Dissimilar background genes control susceptibility to autoimmune disease in the context of different MHC haplotypes: NOD.H-2(s) congenic mice are relatively resistant to both experimental autoimmune encephalomyelitis and type I diabetes

Nonobese diabetic (NOD) mice develop multi-organ autoimmune diseases, including type 1 diabetes. We hypothesized that backcrossing the MHC region from SJL (H-2(s)) mice, which have an endogenous PLP(139-151)-reactive repertoire, onto the background of autoimmune-prone NOD mice would result in a mouse strain that is highly susceptible to experimental autoimmune encephalomyelitis (EAE). Unexpectedly, although we detected an endogenous PLP(139-151) repertoire in the NOD.S mice, they did not develop spontaneous EAE and were relatively resistant to PLP(139-151)-induced EAE when compared to SJL mice. This resistance was associated with lower production of proinflammatory cytokines and a decreased expansion of PLP(139-151)-specific CD4(+) T cells after immunization and restimulation with PLP peptide in vitro. V(beta) chain usage among PLP(139-151)-reactive T cells differed between SJL and NOD.S mice. Furthermore, NOD.S mice were resistant to the development of insulitis and cyclophosphamide-induced diabetes, but not sialadenitis. Altogether, even though NOD mice develop spontaneous autoimmune diseases, they become relatively resistant to induction of EAE even when they express the EAE-permissive class II molecule I-A(s). Our data show that certain combinations of otherwise susceptibility-conferring MHC and non-MHC genes can mediate autoimmune-disease resistance when they are paired together. These findings do not support the "shared autoimmune gene" hypothesis.     

TNF-alpha impairs peripheral tolerance towards beta-cells,and local costimulation by B7.1 enhances the effector function of diabetogenic T cells

Maintenance of peripheral tolerance and inactivation of autoreactive T cells is based on a delicate balance between pro-inflammatory and protective cytokines that is poorly understood. We have here addressed how the local expression of the inflammatory cytokine TNF-alpha can impair peripheral tolerance and lead to autoreactivity. After transplantation of pancreata that are immunogenic due to beta-cell expression of B7.1 and TNF-alpha, into thymectomized and euthymic syngeneic mice, we found that only euthymic mice rejected the grafts. This result suggests that under normal circumstances autoreactive T cells are functionally inactivated, and initiation of an autoreactive response requires de-novo generation of T cells. By contrast, thymectomized mice expressing TNF-alpha on the endogenous islets rejected the grafts, showing that expression of TNF-alpha prevents functional silencing of the autoreactive T cells. Thus, this study provides a mechanism by which TNF-alpha and possibly chronic inflammatory responses may promote autoimmune diseases. Furthermore, we have investigated whether B7.1 can enhance T cell responses of already activated T cells leading to islet rejection. By transplantation of wild-type and B7.1-expressing islets into overtly diabetic mice we found that only the wild-type islets could restore normoglycemia, suggesting that costimulation by B7.1 is required in the expansion or effector phase of the response.     

Adaptive modification of ingestive behavior in beach mice (Peromyscus polionotus).

The ability of an inland and beach race of the old-field mouse to use increasing concentrations of NaCl solutions was compared. Inland mice drank significantly more fluid at all concentrations than did beach mice. These differences became more pronounced as the salt concentration was increased. Food consumption was similar in both races while drinking water or a dilute salt solution, but beach mice ate significantly greater amounts when the concentration of salt was increased above 0.2 M. Weight losses on salt solutions were approximately equal in both races, although beach mice survived longer and tolerated the higher concentrations better. There was no difference in the ability of the races to concentrate urine or excrete Na⁺. When given a choice of distilled water or two salt solutions, beach mice consumed significantly more water (77%) than salt solutions (23%) whereas inland mice drank approximately equal amounts of water (54%) and salt solutions (46%). When deprived of anything to drink, beach mice almost stopped eating for the first two days while inland mice did not reduce their food consumption as quickly and died sooner. Thus, it appears that adaptive modifications of ingestive behavior are important for survival in habitats where salt accumlates and summer droughts may be a problem.     

Lack of Autoimmune Serological Reactions in Rodent Models of Insulin Dependent Diabetes Mellitus

Spontaneous insulitis with insulin-dependent diabetes mellitus (IDDM) in rodent models, the BB rat and NOD mouse, has clarified the pathogenesis of and guided decisions on interventional therapy for human IDDM. However, the occurrence in such models of a standard marker of human IDDM, autoantibodies to β islet cell constituents, has been controversial. Hence we assessed diabetes-prone rodents for the frequencies of raised levels of auto-antibodies to glutamic acid decarboxylase GAD (anti-GAD), insulin and heat shock protein 65 (HSP-65) in relation to levels in non-diabetes-prone animals and levels in human diabetic sera. Assays were performed sequentially at various ages of life. The immunoassays used for anti-GAD and anti-insulin were those validated for sensitivity and specificity for detection of the corresponding autoantibodies in human IDDM sera at international workshops. Positive controls included human IDDM sera with reactivity with GAD or insulin and, for mouse anti-GAD, the highly reactive monoclonal antibody, GAD-6. The results were that levels of autoantibodies in diabetes-prone BB rats or NOD mice to the ‘IDDM-relevant’ autoantigens in our panel did not exceed levels in control rats or mice, and were much lower than levels in humans with IDDM. We conclude that the BB rat and NOD mouse represent a model, but not a facsimile, of human IDDM and that therapeutic successes in such models should be interpreted with caution in relation to interventional therapy for human IDDM.     

Nordimaprit,homodimaprit, clobenpropit and imetit: affinities for H3 binding sites and potencies in a functional H3 receptor model

Summary We determined the affinities of nordimaprit, homodimaprit, clobenpropit and imetit for H₃ binding sites (labelled by ³H-N-methylhistamine) in rat brain cortex homogenates and their potencies at presynaptic H_3A receptors on noradrenergic nerve endings in mouse brain cortex slices. ³H-N-Methylhistamine bound saturably to rat brain cortex homogenates with a K_d of 0.70 nmol/l and a B_max of 98 fmol/mg protein. Binding of ³H-N-methylhistamine was displaced monophasically by dimaprit (pK_i 6.55), nordimaprit (5.94), homodimaprit (6.44), clobenpropit (9.16), imetit (9.83), R-(–)--methylhistamine (8.87) and histamine (8.20), and biphasically by burimamide (pK_{i high} 7.73, pK_{i low} 5.97). In superfused mouse brain cortex slices preincubated with ³H-noradrenaline, the electrically (0.3 Hz) evoked tritium overflow was inhibited by imetit (pIC₃₅ 8.93),R-(–)--methylhistamine (7.87) and histamine (7.03). The effect of histamine was attenuated by nordimaprit, homodimaprit, clobenpropit and N-ethoxycarbonyl-2- ethoxy-1,2-dihydroquinoline (EEDQ); EEDQ (but not nordimaprit, homodimaprit and clobenpropit) attenuated the effect of histamine also in slices pre-exposed to the drug 60–30 min prior to superfusion. The concentration-response curve of histamine was shifted to the right by homodimaprit and clobenpropit; Schild plots yielded straight lines with a slope of unity for both drugs (pA₂ 5.94 and 9.55, respectively). Nordimaprit depressed the maximum effect of histamine (pD₂ 5.55) and also slightly increased the concentration of histamine producing the half-maximum effect.In conclusion, nordimaprit and homodimaprit possess similar affinities for H₃ binding sites like dimaprit; nordimaprit and homodimaprit as well as clobenpropit and imetit do not differentiate between H_3A and H_3B binding sites. Nordimaprit is a reversible noncompetitive H₃ receptor antagonist, homodimaprit and clobenpropit are reversible competitive H₃ receptor antagonists and imetit is an H₃ receptor agonist. Correspondence to: E. Schlicker at the above address     

Prostanoid receptors of the EP3 subtype mediate the inhibitory effect of prostaglandin E2 on noradrenaline release in the mouse brain cortex

Mouse or rat brain cortex slices were preincubated with ³H-noradrenaline and superfused with physiological salt solution containing desipramine. We studied the effects of prostaglandin E₂ (PGE₂), prostaglandin D₂ (PGD₂) and related drugs on the electrically evoked (50 mA, 2 ms, 0.3 Hz) tritium overflow.PGE₂ inhibited the electrically evoked tritium overflow from mouse brain cortex slices; the maximum effect of PGE₂ (79010) was attenuated by the ₂-adrenoceptor agonist talipexole (to 52010) and enhanced by the ₂-adrenoceptor antagonist rauwolscine (to 92%). Rauwolscine was added to the superfusion medium in all subsequent experiments. The effect of PGE₂ was readily reversible upon withdrawal from the medium and remained constant upon prolonged exposure of the tissue to the prostanoid. Studies with EP receptor agonists, mimicking the inhibitory effect of PGE₂, showed the following potencies (pIC₅₀): sulprostone (8.22); misoprostol (8.00); PGE₂ (7.74); PGEZ (7.61); iloprost (5.86). The concentration-response curve of PGE₂ was marginally shifted to the right by the EP₁ receptor antagonist AH 6809 (6-isopropoxy-9-oxoxanthene-2-carboxylic acid; apparent pA₂ 3.97) and by the TP receptor antagonist vapiprost (4.50). AH 6809, by itself, did not affect the evoked overflow whereas vapiprost increased it. PGD2 inhibited the evoked overflow at high concentrations (pIC₅₀ 4.90); this effect was not altered by the DP receptor antagonist BW A868C (3-benzyl-5-(6-carboxyhexyl)-1-(2-cyclohexyl-2hydroxyethylamino)hydantoin), which, by itself, did not affect the evoked overflow. Indometacin slightly increased the evoked overflow and tended to increase the inhibitory effect of PGE₂. PGE₂ inhibited the electrically evoked tritium overflow also in rat brain cortex slices. The maximum effect (obtained in the presence of rauwolscine) was 61%; the pIC₃₀ value was 7.67.The present study suggests that PGE₂ inhibits noradrenaline release from mouse brain cortex via EP₃ receptors and that its maximum effect is more marked in the mouse than in the rat. The inhibitory effect of PGD₂ (in the mouse brain) does not involve DP receptors and may also be related to EP₃ receptors. The EP₃ receptors interact with a2-adrenoceptors and may be activated by endogenous prostanoids.     

北京地区啮齿动物种类和地理分布调查

目的：了解北京地区啮齿动物种类和地理分布。方法：依据历年积累资料、标本、文献记载及近几年实地调查。结果：有２７种啮齿动物,隶属于２目５科１７属及４种生态类型、５种不同水热型。结论：北京地区啮齿动物的分布随生态类型和水热型不同而有所不同。     

Historadioautographic localisation of oxytocin and vasopressin binding sites in the central nervous system of the merione (Meriones shawi)

The distribution of vasopressin and oxytocin binding sites in the central nervous system of the merione (Meriones shawi), a rodent adapted to desert life, was studied by means of conventional film radioautography at macroscopic scale and historadioautography at cellular level using radioiodinated ligands highly selective for either oxytocin or type V1 a vasopressin receptors. Both types of binding sites exhibited the same selectivity for endogenous peptides as in the rat. Distribution of oxytocin binding sites was similar in some structures (limbic system, spinal cord) to that described in the rat and in other rodents. Vasopressin binding sites were much more widely distributed in the merione than in the rat brain. In addition to locations common to most rodents (lateral septum and suprachiasmatic nucleus), in merione vasopressin binding sites occurred in several areas known to express oxytocin binding sites in the rat (olfactory system, hypothalamus). Colocalisation of vasopressin and oxytocin binding sites, which occurred in the CA1 and CA2 fields of Ammon's horns of the hippocampus, the caudate-putamen and the fundus striati of the merione, has so far not been reported in any other rodent.     

Sequence Analysis of Genes Encoding Rodent Homologues of the Human Tumor-rejection Antigen SART-1

Human SART-1 ( hSART-1 ) gene encodes a 125 kD protein with a leucine-zipper motif expressed in the nucleus of all proliferating cells, and a 43 kD protein expressed in the cytosol of most epithelial cancers. In this study, two rodent genes ( rSART-1 and mSART-1 ) homologous to hSART-1 were cloned from cDNA libraries of murine brain and a rat tumor cell line, respectively. mSART-1 and rSART-1 were highly homologous to hSART-1 with 86% and 84% identity at the nucleotide level, and 95% and 91% at the protein level, respectively. The leucine zipper domain and two basic amino acid portions that bind DNA, as well as peptide sequences recognized by human cyto-toxic T lymphocytes (CTLs), were all conserved in these rodent genes. Nuclear protein homologous to the 125 kD hSART-1₈₀₀ protein, but not to the 43 kD cytosol SART-1₂₅₉ protein, was detectable with specific antibody in the nuclear fractions of rodent tumor cell lines, and normal rodent fetal liver and testis. These rodent genes should be a novel tool for studies on the biological roles of the SART-1 gene, and also in the construction of animal models of specific immuno-therapy using SART-1 gene products.     

塔里木盆地啮齿动物体外寄生虫群落结构及其聚类分析

目的 掌握塔里木盆地啮齿动物体外寄生虫群落组成、结构和分类。方法 根据地理区划和生境类型选择调查点，按样方法捕获啮齿动物，对体外寄生虫进行单独鉴定，采用群落生态学技术方法，计算各鼠类、蚤类群落的组成和结构参数，并采用聚类分析的方法，对该地区啮齿动物体外寄生虫群落进行分类。结果 在塔里木盆地共捕获啮齿动物7种351只，检获体外寄生蚤10种683只，蜱类3种321只，螨621只，虱29只，构建7个鼠类、蚤类群落；子午沙鼠体外寄生蚤的蚤指数、丰富度和多样性3项指标均较高，对该地区啮齿动物体外寄生虫群落的构成和稳定起到了积极作用，三趾跳鼠体外寄生虫群落与子午沙鼠存在一定的互补性，对维持塔里木盆地蚤类群落结构亦具有重要的作用。结论 经聚类分析可将塔里木盆地7种啮齿动物体外寄生虫群落聚类为4个类型：（1）短耳沙鼠、小林姬鼠、灰仓鼠和小家鼠体外寄生虫群落；（2）三趾跳鼠体外寄生虫群落；（3）大耳跳鼠体外寄生虫群落；（4）子午沙鼠体外寄生虫群落。