ConA引起小鼠肝损伤实验研究

目的探讨conA引起免疫性肝损伤机实验条件。方法测定两个浓度,不同时间点ConA尾静脉注射后小鼠转氨酶水平及肝、脾病理变化。结果15mg／kgConA尾静脉注射后8h,血清转氨酶升高,但病检无明显改变;20mg／kgConA尾静脉注射,脾指数6h达峰值,10h肝脏病理变化显著,转氨酶水平达峰值。结论20mg／kgConA小鼠尾静脉注射6h后脾病变达高峰,10h可引起显著性肝损害。     

天然真菌与人工发酵制品对免疫系统的影响研究概况

整理分析有关真菌及其生物技术制品生物活性的研究文献,发现真菌类中药资源丰富、品种繁多、成分复杂、药理作用广泛。目前已被动物实验或临床研究证实具有显著生物活性的主要成分是多糖类、三萜类、核苷类以及多肽类等天然化合物。尤其是作为真菌细胞结构物质的高分子多糖体对机体免疫系统具有显著的影响。如在保护机体免疫器官、增加免疫器官重量,以及对单核吞噬细胞系统、T细胞、B细胞、红细胞、NK细胞、LAK细胞、补体系统、白细胞介素、干扰素、集落刺激因子、肿瘤坏死因子及一氧化碳等多项或单项免疫功能具有显著的增强或调节作用。在抗病毒与抗肿瘤免疫等方面显示出自身特点和优势。虽然也有一些真菌及其提取物被证明对机体免疫功能具有显著的、与药物剂量相关的抑制作用,但并未发现对机体免疫器官或免疫细胞有任何的毒副反应。作者拟将20年来有关真菌及其提取物对机体免疫系统的影响研究文献进行了整理,并按免疫功能分类进行了综述,对相关问题在文后还作了讨论,以期为真菌类药物在医学上进行深入的临床研究与应用提供思路。     

蛋氨酸脑啡肽对免疫系统恢复作用的研究

采用固相合成法合成蛋氨酸脑啡肽,制备成注射液。对经放化疗后免疫系统受到伤害的晚期肿瘤志愿者进行治疗,经静脉滴注15 d。患者免疫系统指标全面迅速恢复,淋巴细胞亚群间比例趋于合理,证明蛋氨酸脑啡肽可以用于癌症患者的免疫系统的恢复治疗。     

Functional diversification of the toll-like receptor gene family

Phylogenetic analyses supported the hypothesis that the vertebrate toll-like receptors (TLRs) include two very ancient groups that arose by gene duplication prior to the divergence of protostomes and deuterostomes: (1) the TLR1 family (including mammalian TLR1, TLR2, TLR6, and TLR10); and (2) a clade including the remainder of mammalian TLRs. Correlating data on ligand type, subcellular localization, and gene expression in leukocytes and other tissues with the phylogeny provided evidence that certain major functional specializations within the TLRs occurred after ancient gene duplication events and that these traits have been retained through further events of gene duplication. For example, the recognition of bacterial lipoproteins appears to have arisen in the ancestor of the TLR1 family and continues to characterize members of that family whose ligands are known. Likewise, expression on the endosomal membrane and the recognition of nucleic acids appears to have been arisen in the ancestor of the TLR7 family and some related TLRs. On the other hand, gene expression patterns across tissues appear to have been much more volatile over the evolution of the vertebrate TLRs, since genes may show expression profiles similar to those of distantly related genes but dissimilar to those of closely related genes. Thus, the vertebrate TLRs provide an example of a multi-gene family in which gene duplication has been followed by extensive changes in certain aspects of gene function, while others have been conserved throughout vertebrate history. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Material basis for inhibition of Dragon’s Blood on evoked discharges of wide dynamic range neurons in spinal dorsal horn of rats

In vivo experiments were designed to verify the analgesic effect of Dragon’s Blood and the material basis for this effect. Extracellular microelectrode recordings were used to observe the effects of Dragon’s Blood and various combinations of the three components (cochinchinenin A, cochinchinenin B, and loureirin B) extracted from Dragon’s Blood on the discharge activities of wide dynamic range (WDR) neurons in spinal dorsal horn (SDH) of intact male Wistar rats evoked by electric stimulation at sciatic nerve. When the Hill's coefficients describing the dose-response relations of drugs were dif-ferent, based on the concept of dose equivalence, the equations of additivity surfaces which can be applied to assess the interaction between three drugs were derived. Adopting the equations and Tal-larida's isobole equations used to assess the interaction between two drugs with dissimilar dose-response relations, the effects produced by various combinations of the three components in modulating the evoked discharge activities of WDR neurons were evaluated. Results showed that Dragon’s Blood and its three components could inhibit the evoked discharge frequencies of WDR neurons in a concentration-dependent way. The Hill's coefficients describing dose-response relations of three components were different. Only the combined effect of cochinchinenin A, cochinchinenin B and loureirin B was similar to that of Dragons Blood. Furthermore, the combined effect was synergistic. This investigation demonstrated that through the synergistic interaction of the three components Dragon’s Blood could interfere with the transmission and processing of pain signals in spinal dorsal horn. All these further proved that the combination of cochinchinenin A, cochinchinenin B, and loureirin B was the material basis for the analgesic effect of Dragon’s Blood.     

Comparison of pathogenic properties of the murid gammaherpesvirus (MuHV 4) strains: a role for immunomodulatory proteins encoded by the left (5′-)end of the genome

The murid herpesvirus 4 (MuHV 4) species encompasses 7 isolates, out of which at least two (MHV-68, MHV-72) became in vitro propagated laboratory strains. Following intranasal inoculation, MuHV 4 induces an acute infectious mononucleosis-like syndrome with elevated levels of peripheral blood leukocytes, shifts in the relative proportion of lymphocytes along with the appearance of atypical mononuclear cells. At least two isolates exhibited spontaneous deletions at the left hand (5′-end) of their genome, resulting in the absence of M1, M2, M3 genes (strain MHV-72) and also of the M4 gene (strain MHV-76). Based on DNA sequence amplifications only, another two isolates (MHV-Šum and MHV-60) were shown to possess similar deletions of varying length. During latency (until 24 months post-infection), the mice infected with any MuHV 4 isolate (except MHV-76) developed lymphoproliferative disorders. The lack of tumor formation in MHV-76 infected mice was associated with persistent virus production at late post-infection intervals. In addition to careful analysis of spontaneously occurring 5′-end genome defects, our knowledge of the function of 5′-end genes relies on the behaviour of mutants with corresponding deletions and/or insertions. While M2 and M3 genes encode immune evasion proteins, M4 codes for a soluble glycopeptide acting as immunomodulator and/or immunostimulator.     

Plasmodium berghei: parasite clearance after treatment with dihydroartemisinin in an asplenic murine malaria model

Clinical reports indicate that malaria-infected asplenic patients have a reduced capacity for parasite clearance despite intensive antimalarial therapy. The aim of this study was to evaluate the efficacy of dihydroartemisinin in an asplenic murine malaria model. Mice were inoculated with Plasmodium berghei parasitised erythrocytes and received a single dose of dihydroartemisinin 56 h later, at 2-5% parasitaemia. Haematology, liver biochemistry and histopathology of key organs were performed to evaluate organ response to malaria infection. The nadir parasitaemia occurred 20 h after dihydroartemisinin administration, falling 2.8- to 6.0-fold and 2.7- to 6.9-fold in asplenic and intact mice, respectively, (10-100 mg/kg). Histopathology indicated increased stimulation of liver function/activity during malaria infection of asplenic mice (as compared to intact mice). Overall efficacy of single-dose dihydroartemisinin treatment in asplenic mice was similar to intact mice although the rate of recrudescence in asplenic mice was significantly greater than intact mice at 30 and 100 mg/kg. The asplenic murine malaria model could be used in pre-clinical studies of splenic function and clearance of malaria parasites, pathophysiological studies or antimalarial drug efficacy in asplenia.     

Reciprocal influences of CB1 cannabinoid receptor agonists on ERK and JNK signalling in N1E-115 cells

Agonists acting at the CB₁ cannabinoid receptor in N1E-115 neuroblastoma cells were found to activate MAPK family members with reciprocal efficacies. Thus, HU 210 robustly increased phosphorylation of ERK1/2 whereas CP 55,940 was more effective in activating JNK. The use of selected kinase inhibitors confirmed that distinct signalling cascades were involved in these responses. This reciprocal control of MAPK activity was correlated with the observation that HU 210- and CP 55,940-mediated regulations of tyrosine hydroxylase gene expression were respectively impaired by MEK and JNK inhibitors. These data indicate that complex interactions of the CB₁ receptor with intracellular signalling partners controlling MAPK activities may explain the apparent disparities in cellular responses to functional selective agonists.     

Which mechanisms are involved in taurine-dependent granulocytic immune response or amino- and α-keto acid homeostasis?

We examined the effects of beta-alanine (taurine analogue and taurine transport antagonist), taurine (regarding its role in neutrophil (PMN) immunonutrition) and taurine combined either with L-NAME (inhibitor of *NO-synthase), SNAP (*NO donor), DON (glutamine-analogue and inhibitor of glutamine-requiring enzymes), DFMO (inhibitor of ornithine-decarboxylase) and beta-alanine on neutrophil amino- and alpha-keto acid profiles or important PMN immune functions in order to establish whether taurine transport-, nitric oxide-, glutamine- or ornithine-dependent mechanisms are involved in any of the taurine-induced effects. According to the present findings, the taurine-mediated effect appears to be based primarily on a modulation of important transmembraneous transport mechanisms and only secondarily on directly or indirectly induced modifications in intragranulocytic amino- and alpha-keto acid homoeostasis or metabolism. Although a direct relation to the parallel observed immunological modifications can only be presumed, these results show very clearly that compositional modifications in the free intragranulocytic amino- and alpha keto-acid pools coinciding with changes in intragranulocytic taurine levels are relevant metabolic determinants that can significantly influence the magnitude and quality of the granulocytic immune response.     

Experimental manipulations of afferent immune responses influence efferent immune responses to brain tumors

Tumors grow more readily in the brain than in the periphery, in part due to immune privilege. Differences in both afferent and efferent components of the immune response contribute to this lower level of responsiveness. On the afferent side, despite the lack of lymphatic vessels in the brain, antigens from brain arrive in lymph nodes and spleen by several routes, and the route taken may influence the type of response generated. Work with viruses and soluble antigens in mice has shown that the intracerebral location and the volume of the inoculation influence the strength of the cytotoxic T cell response. We examined whether these factors influence the T cell response against experimental brain tumors in mice. Placement of tumor cells in the cerebral ventricles instead of the parenchyma generated an immune response sufficient to increase survival time. A large volume of an intraparenchymal infusion of tumor cells caused spread of cells to the ventricles, and resulted in longer survival time relative to a small volume infusion. Infusion of the same dose of radiolabeled tumor cells in either a small volume or a large volume allowed tracking of potential tumor antigens to the periphery. Both modes of infusion resulted in similar levels of radioactivity in blood, spleen and kidney. Unexpectedly, cells infused intraparenchymally in a small volume, compared to a large volume, resulted in (1) more radioactivity in cervical lymph nodes (parotid and deep cervical lymph nodes), (2) a greater number of CD11b+/Gr1+ myeloid suppressor cells in the tumors, and (3) fewer CD8+ cells within the tumor mass. Consistent with these observations, providing a stronger afferent stimulus by giving a concurrent subcutaneous injection of the same tumor cells infused into the brain increased CD8+ T cell infiltration of the tumor in the brain. These results suggest that the immune response elicited by antigens that drain predominantly to the cervical lymph nodes may be less effective than responses elicited at other lymph nodes, perhaps due to immunosuppressive cells. Directing therapies to the optimal peripheral sites may improve immune responses against brain tumors.