Interleukin-12/T cell stimulating factor,a cytokine with multiple effects on T helper type 1 (Th1) but not on Th2 cells

At least two subsets of CD4⁺ T helper cell lymphocytes termed T_h1 and T _h, 2 exist in the mouse and probably in humans. They are characterized by the secretion of different lymphokines and by their functional behavior. Dysregulated expansion of one or the other subset may be one reason for the development of certain diseases. Thus, it is of importance to define the signals involved in the differentiation and activation of the two T_h cell subsets. It is known and has been confirmed in this report that the cytokine interleukin (IL)-1 acts onT_h2 cells but not on T_h1 cells. We now report that a previously identified cytokine which was provisionally termed T cell stimulating factor is identical with IL-12 and exhibits a reciprocal behaviour to IL-1. IL-12 has several effects on T_h1 cells. It can induce the proliferation of certain T_h1 cells in combination with IL-2. Synthesis of interferon (IFN)-γ by T_h1 cells can be triggered by IL-2 plus IL-12. In contrast to the IFN-γ production observed after T cell receptor (TcR) CD3 stimulation of T_h1 cells with lectin Concanavalin A the IFN-γ production induced by IL-12+IL-2 is insensitive to the immunosuppressive drug cyclosporin A. Furthermore, IL-12 enhances the TcR/CD3-induced synthesis of IFN-γ of several T_h1 clones. Finally, IL-12 (+ IL-2) induces homotypic cell aggregation of T_h1 clones. This type of cell aggregation depends on the participation of LFA-1 and ICAM-1 molecules. In all activation systems with T_h1 cells no effect of IL-1 was demonstrable. In contrast, only IL-1 but not IL-12 served as a co-stimulatory signal for several T_h2 cell lines activated via the TcR/CD3 complex.     

Lack of selective Vβ deletion in peripheral CD4+ T cells of human immunodeficiency virus-infected infants

To investigate the possibility of superantigen-mediated deletions of T cells expressing particular T cell receptor Vβ (TcR Vβ) gene segments during human immunodeficiency virus (HIV) infection, TcR Vp usage in CD4⁺ and CD8⁺ subsets was analyzed in a cohort of infants maternally infected by HIV and in a group of healthy neonates. We used a semi-quantitative anchored polymerase chain reaction technique together with cytofluorographic analysis with anti-Vβ monoclonal antibodies. The representation of the 24 vβ families in CD4⁺ and CD8⁺ T cells from normal neonates was very similar to that in adults. Preferential expression of Vβ2 in the CD4⁺ subset was observed in both the neonates and in healthy adults. The representation of the 24 Vβ families in peripheral CD4⁺ T cells from the HIV-infected infants showed no selective vβ deletion, even when the CD4⁺ subset was globally depleted. Moreover, the main characteristics of the control group (predominance of certain Vβ families and Vβ2 skewing towards the CD4⁺ subset) were also present in all the HIV-infected infants.     

分泌性中耳炎中耳积液和血清中sIL－2R水平的初步研究

应用酶联免疫吸附法（ＥＬＩＳＡ）对３０例正常人血清（对照组）和６０例分泌性中耳炎患者（ＳＯＭ组）中耳积液和血清中可溶性白细胞介素２受体（ｓＩＬ－２Ｒ）进行了检测。结果示ＳＯＭ组血清ｓＩＬ－２Ｒ水平明显高于对照组，ＭＥＦ中其含量明显高于血清；鼻咽癌组血清及ＭＥＦ中ｓＩＬ－２Ｒ水平明显高于─般ＳＯＭ组；粘液组高浆液组；慢性组高于急性组（均Ｐ＜０．０１）。提示：血清及ＭＥＦ中ｓＩＬ－２Ｒ水平的测定有助于对ＳＯＭ患者免疫状态的评估；ＭＥＦ中ｓＩＬ－２Ｒ可能主要由局部中耳粘膜产生；ＭＥＰ中高浓度的ｓＩＬ－２Ｒ存在可能是ＳＯＭ迁延不愈的─个原因。     

The myelin basic protein-specific T cell repertoire in (transgenic) Lewis rat/SCID mouse chimeras: preferential Vβ8.2 T cell receptor usage depends on an intact Lewis thymic microenvironment

In the Lewis rat, myelin basic protein (MBP)-specific, encephalitogenic T cells preferentially recognize sequence 68–88, and use the Vβ8.2 gene to encode their T cell receptors. To analyze the structural prerequisites for the development of the MBP-specific T cell repertoire, we reconstituted severe-combined immunodeficient (SCID) mice with fetal (embryonic day 15–16) Lewis rat lymphoid tissue, and then isolated MBP-specific T cell lines from the adult chimeras after immunization. Two types of chimera were constructed: SCID mice reconstituted with rat fetal liver cells only, allowing T cell maturation within a chimeric SCID thymus consisting of mouse thymic epithelium and rat interdigitating dendritic cells, and SCID mice reconstituted with rat fetal liver cells and rat fetal thymus grafts, allowing T cell maturation within the chimeric SCID and the intact Lewis rat thymic microenvironment. Without exception, the T cell lines isolated from MBP-immunized SCID chimeras were restricted by MHC class II of the Lewis rat (RT1.B¹), and none by I-A^d of the SCID mouse. Most of the T cell lines recognized the immunodominant MBP epitope 68–88. In striking contrast to intact Lewis rats, in SCID mice reconstituted by rat fetal liver only, MBP-specific T cell clones used a seemingly random repertoire of Vβ genes without a bias for Vβ8.2. In chimeras containing fetal Lewis liver plus fetal thymus grafted under the kidney capsule, however, dominant utilization of Vβ8.2 was restored. The migration of liver-derived stem cells through rat thymus grafts was documented by combining fetal tissues from wild-type and transgenic Lewis rats. The results confirm that the recognition of the immunodominant epitope 68–88 by MBP-specific encephalitogenic T cells is a genetically determined feature of the Lewis rat T cell repertoire. They further suggest that the formation of the repertoire requires T cell differentiation in a syngeneic thymic microenvironment.     

Long-lived alphaMUPA transgenic mice show reduced SOD2 expression, enhanced apoptosis and reduced susceptibility to the carcinogen dimethylhydrazine

Calorie restriction (CR) extends the life span of various species through mechanisms that are as yet unclear. Recently, we have reported that mitochondrion-mediated apoptosis was enhanced in alphaMUPA transgenic mice that spontaneously eat less and live longer compared with their wild-type (WT) control mice. To understand the molecular mechanisms underlying the increased apoptosis, we compared alphaMUPA and WT mice for parameters associated with SOD2 (MnSOD), a mitochondrial antioxidant enzyme that converts superoxide radicals into H(2)O(2) and is also known to inhibit apoptosis. The SOD2-related parameters included the levels of SOD2 mRNA, immunoreactivity and enzymatic activity in the liver, lipid oxidation and aconitase activity in isolated liver mitochondria, and the sensitivity of the mice to paraquat, an agent that elicits oxidative stress. In addition, we compared the mice for the levels of SOD2 mRNA after treatment with bacterial lipopolysaccharides (LPS), and for the DNA binding activity of NFkappaB as a marker for the inflammatory state. We extended SOD2 determination to the colon, where we also examined the formation of pre-neoplastic aberrant crypt foci (ACF) following treatment with dimethylhydrazine (DMH), a colonic organotypic carcinogen. Overall, alphaMUPA mice showed reduced basal levels of SOD2 gene expression and activity concomitantly with reduced lipid oxidation, increased aconitase activity and enhanced paraquat sensitivity, while maintaining the capacity to produce high levels of SOD2 in response to the inflammatory stimulus. alphaMUPA mice also showed increased resistance to DMH-induced pre-neoplasia. Collectively, these data are consistent with a model, in which an optimal fine-tuning of SOD2 throughout a long-term regimen of reduced eating could contribute to longevity, at least in the alphaMUPA mice.     

阴道镜下高频电灼术联合α-2a干扰素凝膏治疗尖锐湿疣疗效分析

目的探讨阴道镜下高频电灼术联合重组人干扰素α-2a治疗尖锐湿疣（CA）的效果。方法将165例CA分为3组，A组应用阴道镜下高频电灼术联合重组人干扰素α-2a；B组单纯采用阴道镜下高频电灼治疗；C组应用NS-FII型多功能光谱治疗仪联合肌注重组人干扰素α-2a。结果治疗后3-6个月A、B、C组复发率分别为0％、4．4％、65．4％：半年后人乳头瘤病毒（HPV）转阴率分别为93．5％、85．4％、43．8％，A组明显优于B组，B组明显优于C组，3组比较差异有统计学意义（P〈0．01）。结论阴道镜下高频电灼术联合重组人干扰素α-2a治疗CA可明显降低CA复发率和提高HPV转阴率。     

人胸腺基质淋巴生成素的研究进展

人胸腺基质淋巴生成素(hTSLP)是一种结构类似IL-7的新型细胞因子.正常情况下其mRNA主要表达于基质细胞、上皮细胞和肥大细胞,病理状态下,TSLPmRNA在一些前炎症细胞因子的作用下表达增加.hTSLP直接作用的效应细胞主要是树突状细胞(DC),通过调节DC的成熟来发挥作用.一方面.hTSLP-DC在外周能够诱导初始T细胞向一类特殊的Th2细胞分化,从而启动炎症反应;另一方面,hTSLP-DC能够促进胸腺中CD4+CD25-T细胞分化成CD4+CD25+调节性T细胞,从而在免疫耐受的发生和调控中发挥作用.     

Cyclooxygenase-2 expression in colorectal cancer liver metastases

Cyclooxygenase-2 (COX-2) is up-regulated in 85-90% of primary human colorectal cancers and is a putative target for the chemopreventative activity of non-steroidal anti-inflammatory drugs. However, COX-2 expression by human colorectal cancer liver metastases has been poorly characterized. We studied a consecutive series of 38 patients who underwent liver resection for metastatic disease, for whom long-term (up to 57 months), prospective follow-up data were available. Semi-quantitative immunohistochemistry for COX-2 was performed on 54 metastases from 35 patients, for whom adequate histological material was available. Diffuse cytoplasmic staining for COX-2 protein was detected in cancer cells in 100% of metastases (COX-2 score 1, n=25; score 2, n=29). There was no relationship between metastasis size or differentiation grade and the level of COX-2 protein expression. There was no difference in colorectal cancer-free or overall survival between patients with high (score 2) and low (score 1) COX-2 scores (Kaplan–Meier survival analysis and log rank test, both P=0.97). Multivariate Cox regression analysis identified age, incomplete resection and presence of extra-hepatic disease as independent predictors of disease-free and overall survival following surgery. COX-2 protein was also localized to a subset of stromal fibroblasts and mononuclear cells within metastases as well as hepatocytes from resection specimens. COX-2 protein was expressed by cancer cells in all human colorectal cancer liver metastases which were studied. Investigation of the effect of selective COX-2 inhibition on metastasis growth and metastasis cancer cell proliferation/apoptosis in vivo are warranted.     

Changed Bcl:Bax ratio in endometrium of patients with unexplained infertility

Apoptosis has been shown to be an important regulator of endometrial function during the menstrual cycle and implantation. Recently, some possible implantation defects were identified in patients with unexplained infertility. In this study, we investigated the role of spontaneous apoptosis, which is regulated by death regulatory genes, such as Bcl-2, Bax, p53, and isoenzymes of nitric oxide synthases; eNOS and iNOS during the implantation window in women with unexplained infertility. Endometrial samples were evaluated from fertile (n=15) and unexplained-infertile women (n=15) during post-ovulatory 7th or 8th day of their menstrual cycles. Apoptotic cells were detected using the dUTP nick-end labelling assay and Bcl-2, Bax, p53, iNOS and eNOS were assessed immunohistochemically. Reduced apoptotic cells, weak immunoreactivity of p53 and strong immunoreactivity of Bcl-2 were observed in the unexplained-infertile group compared with the fertile group (p<0.001). Bax intensity was similar in both groups. While weak iNOS immunoreactivity was detected in both groups, moderately increased eNOS immunoreactivity was observed in infertile cases. Spontaneous apoptosis is reduced in the endometrium of unexplained-infertile women, and is associated with the changed Bcl-2:Bax ratio. This finding may be a contributing factor to defective implantation causing infertility in this group of patients.     

In vitro and ex vivo blood compatibility study of 2-methacryloyloxyethyl phosphorylcholine (MPC) copolymer-coated hemodialysis hollow fibers

To identify the advantages of 2-methacryloyloxyethyl phosphorylcholine (MPC) copolymer-coated polysulfone (PSf) hollow fibers for hemodialyzer and hemofilter minimodules with hollow fibers were made and blood compatibility was evaluated in vitro and ex vivo. Three types of hollow fibers, i.e., pure PSf (no additives), PSf alloyed with poly(1-vinyl-2-pyrrolidone) (PVPy), and PSf coated with the MPC copolymer, were processed in wet conditions. Commercially available hollow fibers (APS) were used as a control sample. The PSf hollow fibers have a condensed structure. A porous structure was observed when the PVPy was alloyed before wet processing, and no effect of the innercoated MPC copolymer on the porous structure was observed. One-tenth-sized minimodules of the conventional hemodialyzer were fabricated with 200 fibers each. The solute permeability of the hollow fibers was evaluated using 10% bovine serum in a buffer solution containing cytochrome C, which is a model protein of ₂-microglobulin. After circulation for 2.5h, the solute permeability of APS and PVPy-alloyed PSf hollow fibers decreased to 50% compared with their initial values. In contrast, the value for the hollow fibers innercoated with the MPC copolymer maintained its initial level. The inner surface of the dialysis membranes was observed with a transmission electron microscope and a layer of adsorbed protein on the PSf, APS, and PVPy-alloyed PSf hollow fibers was observed, but not on the MPC copolymer-coated fibers. Blood cell adhesion was then evaluated by circulation of whole rabbit blood without any anticoagulant ex vivo. Many adherent cells were observed on the PVPy-alloyed PSf hollow fibers; however, blood cells did not adhere or aggregate on the MPC copolymer-coated hollow fibers. From these results, we concluded that the in-situ coating of MPC copolymer on PSf hollow fibers is effective in preventing blood coagulation and maintaining the solute permeability of the fibers.