Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells

Summary: Emerging evidence indicates that the Achilles' heel of cancer immunotherapies is often the complex interplay of tumor-derived factors and deviant host properties, which involve a wide range of immune elements in the lymphoid and myeloid compartments. Regulatory lymphocytes, tumor-conditioned myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages, and dysfunctional and immature dendritic cells take part in a complex immunoregulatory network. Despite the fact that some mechanisms governing tumor-induced immune tolerance and suppression are starting to be better understood and their complexity dissected, little is known about the diachronic picture of immune tolerance. Based on observations of MDSCs, we present a time-structured and topologically consistent idea of tumor-dependent tolerance progression in tumor-bearing hosts.     

Biochemical characterization of I-Ak proteins from mutant antigen-presenting B-cell--B-lymphoma hybridomas

Chemically induced mutants of an I-Ak,d expressing antigen-presenting B-cell--B-lymphoma hybridoma have recently been generated by immunoselection in vitro and were found to possess alterations in some of their serologically and functionally defined I-Ak region dependent functions. In order to identify at the structural level the origin of the differences in serological and functional properties of these mutants, I-Ak molecules from several of these mutant hybridomas were compared biochemically to wild-type I-Ak polypeptides by two-dimensional gel electrophoresis and high-pressure liquid chromatographic tryptic peptide analyses. Two-dimensional gel electrophoresis indicated that no major structural alterations, resulting in changes in mol. wt or charge, had occurred in the Ak alpha or Ak beta polypeptides from the mutant cells. Likewise, Ak alpha peptide maps of the mutants were indistinguishable from the normal Ak alpha peptide maps. However, two of the three mutants studied did exhibit one additional peptide in their Ak beta peptide maps. These results suggest that the major deficiencies in T-cell-activating functions of these mutants are a result of a limited alteration in the Ak beta polypeptide primary structure.     

视网膜节细胞与视交叉上核AVP神经元联系的研究Ⅱ.假狂犬病毒顺行追踪与免疫荧光双重标记

为进一步揭示视网膜节细胞与视交叉上校精氨酸血管加压素神经元间有无直接的联系，本文将假狂犬病毒注入大鼠眼球内通过顺行追踪结合免疫荧光双重标记法观察到：（1）视交叉上核神经元被病毒感染的时间始于病毒注入后56h，并随存活时间的延长而增多；（2）呈绿色荧光的病毒感染神经元见于双侧视交叉上核，注射对侧优于同侧，主要位于视交叉上核的腹外侧部和嘴侧份，个别散在于二者之外;（3）视交叉上核内个别病毒感染的神经元可同时呈精氨酸血管加压素的红色荧光，此类双标神经元系病毒由视网膜节细胞顺行运输并跨突触传给视交叉上核的精氨酸血管加压素神经元所致。表明视网膜节细胞与视交叉上核的精氨酸血管加压素神经元间有直接的突触性联系。这一结果为视交叉上核节律机制和精氨酸血管加压素神经元的机能调控提供了进一步研究的线索。     

L-Arginine Reduces Nitro-Oxidative Stress in Cultured Cells with Mitochondrial Deficiency

L-Arginine (L-ARG) supplementation has been suggested as a therapeutic option in several diseases, including Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like syndrome (MELAS), arguably the most common mitochondrial disease. It is suggested that L-ARG, a nitric oxide (NO) precursor, can restore NO levels in blood vessels, improving cerebral blood flow. However, NO also participates in mitochondrial processes, such as mitochondrial biogenesis, the regulation of the respiratory chain, and oxidative stress. This study investigated the effects of L-ARG on mitochondrial function, nitric oxide synthesis, and nitro-oxidative stress in cell lines harboring the MELAS mitochondrial DNA (mtDNA) mutation (m.3243A>G). We evaluated mitochondrial enzyme activity, mitochondrial mass, NO concentration, and nitro-oxidative stress. Our results showed that m.3243A>G cells had increased NO levels and protein nitration at basal conditions. Treatment with L-ARG did not affect the mitochondrial function and mass but reduced the intracellular NO concentration and nitrated proteins in m.3243A>G cells. The same treatment led to opposite effects in control cells. In conclusion, we showed that the main effect of L-ARG was on protein nitration. Lowering protein nitration is probably involved in the mechanism related to L-ARG supplementation benefits in MELAS patients.     

自发性高血压大鼠应用卡托普利加左旋精氨酸、牛磺酸的实验研究

目的：为研究左旋精氨酸、牛磺酸、卡托普利三药合用对自发性高血压大鼠的血压、血脂以及同同型半胱氨酸的影响。方法：用酶法测血脂,用高效液相色谱法测血浆HCY,在大鼠清醒状态下,测鼠尾的尾动脉收缩压,观察两组自发性高血压大鼠（卡托普利单用组,左旋精氨酸＋牛磺酸＋卡托普利三药合用组）在用药前后各指标的变化。结果：①经过四周药物治疗,合用组血压下隆比卡托普利组明显（P＜0.01）。②卡托普利组血脂无降低（P＞0.05）。合用组TC和TG均降低,（P＜0.005)。③两组HCY均下降。用药前,大鼠血压高低与血浆HCY的浓度无相关性（P＞0.05）,用药后,血压的下降与血浆HCY浓度的变化无相关性（P＞0.05）。结论：①卡托普利与有氨酸、牛磺酸合用对血压、血脂的控制比单用卡托普利。②血压的下降与同型半胱氨酸的下降无相关性（P＞0.05）。     

L—精氨酸对梗阻性黄疸大鼠肾脏的影响

目的探讨L-精氨酸（L-Arg）对梗阻性黄疸大鼠肾脏的影响及机制。方法双重结扎大鼠胆总管造成梗阻性黄疸模型,14d后,分别给予不同组大鼠L-Arg500mg     

辛伐他汀对血管升压素诱导大鼠心脏成纤维细胞增殖的影响

目的　探讨辛伐他汀 (Simvastatin ,Sim)对血管升压素 (AVP)诱导的新生SD大鼠心脏成纤维细胞 (CFs)增殖的影响 ,为防治高血压心肌纤维化提供理论依据。方法　采用胰酶消化、差速贴壁法培养新生SD大鼠CFs,以3H 胸腺嘧啶核苷 (3H TdR)掺入法测定DNA合成、四氮唑盐 (MTT)比色法测定细胞数目 ,分别观察不同浓度Sim对AVP诱导CFs增殖的作用及甲羟戊酸 (Meval onate,MVA)干预的影响。结果　①CFs(2 0 0个细胞 )的3H TdR掺入率随着Sim干预浓度的增加而降低 ,其中 1 0 - 6mol/LSim和 1 0 - 5mol/LSim组的3H TdR掺入率分别为 (1 1 75± 2 0 2 6 6 )、(771± 1 6 4 86 )cpm ,明显低于对照组 (1 95 5± 3 72 45 )cpm(P <0 0 1 ) ;②MTT比色法A490 值随Sim浓度的增加而降低 ,其中 1 0 - 6、1 0 - 5mol/LSim组的A490 值分别为 0 2 1 5± 0 0 4 1和 0 1 6 3± 0 0 1 8,均较对照组A490值 0 3 93± 0 0 4 8显著降低 (P <0 0 1 ) ;③ 1 0 - 5mol/LSim +1 0 - 3mol/LMVA组的3H TdR掺入率、MTT比色法A490 值分别为 (1 995±3 5 3 83 )cpm和 0 41 8± 0 0 4 5 ,均显著高于 1 0 - 5mol/LSim组 (P <0 0 1 )。结论　辛伐他汀可抑制AVP诱导的CFsDNA的合成和细胞数目增加 ,提示Sim可抑制CFs增殖 ,其机制可能通过甲     

L-精氨酸对兔血管平滑肌细胞体外增殖的影响

目的：探讨Ｌ－精氨酸抗动脉粥样硬化（ＡＳ）的作用机制。方法：观察Ｌ－ａｒｇ对兔血管平滑肌细胞（ＶＳＭＣ）体外增殖的影响。结果：Ｌ－ａｒｇ显著增加一氧化氮（ＮＯ）含量,明显抑制ＶＳＭＣ,并呈剂量依赖性。加入单甲基－Ｌ－精氨酸（Ｌ－ＮＭＭＡ）,上述作用被逆转 。结论：Ｌ－ａｒｇ可显著抑制兔ＶＳＭＣ体外增殖,且此作用由Ｌ－ａｒｇ转则ａｒｇ抗ＡＳ的作用可能与此有关。     

L-Arg-NO通路对大鼠延髓腹面加压区心血管活动的影响及与L-Glu通路的关系

目的：研究一氧化氮（ＮＯ）前体Ｌ－精氨酸（Ｌ－Ａｒｇ）单侧微量注入大鼠延髓腹面加压区（ＶＳＭｐ）对动脉血压（ＡＰ）、心率（ＨＲ）、肾灌流压（ＰＰｋ）的影响及与Ｌ－谷氨酸（Ｌ－Ｇｌｕ）升压作用的关系。方法 采用延髓腹外侧部微量注射法,以整体灌流肾为模型观察与ＮＯ有关药物对心血管活动的影响。结果 （１）ＶＳＭｐ内微量注入Ｌ－Ａｒｇ（４０～１００ｎｍｏｌ）,ＡＰ和ＨＲ呈剂量依赖性下降,与生理盐水注入后的变化相比较,差异均有显著性。如预先注入ＮＯ合酶抑制剂Ｌ－硝基－精氨酸甲酯（Ｌ－ＮＡＭＥ）或鸟苷酸环化酶抑制剂甲基蓝,Ｌ－Ａｒｇ的降压效应被衰减。（２）ＶＳＭｐ内微量注入Ｌ－Ａｒｇ（１００ｎｍｏｌ）,ＰＰｋ与ＡＰ同步下降,与基础值比较,差异有显著性。（３）ＶＳＭｐ内微量注入Ｌ－Ｇｌｕ（３５０ｎｍｏｌ）,ＡＰ上升。如预先注     

L-硝基精氨酸甲酯对实验性葡萄膜炎的影响

目的：观察一氧化氮（ＮＯ）含量含量在葡萄炎房东水及玻璃体中的变化及Ｌ－硝基精氨酸甲酯（Ｎ＾Ｇ－ｎｉｔｒｏ－Ｌ－ａｒｇｉｎｉｎｅ ｍｅｔｈｙｌ ｅａｒｔｅｒ,Ｌ－ＮＡＭＥ）的治疗效果。方法;采用兔眼玻璃２本内注射内毒素脂多糖（ＬＰＳ）制备葡萄膜炎模型,以检测房水蛋白浓度,结果：葡萄为房水及玻璃体及玻璃体中显著增高,即刻使用Ｌ ＮＡＭＥ;显著降低了ＮＯ水平,同时其蛋白浓度、细胞数目及组织炎症程度明显降