In vivo activity against HIV and favorable toxicity profile of 2',3'-dideoxyinosine

The purine analog 2',3'-dideoxyinosine (ddI), which has anti-retroviral activity in vitro was administered for up to 42 weeks to 26 patients with acquired immunodeficiency syndrome (AIDS) or severe AIDS-related complex (ARC). Ten of these individuals were AZT-intolerant. Eight dose regimens were studied. The drug was orally bioavailable and penetrated into the cerebrospinal fluid (CSF). Comparatively little evidence of an effect against human immunodeficiency virus (HIV) was seen at the lowest four doses. However, patients in the four highest dose groups (ddI at 1.6 milligrams per kilogram intravenously and then greater than or equal to 3.2 milligrams per kilogram orally at least every 12 hours or higher) had increases in their circulating CD4+ T cells (P less than 0.0005), increased CD4/CD8 T cell ratios (P less than 0.01), and, where evaluable, more than an 80% decrease in serum HIV p24 antigen (P less than 0.05). The patients also had evidence of improved immunologic function, had reduced viremic symptomatology, and gained a mean of 1.6 kilogram with these comparatively infrequent dosing schedules (every 8 or 12 hours). The most notable adverse effects directly attributable to ddI administration at the doses used in this study included increases in serum uric acid (due to hypoxanthine release) and mild headaches and insomnia. These results suggest that serious short-term toxicity at therapeutic doses is not an inherent feature in the profile of agents with clinical anti-HIV activity. Further controlled studies to define the safety and efficacy of this agent may be worth considering.     

杀菌剂对芒果果腐病原粉红单端孢菌的室内毒力测定

采用生长速率法,测定了8种杀菌剂对芒果果腐病原粉红单端孢菌的室内毒力.结果表明,8种杀菌剂对芒果果腐病均有抑制效果,除氟硅唑外,其余7种均可用于防治芒果粉红单端孢菌引起的病害.其中,多菌灵对粉红单端孢菌的抑制效果最好,其EC50和EC75值分别为1.30和3.09 mg·L-1;其次依次为咪鲜胺锰盐、戊唑醇、腈菌唑和醚菌酯;代森锰锌和百菌清对病菌的抑制效果较差.     

8-羟基喹啉对草鱼急性毒性和遗传毒性的研究

以8-羟基喹啉为诱变剂,研究了其对草鱼(Ctenopharyngodon idellus)的急性毒性和遗传毒性效应.急性毒性实验测得8-羟基喹啉对草鱼的24、48、96 h的LC50分别为32.30、26.93、20.95 mg/L,表现出较强的急性毒性,其安全浓度为11.62 mg/L.遗传毒性结果表明,处理组与空白对照组相比,微核率均达到显著或极显著差异水平(P＜0.05或P＜0.01),并且表现出明显的时间效应和剂量效应.因此,8-羟基喹啉在达到一定浓度和染毒时间以后对草鱼具有一定的遗传毒性,因而推测其大量使用可能对永生生物及生态环境具有一定的毒害作用.     

Purine overproduction in man associated with increased phosphoribosylpyrophosphate synthetase activity

In hemolyzates from red cells of two brothers with purine overproduction and gout, activity of phosphoribosylpyrophosphate synthetase is more than twofold greater than that measured in normal or other gouty individuals. The increased enzyme activity, which is also demonstrable in fibroblasts of the one patient tested, is associated with increased production of 5-phosphoribosyl-1-pyrophosphate by intact cells, an indication that the enzyme abnormality is the basis for the purine overproduction. This genetic abnormality is an example of an increased enzyme activity producing a disease state.     

仔猪人工感染猪囊尾蚴后外周血中淋巴细胞亚群的动态变化研究

试验研究了仔猪人工感染猪囊尾蚴后外周血中CD_3~ 、CD_4~ 、CD_8~ T淋巴细胞的变化规律。将10头仔猪随机分为2组,即攻虫组和对照组,每组5头,用流式细胞仪检测攻虫后10,20,30,40,70 d试验猪外周血中T淋巴细胞亚群的变化情况。结果显示整个检测过程中CD_3~ T细胞比例一直处于较低水平。在感染初期CD_4~ T细胞和CD_8~ T细胞比例明显降低,且CD_4~ T细胞比例明显高于CD_8~ T细胞;感染中期CD_8~ T细胞数量有所增加,但仍以CD_4~ T细胞比例占优势;感染后期CD_4~ T细胞和CD_8~ T细胞数量都有所恢复。     

Second structural motif for recognition of DNA by oligonucleotide-directed triple-helix formation

Relative orientations of the DNA strands within a purine.purine.pyrimidine triple helix have been determined by affinity cleaving. A purine-rich oligonucleotide bound in the major groove of double-helical DNA antiparallel to the Watson-Crick purine strand. Binding depended upon the concentration of multivalent cations such as spermine or Mg2+, and appeared to be relatively independent of pH. Two models with specific hydrogen-bonding patterns for base triplets (G.GC, A.AT, and T.AT) are proposed to explain the sequence specificity of binding. The two models differ in the conformation about the glycosyl bond (syn or anti) and the location of the phosphate-deoxyribose backbone in the major groove of DNA. This motif broadens the structural frameworks available as a basis for the design of sequence-specific DNA binding molecules.     

Multiple sclerosis: distribution of T cell subsets within active chronic lesions

The distribution of T cells and T cell subsets was examined within the human central nervous system in active lesions from seven patients with chronic multiple sclerosis. The monoclonal antibodies anti-T11, anti-T4, and anti-T8 were used to detect total (whole) T cells, helper T cells, and suppressor-cytotoxic T cells, respectively, and a monoclonal antibody against human Ia was used for macrophages and B cells. Lesion progression was associated with large numbers of T4+ cells at the lesion margin and these extended great distances into the adjacent normal-appearing white matter. T8+ cells were most commonly concentrated around the lesion margin and displayed a preferential perivascular distribution. Within the lesion center, only a few T cells were found. Ia+ macrophages were most numerous within the centers of active lesions and were always present in the adjacent normal white matter. The monoclonal antibodies to T cells did not cross-react with glial cells including oligodendrocytes. These results indicate that T4+ cells are actively involved in lesion extension and Ia+ cells, in demyelination.     

Defective CD8 T cell memory following acute infection without CD4 T cell help

The CD8+ cytotoxic T cell response to pathogens is thought to be CD4+ helper T cell independent because infectious agents provide their own inflammatory signals. Mice that lack CD4+ T cells mount a primary CD8 response to Listeria monocytogenes equal to that of wild-type mice and rapidly clear the infection. However, protective memory to a challenge is gradually lost in the former animals. Memory CD8+ T cells from normal mice can respond rapidly, but memory CD8+ T cells that are generated without CD4 help are defective in their ability to respond to secondary encounters with antigen. The results highlight a previously undescribed role for CD4 help in promoting protective CD8 memory development.     

A role for CD40 expression on CD8+ T cells in the generation of CD8+ T cell memory

The delivery of CD4 help to CD8+ T cell responses requires interactions between CD40 and CD40 ligand and is thought to occur through antigen-presenting cell (APC) activation. Here we show that generation of memory CD8+ T cells displaying an enhanced capacity for cell division and cytokine secretion required CD4 help but not CD40 expression by the APCs. Activated CD4+ and CD8+ T cells expressed CD40; and in the absence of this protein, CD8+ T cells were unable to differentiate into memory cells or receive CD4 help. These results suggest that, like B cells, CD8+ T cells receive CD4 help directly through CD40 and that this interaction is fundamental for CD8+ T cell memory generation.     

Activators of protein kinase C induce dissociation of CD4, but not CD8, from p56lck

The CD4 and CD8 T cell receptor accessory molecules can both be isolated from T lymphocytes in association with p56lck, a membrane-associated, cytoplasmic tyrosine protein kinase that is expressed exclusively in lymphoid cells. The enzymatic activity of p56lck may therefore be regulated by CD4 and CD8 and be important in antigen-induced T cell activation. Exposure of human T cells and some mouse T cells to the tumor promoter 12-O-tetradecanoyl phorbol-13-acetate (TPA), an activator of protein kinase C, caused the dissociation of p56lck and CD4. Activation of protein kinase C may therefore interrupt regulation of p56lck by CD4 and alter the ability of p56lck to interact with polypeptide substrates. In contrast, exposure of cells to TPA did not cause dissociation of p56lck and CD8. Regulation of p56lck by CD4 may therefore differ from regulation by CD8.     

CD8alphaalpha-mediated survival and differentiation of CD8 memory T cell precursors

Memory T cells are long-lived antigen-experienced T cells that are generally accepted to be direct descendants of proliferating primary effector cells. However, the factors that permit selective survival of these T cells are not well established. We show that homodimeric alpha chains of the CD8 molecule (CD8alphaalpha) are transiently induced on a selected subset of CD8alphabeta+ T cells upon antigenic stimulation. These CD8alphaalpha molecules promote the survival and differentiation of activated lymphocytes into memory CD8 T cells. Thus, memory precursors can be identified among primary effector cells and are selected for survival and differentiation by CD8alphaalpha.     

T cell receptor peptide therapy triggers autoregulation of experimental encephalomyelitis

Encephalitogenic T cells specific for myelin basic protein share common V beta 8 peptide sequences in their T cell receptor (TCR) that can induce autoregulatory T cells and antibodies that prevent clinical signs of experimental autoimmune encephalomyelitis (EAE). It is not known, however, if TCR peptides can treat established disease. To test its therapeutic value, TCR-V beta 8-39-59 peptide was injected into rats with clinical signs of EAE. This treatment reduced disease severity and speeded recovery, apparently by boosting anti-V beta 8 T cells and antibodies raised naturally in response to encephalitogenic V beta 8+ T cells. These results demonstrate that synthetic TCR peptides can be used therapeutically, and implicate the TCR-V beta 8-39-59 sequence as a natural idiotope involved in EAE recovery. Similarly, human TCR peptides may be effective in enhancing natural regulation of autoreactive T cells that share common V genes.     

重组鸡α-干扰素对鸡外周血T淋巴细胞亚类的影响

重组鸡α-干扰素(rChIFN-α)静脉注射4~6周龄SPF鸡,24 h后采血分离淋巴细胞,通过流式细胞术测定不同时间外周血中CD4+和CD8+T淋巴细胞的百分率。结果显示,rChIFN-α可以在48~72 h内明显提高CD4+T淋巴细胞的百分率,并下调CD8+T淋巴细胞的百分率,证明rChIFN-α具有显著的免疫调节作用。     

Demethylated CD8 gene in CD4+ T cells suggests that CD4+ cells develop from CD8+ precursors

Mature T cells and medullary thymocytes bear either the CD4 or CD8 differentiation antigen. Precursor cells in the thymus express neither CD4 nor CD8 (CD4-8-), but most cortical thymocytes are CD4+8+. Whether CD4+ and CD8+ mature T cells arise directly from CD4-8- precursors or from a CD4+8+ intermediate remains unresolved. In this study, methylation of the CD8 gene in murine T cells and thymocytes was examined. There was progressive demethylation of the CD8 gene in the thymus during the transition from CD4-8- to CD4+8+. A similar pattern of demethylation of the CD8 gene was seen in CD4+ mature T cells, suggesting previous expression of CD8 in the CD4+ lineage.     

鸡腺苷琥珀酸裂解酶(Adsl)基因多态性及其与肌苷酸含量相关研究*

 腺苷琥珀酸裂解酶是嘌呤核苷酸合成过程中的关键酶之一,催化嘌呤核苷酸合成过程中的两个重要反应:(1)由SACIAR生成AICAR的反应;(2)由腺苷酸琥珀酸生成腺苷酸单磷酸的反应。本研究对泰和乌骨鸡、隐性白羽肉鸡腺苷琥珀酸裂解酶基因的cDNA进行了克隆,并对序列进行了分析,共发现有6处碱基突变:249 G→A(TH),717 C→G(TH),985 A→G(TH)仅在泰和乌骨鸡中出现;992 T→C(RW),1400 C→T(RW)仅在隐性白羽肉鸡中出现;而在泰和乌骨鸡和隐性白羽肉鸡中均检测到突变1179 A→C(TH,RW)。其中985 A→G(TH),1400 C→T(RW)处突变导致两处氨基酸突变:Thr→Ala(305),Ala→Val(443),其它4处碱基突变均为同义突变。     

几种杀螨剂对3种叶螨的毒力比较

作者于 1 996年对二斑叶螨 (TetranychusurticaeKoch)、朱砂叶螨 [T .cinnabarinus(Boisdural) ]和山楂叶螨 (T .viennensisZacher)进行了三氯杀螨醇、甲氰菊酯、哒螨酮、霸螨灵等 4种杀螨剂的毒力测定 ,并对 3种叶螨在LC50 和LC95水平上 ,比较了相互之间的毒力差别。结果表明 ,二斑叶螨的毒力最高 ,朱砂叶螨次之 ,山楂叶螨毒力最低。     

BCG-HPV16E7c疫苗对小鼠免疫效应的实验研究

目的研究卡介苗（BCG）-人乳头状瘤病毒16型（HPV16）E7c疫苗对小鼠的免疫效应和致病性。方法用本研究组制备的BCG-HPV 16E7c疫苗腹腔内接种清洁级BALB／c鼠,同时设磷酸盐缓冲液（PBS）对照组、BCG空白菌对照组及BCG-pBCG3000空白载体对照组,用酶联免疫法检测各组血清特异性抗体、流式细胞仪测定脾脏T淋巴细胞亚群及肝、肺组织病理学检查。结果免疫后第2周和第4周BCG-HPV16E7c组每只小鼠的血清中检测到抗HPV16E7c特异性抗体,在第4周诱导产生的特异性IgG抗体滴度明显高于第2周,平均滴度为1：200;免疫后第4周BCG-ETc组与各对照组比较,CD^8＋T细胞的百分率显著升高（P〈0．05）;免疫组小鼠肝、肺组织病理学检查和BCG对照组比较未观察到更为严重的病理学变化。结论本研究组构建的BCCM-IPV16E7c疫苗能诱导小鼠的体液免疫应答和细胞免疫应答,对小鼠无明显的毒性作用。     

Linear differentiation of cytotoxic effectors into memory T lymphocytes

A central question in immunology is the origin of long-lived T cell memory that confers protection against recurrent infection. The differentiation of na?ve T cell receptor transgenic CD8+ cells into effector cytotoxic T lymphocytes (CTLs) and memory CD8+ cells was studied. Memory CD8+ cells that were generated after strong antigenic stimulation were the progeny of cytotoxic effectors and retained antigen-specific cytolytic activity 10 weeks after adoptive transfer to antigen-free recipient mice. Thus, potential vaccines based on CTL memory will require the differentiation of na?ve cells into post-effector memory T cells.     

Self-nonself discrimination by T cells

The alpha beta T cell receptor (TCR) recognizes antigens that are presented by major histocompatibility complex (MHC)-encoded cell surface molecules by binding to both the antigen and the MHC molecules. Discrimination of self from nonself antigens and MHC molecules is achieved by negative and positive selection of T cells in the thymus: potentially harmful T cells with receptors that bind to self antigens plus self MHC molecules are deleted before they can mount immune responses. In contrast, the maturation of useful T cells with receptors that bind foreign antigens plus self MHC molecules requires the binding of their receptor to MHC molecules on thymic epithelium in the absence of foreign antigen. The binding of the TCR to either class I or class II MHC molecules directs differentiation of the selected cells into either CD4-8+ (killer) or CD4+8- (helper) T cells, respectively.