transgenic (Tg) expression of a KRN T cell receptor (TCR) agonist under the major histocompatibility complex class II promoter resulted in thymic deletion with loss of anti-GPI T and B cell responses and attenuated arthritis course. However, double Tg mice succumbed to systemic autoimmunity with multiorgan inflammation and autoantibody production. Extensive thymic deletion resulted in lymphopenia and elimination of CD4+ CD25+ regulatory T cells (Tregs), but spared some CD4+ T cells expressing endogenous TCR, which oligoclonally expanded in the periphery. Disease was transferred by these T cells and prevented by cotransfer of CD4+ CD25+ Tregs. Moreover, we extended our findings to another TCR system (anti-hen egg lysozyme [HEL] TCR/HEL mice) where similarly extensive thymic deletion also resulted in disease. Thus, our studies demonstrated that central tolerance can paradoxically result in systemic autoimmunity through differential susceptibility of Tregs and autoreactive T cells to thymic deletion. Therefore, too little or too much negative selection to a self-antigen can result in systemic autoimmunity and disease.     

Benefits and limitations of animal models in partial bladder outlet obstruction for translational research

The functions of the lower urinary tract have been investigated for more than a century. Lower urinary tract symptoms, such as incomplete bladder emptying, weak urine stream, daytime urinary frequency, urgency, urge incontinence and nocturia after partial bladder outlet obstruction, is a frequent cause of benign prostatic hyperplasia in aging men. However, the pathophysiological mechanisms have not been fully elucidated. The use of animal models is absolutely imperative for understanding the pathophysiological processes involved in bladder dysfunction. Surgical induction has been used to study lower urinary tract functions of numerous animal species, such as pig, dog, rabbit, guinea pig, rat and mouse, of both sexes. Several morphological and functional modifications under partial bladder outlet obstruction have not only been observed in the bladder, but also in the central nervous system. Understanding the changes of the lower urinary tract functions induced by partial bladder outlet obstruction would also contribute to appropriate drug development for treating these pathophysiological conditions. In the present review, we discuss techniques for creating partial bladder outlet obstruction, the characteristics of several species, as well as issues of each model, and their translational value.     

An overview of tolerogenic immunotherapies based on plant-made antigens

Introduction: Over the last two decades, genetically engineered plants became attractive and mature platforms for producing vaccines and other relevant biopharmaceuticals. Autoimmune and inflammatory disorders demand the availability of accessible treatments, and one alternative therapy is based on therapeutic vaccines able to downregulate immune responses that favor pathology progression.

Areas covered: The current status of plant-made tolerogenic vaccines is presented with emphasis on the candidates under evaluation in test animals. Nowadays, this concept has been assessed in models of food and pollen allergies, autoimmune diabetes, asthma, arthritis, and prevention of blocking antibodies induction against a biopharmaceutical used in replacement therapies.

Expert opinion: According to the current evidence generated at the preclinical level, plant-made tolerogenic therapies are a promise to treat several immune-related conditions, and the beginning of clinical trials is envisaged for the next decade. Advantages and limitations for this technology are discussed.     

Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations

The cause of many autoimmune and inflammatory diseases is unresolved, although dysregulated production of tumor necrosis factor (TNF) family members appears to be important in many cases. BAFF, a new member of the TNF family, binds to B cells and costimulates their growth in vitro. Mice transgenic for BAFF have vastly increased numbers of mature B and effector T cells, and develop autoimmune-like manifestations such as the presence of high levels of rheumatoid factors, circulating immune complexes, anti-DNA autoantibodies, and immunoglobulin deposition in the kidneys. This phenotype is reminiscent of certain human autoimmune disorders and suggests that dysregulation of BAFF expression may be a critical element in the chain of events leading to autoimmunity.     

自杀基因抑制K562细胞成瘤的动物实验研究

目的探讨自杀基因胞嘧啶脱氨酶（CD）和胸苷激酶（TK）在小鼠体内对K562细胞的抑制作用。方法将在慢病毒介导下已转染CDglyTK的K562细胞种植于裸鼠皮下，观察其成瘤情况和对前体药物[环氧鸟苷（GCV）、5-氟胞嘧啶（5-FC）3的敏感性。结果种植K562细胞和K562／CDglyTK细胞的裸鼠分别在（7．0土1．2）和（7．1土0．9）d后长出肉眼可见的瘤块。两组裸鼠生存期分别是（52．2土5．3）和（54．2±3．7）d，差异无统计学意义（P〉O．05）；接种K562／CDglyTK细胞的小鼠经GCV和5-FC处理后，其裸鼠分别在（26．9土I．7）、（25．7土I．9）d后肉眼可见肿瘤生长，对照组接种K562细胞后（6．9±I．7）d生长出肉眼可见肿瘤，两者差异有统计学意义（P〈0．01）。结论自杀基因在体内对K562细胞有明显的抑制作用，能增强前体药物GCV和5-FC对肿瘤细胞的药物作用。     

Neointima formation and thrombosis after vascular injury in transgenic mice overexpressing plasminogen activator inhibitor-1 (PAI-1)

Summary.  The controversial role of plasminogen activator inhibitor-1 (PAI-1) in neointima formation and restenosis was studied with the use of a vascular injury model in transgenic mice overexpressing murine PAI-1 (PAI-1 Tg) and in wild-type (WT) controls. Despite the high circulating PAI-1 levels in the PAI-1 Tg mice (52 ± 9.8 ng mL⁻¹ vs. 0.76 ± 0.17 ng mL⁻¹ in WT mice), no significant fibrin deposition was observed in non-injured femoral arteries of 8- to 12-week-old mice. Two weeks after severe electric injury, extensive and comparable fibrin deposition was observed in both genotypes, despite a significantly reduced in situ fibrinolytic activity in arterial sections of the PAI-1 Tg mice. The neointimal and medial areas were similar in WT and PAI-1 Tg mice, resulting in comparable intima/media ratios (e.g. 0.94 ± 0.25 and 1.04 ± 0.17 at the center of the injury). Nuclear cell counts in cross-sectional areas of the neointima of the injured region were also comparable in arteries from WT and PAI-1 Tg mice (224 ± 63, 233 ± 20), and the distribution pattern of α-actin-positive smooth muscle cells was similar. These findings indicate that in a vascular injury model that induces extensive and persistent fibrin deposition in femoral arteries of mice, overexpression of PAI-1 does not affect neointima formation.