共查询到20条相似文献,搜索用时 15 毫秒
1.
Glucocorticoids are used clinically for the treatment of acoustic injury. However, the protective mechanism of glucocorticoid in acoustic injury has not been completely clarified. Also, the effects of phospholipase A2 (PLA2) on acoustic injury have not been examined to the best of our knowledge. The purpose of the present study was to examine the effects of methylprednisolone, a glucocorticoid receptor inhibitor (RU486) and a phospholipase A2 inhibitor (quinacrine) on cochlear injury induced by acoustic overexposure. Seventy-eight mice were exposed to a 4kHz pure tone at 128dB SPL for 4h. The auditory brainstem response (ABR) was used to examine the hearing thresholds. Cochlear morphology was examined to estimate the outer hair cell loss induced by acoustic overexposure. Methylprednisolone and quinacrine significantly alleviated the hearing threshold shift and hair cell loss induced by acoustic overexposure. RU486 antagonized the protective effect of methylprednisolone. The present findings suggest firstly that glucocorticoids exert protective effects against acoustic injury; secondly, that the protective effect of methylprednisolone was exerted by binding glucocorticoid receptors, and finally that activation of PLA2 may be involved in acoustic injury. 相似文献
2.
胸腺肿瘤组织中EB病毒、细胞增殖和凋亡的检测 总被引:10,自引:0,他引:10
目的 研究胸腺肿瘤在广州5所医院的发病情况,与EB病毒(EBV)感染是否相关以及肿瘤细胞增殖和凋亡的等级,方法 以43例胸腺肿瘤和7例胸腺增生组织主研究对象,采用原位分子杂交检测EB病毒编码的EBERs,免疫组化LSAB法检测EBNA-1,LMP-1,PCNA,bcl-2和p53原位细胞凋亡(TUNEL)方法检测细胞凋亡,结果 (1)胸腺疾病在广州5所医院活检中仅占有0.057%,其中肿瘤占74. 相似文献
3.
Yintong Xue Patrick Chomez Esmeralda Castanos-Velez Peter Biberfeld Thomas Perlmann Mikael Jondal 《European journal of immunology》1997,27(8):2048-2056
The orphan nuclear receptor Nur77 has been implicated in thymic negative selection. We studied the effect of two T cell receptor (TCR) transgenes on positive selction and Nur77 mRNA expression in thymus. DO11.10 mice, expressing a transgenic TCR specific for an ovalbumin (OVA) 323–339 peptide presented by I-Ad, were found to have an enlarged thymus with a reduced apoptotic activity, measured by flow cytometry, reduced mitochondrial membrane potential and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) techniques. In contrast, in F5 mice expressing a transgenic TCR recognizing the influenza virus nucleoprotein (NP) 366–374 peptide restricted by Db, this positive selection effect was much less pronounced. Positive thymic selection in DO11.10 TCR+ mice correlated with a reduced level of Nur77 mRNA expression shown by Northern blot. F5 mice expressed levels close to those expressed by the wild type. Both transgenic mouse strains responded with extensive cortical apoptosis, and with up-regulation of Nur77 mRNA, to injection of cognate peptides. As 9-cis-Retinoic acid (9-cis-RA) inhibits Nur77-dependent apoptosis in T cell hybridomas in vitro, mice were pretreated with the drug to investigate a similar effect in vivo. However, the drug itself, at saturating concentrations, caused extensive apoptosis in immature CD4+/CD8+ thymocytes. The result demonstrates a correlation between Nur77 expression and thymic apoptotic activity, both during positive and negative selection events. 相似文献
4.
Negative selection in thymus occurs by apoptosis in CD4+CD81 cells. These immature thymocytes are readily killed, both in vitro and in vivo, by glucocorticoid treatment. Increased levels of intracellular cAMP in vitro also induce apoptosis of thymocytes and T cell receptor (TcR) stimulation potentiate cAMP responses through receptors linked to adenylic cyclase. Presently, we have tested the possibility that TcR-mediated apoptosis in vivo may require the glucocorticoid receptor (GR) as a downstream, intracellular mediator. Use of the GR antagonist RU-486, 24 h before and simultaneous with, anti-CD3 or 5′-(N-ethyl)-carboxamide-adenosine (NECA) treatment, resulted in a selective inhibition of CD4+CD8+ thymocyte death. In addition, a low dose of glucocorticoid potentiated thymocyte death induced by anti-CD3 monoclonal antibodies. These data support a model in which thymic negative selection depends on a defined set of transduction signals which potentiate the GR to become responsive to endogenous levels of glucocorticoid. 相似文献
5.
Mice expressing transgenic T cell receptors (TCR) are used to explore important questions in immunity. However, transgene expression may have unexpected effects. We previously reported a B cell immunodeficiency, comprising decreased B cell numbers and diminished antibody responses, in mice that express a transgenic TCR specific for nicotinic acetylcholine receptor; the mice were generated using cassette vectors designed specifically for transgenic TCR expression [see Kouskoff et al. J. Immunol. Methods 1995. 180: 273-280]. We now show data suggesting that this defect is due to the expression and accumulation of TCR alpha and beta chains inside B cells and induction of an endoplasmic reticulum stress response, causing apoptosis at the pre B-I and later B cell stage. Thus, inappropriate transgene expression can profoundly affect B cells, leading to a previously undescribed mechanism of immunodeficiency. 相似文献
6.
During aging in mice and humans, a gradual decline in thymus integrity and function occurs (thymic involution). To determine whether T cell reactivity or development affects thymic involution, we compared the thymic phenotype in old (12 months) and young (2 months) mice transgenic for rearranged alphabeta or beta 2B4 T cell receptor (TCR) genes, mice made deficient for CD4 by gene targetting (CD4(-/-)), mice made deficient for major histocompatibility complex (MHC) class I (beta2M-/-) or class II genes (A(beta)(b-/-) on C57Bl/6 background) or both. The expected aging-related reductions in thymic weights were observed for all strains except those bearing disruption of both class I and class II MHC genes. Therefore, disruption of MHC class I and class II appeared to reverse or delay aging-related thymic atrophy at 12 months. Immunohistochemical analysis of aging-associated alterations in thymic morphology revealed that TCR alphabeta transgenes, CD4 disruption, and MHC class II disruption all reduced or eliminated these changes. All strains examined at 12 months showed alterations in the distribution of immature thymocyte populations relative to young controls. These results show that aging-associated thymic structural alterations, size reductions, and thymocyte developmental delays can be separated and are therefore causally unrelated. Furthermore, these results suggest that the T cell repertoire and/or its development play a role in aging-related thymic involution. 相似文献
7.
K Yui A Bhandoola M Z Radic S Komori M Katsumata M I Greene 《European journal of immunology》1992,22(7):1693-1700
Mice homozygous for the gld (generalized lymphoproliferative disease) mutation developed systemic autoimmune disease and severe lymphadenopathy due to an age-related accumulation in the peripheral lymphoid organs of polyclonal T cells bearing a unique phenotype (CD4-CD8-TCR alpha beta+B220+). These T cells overexpress T cell receptor (TcR) alpha beta chain RNA, proto-oncogenes c-myb and fyn, and proliferate poorly in response to TcR-mediated stimulation. The origin of these T cells is poorly understood. To study the influence of a functionally rearranged TcR beta chain on the T cell developmental abnormality of the gld mutation and autoimmunity, we have backcrossed TcR V beta 8.1-transgenic mice to C3H-gld/gld to homozygosity (transgenic gld mice). In transgenic gld mice, lymphadenopathy was markedly inhibited and the accumulation of CD4-CD8- T cells did not occur, although the remaining T cells overexpressed c-myb and proliferated poorly in response to TcR occupancy. These features indicate that the pattern of proto-oncogene expression and abnormal function persist in phenotypically normal T cells in transgenic gld mice, and that these characteristics can be dissociated from the accumulation of CD4-CD8- T cells. The hypergammaglobulinemia and anti-double-stranded DNA (anti-dsDNA) antibody production was partially improved in transgenic gld mice, supporting the critical role of T cells in abnormal B cell activation described in autoimmunity-prone mice. To investigate further the mechanisms underlying the inhibition of CD4-CD8- T cell accumulation in transgenic gld mice, the fetal ontogeny of T cells in transgenic mice was compared with that of non-transgenic mice. In transgenic thymus, development of TcR alpha beta+ cells was accelerated as detected by earlier expression of CD4, CD8 and TcR in fetal thymus. In contrast, the number of TcR gamma delta+ cells was reduced. We suggest that altered T cell development in transgenic mice directly or indirectly inhibits the accumulation of abnormal T cells in gld mice. 相似文献
8.
Pieter Brekelmans Peter Van Soest Pieter J. M. Leenen Willem van Ewijk 《European journal of immunology》1994,24(11):2896-2902
Proliferating cells require iron and, therefore, express the transferrin receptor (CD71) that mediates cellular iron uptake. Cycling thymocytes, which have the CD4?8?3?, CD4?8+3?, or CD4+8+3? phenotypes, also express CD71. The importance of CD71-mediated iron uptake for proliferation and maturation of thymocytes was studied using fetal thymus organ cultures at day 14 of gestation and treating them for 7 days with a CD71 monoclonal antibody (mAb). The intracellular iron deficiency caused by this treatment, inhibits both proliferation and maturation of the thymocytes. Cell recovery was reduced by 60%, but cells still expanded tenfold during the culture. Remarkably, the final maturation of αβ T cells was completely blocked as no thymocytes with low or high CD3/αβTcR expression developed. Moreover, only few cells reached the CD4+8+3? stage of T cell development. CD4?8?3? thymocytes, however, as well as its CD44?25+ subset developed in normal numbers, suggesting that CD44?25+ CD4?8?3? cells, or their immediate progeny, were most vulnerable to CD71 mAb treatment. The development of γδ T cells, which also express CD71, was not affected in these cultures. This suggests that γδ T cells are either less iron-dependent or possess alternative iron-uptake mechanisms. Thus, our observations indicate that CD71 treatment, causing decreased intracellular iron levels, severely inhibits the major proliferation phase from the CD44?25+ CD4?8?3? to the CD4+8+3? cells, and completely abrogates the final maturation of CD4+8+3? cells into αβTcR-expressing cells. In contrast, proliferation and differentiation of the earliest thymic precursors into CD44?25+ CD4?8?3? cells is not affected by CD71 treatment. 相似文献
9.
Erlacher M Knoflach M Stec IE Böck G Wick G Wiegers GJ 《European journal of immunology》2005,35(11):3287-3296
Signaling by either the TCR or glucocorticoid receptor (GR) induces apoptosis in thymocytes. Interestingly, it has been shown previously that hybridoma T cells escape apoptosis induced by either TCR or GR when both of these receptors signal simultaneously. Whether such mutual antagonism is present in primary thymocytes was the subject of the present study. Both glucocorticoids (GC) and anti-TCR/CD28 (or anti-CD3/CD28) mAb induced apoptosis in total thymocytes. When these signals were present at the same time, GC-induced apoptosis was partially inhibited by TCR/CD3 signaling. Costimulation by anti-CD28 enhanced the inhibitory effects of anti-CD3 on GC-induced apoptosis about 30-fold. However, subset analysis revealed that most cells rescued from GC-induced apoptosis were mature CD4+ and CD8+ thymocytes, and these cells were resistant to TCR/CD3-induced apoptosis in the absence of GC. Similar results were obtained with mature splenic CD4+ and CD8+ T cells. TCR/CD3 signaling alone, while inducing apoptosis in CD4+(CD8+)TCRlow thymocytes, rescued a small subset of CD4+(CD8+)TCRlow thymocytes from GC-induced apoptosis. Thus, TCR signaling increasingly reverses GC-induced apoptosis as thymocyte development progresses. As GC are infinitely present in vivo, these findings support a model wherein TCR signaling may be required to prevent GC-induced apoptosis both under basal and immune challenging conditions. 相似文献
10.
Katherine A. Kelly Hanspeter Pircher Harald von Boehmer Mark M. Davisand Roland Scollay 《European journal of immunology》1993,23(8):1922-1928
The thymus produces many more cells than it releases into the periphery. According to generally accepted models of T cell development most of this loss occurs in the thymic cortex, among CD4+8+ thymocytes. An interesting situation arises in the case of T cell receptor (TcR) transgenic mice in which all cells can potentially be positively selected, leading to a theoretical increase of about 30-fold in the survival rate of CD4+8+ cells and in their transition to mature CD4+8?or CD4?8+ thymocytes. This in turn should lead to a 30-fold increase in the size of the thymic medulla, in the emigration rate and in the size of the peripheral Tcell pool. Increases in medullary or peripheral pool sizes of this magnitude are not seen in TcR transgenic mice. The question was therefore asked whether some form of homeostatic process regulated the size of the mature T cell pool and at what level it might operate. In this report we demonstrate that the increased rate of double-positive to single-positive transition in the TcR transgenic mice is directly reflected in an increased emigration rate, and that the medulla seems to be relatively efficient regardless of the number of cells passing through it. However, the potential increases in emigrant numbers in TcR transgenic mice are offset by the reduced size of the CD4+8+ thymocyte pool. It would appear then that regulation of T cell production, if it occurs, probably does so through regulation of the size of the CD4+8+ thymocyte pool. Mechanisms for regulation of this kind are not yet known. 相似文献
11.
目的探讨大剂量的RU486对早孕猕猴腺垂体-肾上腺皮质系统(PAS)的糖皮质激素受体(GR)的表达变化。方法15只早孕猕猴随机分为空白对照组、赋形剂组和RU486组。空白对照组不予任何处理,赋形剂组和RU486组每天分别鼻饲0.5%CMC-Na(1ml/mg)和RU486(15mg/kg),3d后处死动物。应用单克隆抗体链菌素亲生物蛋白过氧化酶(SP)免疫组织化学方法观察腺垂体-肾上腺皮质GR的表达情况,并用电子计算机图像分析技术进行处理。结果RU486组猕猴妊娠终止,该组腺垂体、肾上腺皮质GR的表达减少,积分光密度值分别为32.9±6.6、64.9±4.5,与空白对照组(61.2±3.9、95.9±20.9)的差异有统计学意义(P<0.05)。空白对照组和赋形剂组妊娠没有终止,赋性剂组腺垂体、肾上腺皮质GR积分光密度值分别为63.8±4.8、91.3±14.7。与空白对照组GR表达的差异无统计学意义(P>0.05)。结论RU486可使早孕猕猴腺垂体-肾上腺皮质的GR表达下降,提示RU486的抗糖皮质激素作用可能是其终止妊娠的机制之一。 相似文献
12.
Owen Williams Yujiro Tanaka Mark Bix Marianna Murdjeva Dan R. Littman Dimitris Kioussis 《European journal of immunology》1996,26(3):532-538
The T cell receptor (TCR) recognizes antigenic peptide presented by major histocompatibility complex (MHC) molecules. Analogs of antigenic peptides have been shown to inhibit antigen-specific T cell responses, a phenomenon described as TCR antagonism. We have examined the effect of a natural variant of an antigenic peptide and a synthetic peptide analog, on the responses of mature T cells and immature thymocytes from an αβ TCR-transgenic mouse (F5), the TCR of which recognizes a nonamer peptide from the nucleoprotein (NP) of influenza virus in the context of the H-2Db MHC molecule. Both peptides were shown to antagonize specifically the T cell cytolytic response without being able directly to stimulate mature T cells from these transgenic mice. Furthermore, a negative selection assay in vitro was used to demonstrate for the first time that antagonistic peptides are capable of antagonizing thymocyte deletion induced by antigenic peptides. These data suggest that the final selection of a T cell could be the result of a balance between the positive and negative influences of endogenous peptide ligands. 相似文献
13.
14.
目的 初步探讨实验性自身免疫性脑脊髓炎(EAE)小鼠胸腺萎缩的机制.方法 髓鞘少突胶质细胞糖蛋白(MOG)免疫C57BL/6小鼠诱导EAE,卵清白蛋白(OVA)免疫的小鼠作为对照;不同时间点计数胸腺、脾脏、淋巴结细胞总数,检测脾脏中胸腺来源细胞及中枢神经系统(CNS)浸润细胞.结果 MOG肽成功诱导EAE动物模型,小鼠出现典型的肢体运动功能障碍,脊髓可见大量炎性细胞浸润;MOG和OVA免疫均诱导胸腺细胞增加,第5天达到高峰,随后逐渐下降;EAE发病后胸腺细胞迅速减少,发病高峰期几乎完全消失,胸腺严重萎缩;MOG和OVA免疫后脾脏和淋巴结细胞总数持续升高,新近胸腺来源的T细胞增加尤其明显;EAE发病后脾脏T细胞总数减少,CNS浸润淋巴细胞总数增加.结论 大量T细胞在胸腺发育成熟并释放到外周,进而定向迁移至CNS诱导EAE是胸腺萎缩的主要原因. 相似文献
15.
Antonio J. Oliveira-dos-Santos Josef M. Penninger Theresa Rieker-Geley Goichi Matsumoto Tak M. Mak Georg Wick 《European journal of immunology》1998,28(9):2882-2892
Thymocytes form unique multicellular complexes with epithelial cells (thymic nurse cells, TNC) and rosettes (ROS) with macrophages, epithelial cells and dendritic cells. To investigate the role of differentiation checkpoints in the formation of the thymic heterotypic complexes in vivo, we used mutant mice which have genetically defined blocks at early and late stages of T cell development. We show that RAG-1−/−, TCRβ−/−, and p56lck−/− mice lack thymocyte ROS formation with epithelial cells, macrophages, or dendritic cells. TNC formation was not affected by TCRβ and p56lck gene mutations but partially decreased in RAG-1−/− mice, indicating that TNC are the earliest thymocyte-stromal cell complexes formed in development, whereas ROS only appear after thymocytes have rearranged and expressed a functional TCRβ chain. Genetic blocks in CD8 lineage commitment (CD8−/− and IFN regulatory factor-1−/− mice) and positive and negative T cell selection (CD45−/−, TCRα−/−, and CD30−/− mice) did not affect thymocyte-stromal cell complexes. Surprisingly, CD4−/− mice, but not MHC class II−/− mice, had significantly reduced numbers of TNC and ROS, in particular, a severe defect in ROS formation with thymic dendritic cells. The CD4−/− block in ROS and TNC formation was rescued by the introduction of a human CD4 transgene. Moreover, we show that the adhesion receptors CD44 and LFA-1 cooperate in the formation of the thymic microenvironment. These results provide genetic evidence on the role of defined stages in T cell development and adhesion molecules on thymocyte/stromal cell interactions in vitro. 相似文献
16.
Klaus Joseph Erb Thomas Hanke Anneliese Schimpl Thomas Hünig Georg Stingi Adelheid Elbe 《European journal of immunology》1995,25(5):1442-1445
The mouse epidermis contains a network of Thy-1+ dendritic T cells. Most of these cells express a homogeneous T cell receptor (TCR) configuration (Vγ3/ Vδ1) with only negligible junctional diversity. Because fetal thymocytes are precursors of these dendritic epidermal T cells (DETC) and the addition of interleukin (IL)-4 to fetal thymic organ cultures causes an early arrest in thymopoiesis, we examined DETC development in transgenic (tg) mice expressing IL-4 under the control of major histocompatibility complex class I regulatory sequences. Immunohistologic examination of epidermal sheets and polymerase chain reaction analysis of total skin RNA from IL-4 tg mice failed to reveal TCR Vγ3+ DETC and Vγ3 mRNA, respectively. In contrast, the sizes of TCR γδ subpopulations in lymphoid organs were unchanged in these mice. Although the numbers and staining intensities of TCR Vγ3+ thymocytes in early fetal (days 14–17) IL-4 tg mice were similar to those of littermate controls, we observed a preferential death of these cells in thymic organ cultures from IL-4 tg mice. We observed further that epidermal sheets prepared from 9-day-old mice whose mothers had been treated with an IL-4-neutralizing antibody from day 12 to day 18 of pregnancy contained DETC numbers similar to those of controls. However, upon termination of the anti-IL-4 treatment, DETC ceased to expand. We conclude that IL-4 impairs the survival of TCR Vγ3+ cells. 相似文献
17.
目的: 探讨脑中性内肽酶(NEP)外源表达对神经毒物质β淀粉样肽(Aβ)诱导SK-N-SH细胞凋亡的影响。方法: 采用脂质体法将含中性内肽酶NEP的四质粒系统慢病毒载体转染293FT包装细胞,制备高滴度病毒载体,感染Aβ处理的SK-N-SH细胞,用Western blotting方法检测NEP对Aβ的降解作用、MTT法检测细胞存活率、流式细胞术分析细胞凋亡情况、RT-PCR技术测定凋亡相关基因bcl-2及bax的表达及caspase-3活性检测。结果: 胞内高表达的NEP能够显著降解Aβ,其降解程度与NEP的表达量有剂量依赖关系。细胞存活率及流式细胞术检测结果显示NEP高表达可减轻Aβ诱导的细胞凋亡,细胞存活率于感染病毒后48 h最强,为对照的170%(P<0.01),NEP活性组的凋亡率为3.86%,低于对照组的6.41%;RT-PCR结果显示NEP对Aβ诱导的细胞凋亡保护作用可能是通过减少bax的表达,抑制了caspase-3的激活程度来实现的。结论: NEP可以降解Aβ,可以保护由Aβ沉积所致的神经细胞凋亡。 相似文献
18.
目的通过用地塞米松诱导小鼠胚胎成骨细胞前体细胞(MC3T3-E1)的凋亡,建立激素性股骨头坏死的细胞模型,探讨抗氧化剂(N-乙酰-L-半胱氨酸,NAC)和钙蛋白酶的抑制剂(PD151746)对MC3T3-E1细胞抑制凋亡的作用和可能机制的研究。方法 CCK-8检测NAC和PD151746不同药物浓度对MC3T3-E1细胞增殖的影响,选择合适的药物浓度。细胞分组:正常组(10%FBS),激素组(地塞米松1×10~(-6) mol/L),NAC组(NAC1 mmol/L+地塞米松1×10~(-6) mol/L)和PD151746组(简称PD组,PD 10 mol/L+地塞米松1×10-6 mol/L),流式细胞仪检测细胞凋亡率和ROS含量,激光扫描共聚焦显微镜检测各组ROS荧光强度和钙离子荧光强度,Western blot测定细胞蛋白AIF、PARP-1和Cyt-c的表达水平。结果 CCK-8结果显示,NAC和PD151746的实验浓度分别取1 mmol/L和10 mol/L。流式细胞仪检测凋亡率结果显示,激素组、NAC组和PD组的凋亡率与正常组比较,差异有统计学意义(0.05),激素组与NAC组、PD组比较差异有统计学意义(0.05)。流式细胞仪和激光扫描共聚焦显微镜检测各组ROS含量,结果显示激素组荧光强度最高,与NAC组和PD组比较明显增高(0.05),其他三组与正常组比较差异也具有统计学意义(0.05)。激光扫描共聚焦显微镜检测钙离子荧光强度,与NAC组和PD组比较明显增高(0.05),其他三组与正常组比较差异也具有统计学意义(0.05)。Western blot检测各组AIF、PARP-1和Cyt-c的表达水平,激素组、NAC组和PD组的凋亡率与正常组比较,差异有统计学意义(0.05),激素组与NAC组、PD组比较差异有统计学意义(0.05)。结论 NAC能抑制地塞米松诱导的ROS产生,PD151746能有效抑制钙蛋白酶的活性,抑制PAPR-1/AIF的释放,抑制成骨细胞凋亡,ROS/PARP-1/AIF通路参与了地塞米松诱导MC3T3-E1细胞的凋亡过程。 相似文献
19.
Engagement of the TCR may result in proliferation and cytokine release or programmed cell death. These two outcomes may be the consequence of distinct T cell receptor-coupled signal transduction pathways or may reflect quantitative differences in signaling strength via a single pathway. Here we show that genetic inhibition of MAP kinase kinase (MEK) by a dominant negative mutant or through chemical inhibition by PD98059 inhibits IL-2 secretion but not programmed cell death after TCR ligation by superantigen. This supports the hypothesis that T cell cytokine release and apoptosis result from signaling through distinct pathways and implies that the molecular signaling mechanisms regulating apoptosis of mature T cells and negative selection of thymocytes may be similar. 相似文献
20.
Valrie Kouskoff Kathy Signorelli Christophe Benoist Diane Mathis 《Journal of immunological methods》1995,180(2):273-280
We describe a pair of cassette vectors that can be used to express rearranged T cell receptor genes in transgenic mice. Short DNA fragments containing rearranged V and Vβ segments are readily amplified from T cells and introduced between artificial cloning sites. Transgene-derived mRNAs are transcribed under the control of the natural TCR and -β promoter/enhancer elements. Using this vector, we have obtained transgenic mouse lines which display transgene-encoded TCR and β chains on a majority of T cells. 相似文献