调节性T细胞与常见自身免疫性疾病

人体免疫系统可以通过杀伤受感染的细胞的方式保护不受侵入的病原体与微生物的侵害,而只对正常组织造成最小程度的损害。为了维持这种平衡,CD4＋CD25＋调节性T细胞在控制免疫应答与维持外周免疫耐受中起重要作用。这种T细胞的数量减少或功能的缺失可能导致自身免疫疾病的发生。增强调节性T细胞免疫抑制功能的治疗措施已经被证明可以改善自身免疫性疾病的病情,本文就调节性T细胞的作用机制及与常见自身免疫性疾病的关系做一综述。     

CD4^＋CD25^＋调节性T细胞与自身免疫性疾病的研究进展

自身免疫性疾病是由于正常免疫耐受功能受损导致免疫细胞及其成分对自身组织结构和功能的破坏,并出现一定临床表现的一类疾病,大多数发病机制不清楚。近年研究认为CD4^＋CD25^＋调节性T细胞在自身免疫性疾病中发挥着重要作用,其在体内的正常水平和功能发挥可以抑制自身反应性淋巴细胞的活化、增殖来维持机体的免疫耐受,从而避免自身免疫性疾病的发生;该类细胞的缺乏或功能缺陷可能导致自身免疫性疾病。我们就其与自身免疫性疾病的研究进展进行综述。     

中药单体基于肠道菌群调节Th17/Treg轴对自身免疫性疾病的干预研究现状

自身免疫性疾病(ADs)是一类机体对自身抗原发生免疫反应而导致自身组织损害的疾病。促炎性的辅助性T细胞17(Th17)和抗炎性的调节性T细胞(Treg)在功能上相互拮抗,两者间的免疫失衡及相关细胞因子失调与多种ADs发生密切相关。大量证据表明,肠道菌群可通过调节细胞因子产生、调控转录因子表达、影响能量代谢等调节Th17/Treg分化,重建自身免疫耐受,延缓ADs进程。本文综述了红景天苷、人参皂苷Rg₁、白芍总苷、熊果酸等中药单体基于肠道菌群调节Th17/Treg分化平衡途径在干预溃疡性结肠炎、类风湿性关节炎、1型糖尿病等ADs中的作用,结果显示其作用机制可能为恢复促炎因子与抗炎因子平衡从而缓解肠黏膜屏障受损、降低滑膜血管新生及改善胰腺β细胞破坏等。这可为ADs的中西医结合防治提供思路。     

特异性免疫治疗对哮喘大鼠白细胞介素-10和CD_4~＋CD_（25）~＋调节性T细胞的影响

目的：探讨特异性免疫治疗（specific immunotherapy,SIT）对哮喘大鼠白细胞介素-10（IL-10）和CD4＋CD25＋调节性T细胞（CD4＋CD25＋Tr）的影响。方法：40只健康雄性清洁级Wistar大鼠随机均分成正常对照组、哮喘组、SIT对照组和SIT治疗组,每组10只。通过卵蛋白（OVA）雾化吸入的方法对致敏大鼠进行SIT干预,观察各组支气管肺泡灌洗液（BALF）中细胞分类及计数结果、血清和BALF中IL-10水平及外周血CD4＋CD25＋Tr百分率变化。结果：正常对照组BALF和血清中IL-10浓度分别高于哮喘组和SIT对照组（均为P〈0.01）,哮喘组和SIT对照组BALF和血清中IL-10浓度低于SIT治疗组（P〈0.01,P〈0.05）;正常对照组外周血CD4＋CD25＋Tr百分率显著高于哮喘组、SIT对照组和SIT治疗组（P〈0.01）,而SIT治疗组CD4＋CD25＋Tr百分率分别高于哮喘组和SIT对照组（P〈0.05）。结论：通过上调体内IL-10和CD4＋CD25＋Tr趋于正常状态可能是SIT治疗哮喘有效的重要机制。     

1,25-(OH)_2D3的免疫调节特性及对相关疾病的作用

1,25-(OH)2D3(骨化三醇)是维生素D的衍生物,具有广泛的生物活性。此文主要从其对免疫细胞生物学效应及免疫相关疾病的可能治疗机制和副作用等方面做一综述。     

lncRNA与自身免疫性疾病CD4+ T淋巴细胞亚群分化的关系研究进展

长链非编码RNA (lncRNA)具有广泛的生物学功能,在表观遗传、细胞周期和细胞分化等生命活动中均有调控作用,且能影响免疫细胞的发育分化与免疫系统稳态的维持。CD4⁺ T细胞亚群是具有不同功能的异质性细胞,能促进T细胞和B细胞等免疫细胞的增殖与分化,协调免疫细胞之间的相关作用。自身免疫性疾病(AID)是一种自身抗原免疫反应引起的慢性炎症性疾病,在疾病的发生及活动期均有lncRNA与CD4⁺ T细胞亚群的参与。本文将针对lncRNA与AID CD4⁺ T细胞亚群分化的关系进行综述。     

6-苯硫基-2-乙基-3-羟基-4(1H)-吡啶酮的抗氧化作用

目的　以正常大鼠组织匀浆、肝亚细胞及给药小鼠肝匀浆、血清等为材料研究 6 苯硫基 2 乙基 3 羟基 4(1H) 吡啶酮 (HDP)的抗氧化作用。方法　组织匀浆或肝亚细胞悬液与 6 苯硫基 2 乙基 3 羟基 4(1H) 吡啶酮共浴 ,以VitC/FeSO4 激发脂质过氧化反应 ,以丙二醛 (MDA)产生、还原型谷胱甘肽耗竭、线粒体膨胀作为评价脂质过氧化程度指标。小鼠ipHDP每天一次 ,连续 2 0d后摘眼球取血 ,分离血清 ,测定MDA含量 ,取肝制成匀浆 ,测定MDA含量。结果　 6 苯硫基 2 乙基 3 羟基 4(1H) 吡啶酮可抑制VitC/FeSO4 激发的MDA的产生 ;抑制肝组织匀浆还原型谷胱甘肽耗竭及线粒体膨胀 ;降低给药小鼠肝匀浆及血清中的脂质过氧化物水平。结论　 6 苯硫基 2 乙基 3 羟基 4(1H) 吡啶酮具有抗氧化作用。     

N~1-(4-取代氨基-6-甲基-2-嘧啶基)-N~3-(对氯苯基)胍类的合成及其抗丝虫作用

报道了 N~1-[4-[3-(二烷胺基)甲基-和3,5-双[(二烷胺基)甲基]-4-羟基苯基]氨基]-6-甲基-2-嘧啶基]-N~3-(4-氯苯基)胍的合成。所合成的10个化合物进行了药理初筛,其中8个对感染沙鼠的棉鼠丝虫微丝蚴或成虫显示一定的杀灭作用。     

活性维生素D在肾脏病领域的应用进展

活性维生素D3自临床应用以来,在治疗慢性肾衰竭继发性甲状旁腺功能亢进取得了显著的效果。本文对继发性甲状旁腺功能亢进的发病机制、活性维生素D3的作用机制、疗效、副作用、治疗指南作一综述,同时介绍了活性维生素D3的临床新用途和新型活性维生素D3类似物。     

Effect of 1,25-dihydroxyvitamin D3 on the immunocompetent cells

This paper deals with the immunosuppressive effects of 1,25-dihydroxy vitamin D3 (1,25(OH)2, D3), a metabolic product which acts in vivo as the active form vitamin D3. Dose and time of exposure-dependent suppressive effects were demonstrated in vitro on PHA blastogenesis of mononuclear cells, IL-2 production of T cells and IL-1 production of macrophages when these human immunocytes were treated with 1,25(OH)2D3. Addition of exogenous IL-1 and IL-2 partially abrogated the suppressive effects of 1,25(OH)2 D3 on IL-2 production and PHA blastogenesis, respectively. Thus, it is suggested that inhibition of PHA blastogenesis results from the reduced production of such growth factors in this IL-1 -IL-2 cascade system. PWM-induced immunoglobulin (Ig) synthesis of B cells was also markedly inhibited by 1,25(OH)2 D3, which was caused not only by direct suppression toward B cells but also by indirect suppression due to reduced helper factor from T cells when these cells were treated with 1,25(OH)2 D3. It is proposed that 1,25(OH)2D3 may act as one of the immunoregulatory factors in vivo, in addition to its well-known action in calcium metabolism.     

活性维生素D3对肾小球上皮间质转化的影响研究

目的:观察活性维生素D₃（1,25-（OH）₂D₃）对糖尿病大鼠肾小球足细胞标志蛋白Nephrin,间质转化标志蛋白Snail及间质标志蛋白Desmin表达的影响,探讨1,25-（OH）₂D₃在上皮间质转化中的作用。方法:24只链脲菌素诱导的糖尿病大鼠随机分为糖尿病组（DM）和1,25-（OH）₂D₃治疗组（DD）,后者给与1,25-（OH）₂D₃按3 ng·100 g^-1·d^-1皮下注射。另以10只大鼠作为对照组（NC）。于6周检测血糖（BG）、24 h尿蛋白（24 h UP）、尿液足细胞（UPC）。处死大鼠,PT-PCR及Westernbolt分别测定肾小球Nephrin、Snail、Desmin mRNA和蛋白质的表达。结果:DM组BG、24 h UP较NC组显著升高,而UPC与NC组相比无显著差异。DM组肾小球Nephrin mRNA和蛋白质的表达水平较NC组显著降低,而Snail、Desmin mRNA和蛋白表达显著增加。DD组BG、UPC与DM组相比无显著差异,而24 h UP较DM组显著降低,肾小球Nephrin mRNA和蛋白质的表达较DM组升高,而Snail、Desmin mRNA和蛋白表达降低。结论:1,25（OH）₂D₃上调Nephrin的表达,并减少Snail、Desmin的表达,可抑制上皮间质转化,减轻肾损伤。     

Anti-tumor effects of 1,25-dihydroxyvitamin D3 and vitamin D analogs

The role of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) as a regulator of cell growth and differentiation is well recognized. Currently, 1, 25-(OH)2D3 and vitamin D analogs are being evaluated for their therapeutic potential in the treatment of hyperproliferative disorders like cancer. In the present review, we will discuss several processes that might be involved in 1,25-(OH)2D3- and vitamin D analog-mediated suppression of cancer cell growth. The effects on tumor cell proliferation, differentiation, apoptosis, angiogenesis, metastases, and parathyroid hormone-related peptide secretion will be highlighted. In addition, combination therapy with other tumor effec tive drugs will be addressed. Furtermore, we will focus on the potential drawbacks and the possible side effects of vitamin D compounds in the treatment of cancer.     

Immunoregulation through 1,25-dihydroxyvitamin D3 and its analogs

Beyond its effects on bone metabolism, calcium and phosphorus homeostasis, 1,25-dihydroxyvitamin D3 (1,25(OH)(2)D(3), calcitriol) exerts profound effects on the immune system. We here provide an overview over the metabolism, molecular and cellular action of 1,25(OH)(2)D(3) with particular regard to its immunomodulatory function. Effects of 1,25(OH)(2)D(3) on the immune system are manyfold and include suppression of T cell activation, shaping of cytokine secretion patterns, induction of regulatory T cells, modulation of proliferation, and interference with apoptosis. 1,25(OH)(2)D(3) further influences maturation, differentiation, and migration of antigen presenting cells. Altogether, its immunomodulatory potency is comparable to other established immunosuppressants without sharing their typical adverse effects. This profile makes 1,25(OH)(2)D(3) a potential drug for the treatment of immune-mediated diseases. Yet, the major obstacle for its clinical use, its potent calcemic activity, is not overcome to date. The identification or generation of novel vitamin D derivatives with dissociated calcemic and immunomodulatory properties is therefore a major task. Its success might eventually lead to promising drugs for future therapeutic exploitation of a wide array of immune diseases, such as psoriasis, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, and others.     

Specific 1,25-dihydroxyvitamin D3 binding sites in choroid plexus.

Quantitative autoradiographic analysis of [3H] 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) binding in vitamin D deficient mice provided evidence for high levels of specific binding in choroid plexus and, to a lesser extent, ventral hippocampus. Sucrose gradient analysis yielded a 3-4S peak of specific [3H]1,25(OH)2D3 binding in bovine choroid plexus, but not amygdala or hippocampus. Scatchard analysis of [3H]1,25(OH)2D3 binding in bovine choroid plexus yielded KD = 0.23 +/- 0.06 nM and Nmax = 43.5 +/- 0 fmol/g tissue (n = 5). This result indicates the presence of significant receptor-like [3H]1,25(OH)2D3 binding sites in the choroid plexus and, thus, suggests roles for this hormone in regulating the entry of calcium into the brain and/or in the central regulation of calcium homeostasis.     

Inhibitory effects of 1,25-dihydroxyvitamin D3 and its low-calcemic analogues on staurosporine-induced apoptosis

The active form of vitamin D3 and some of its related compounds show neuroprotective effects in various models of neuronal damage, however, mechanism of their anti-apoptotic action has not been elucidated. Therefore, the present study was designed to investigate the effects of 1,25-dihydroxyvitamin D3 and its low-calcemic analogues, PRI-2191, PRI-1890 and PRI-1901 on staurosporine-induced apoptosis in human neuroblastoma SH-SY5Y cells. Twenty-four hour incubation with staurosporine (1 microM) enhanced the caspase-3 activity, decreased mitochondrial membrane potential and increased the number of apoptotic cells as visualized by Hoechst staining. 1,25-Dihydroxyvitamin D3 and PRI-2191 attenuated the staurosporine-induced caspase-3 activity at 5, 50 and 500 nM, whereas PRI-1890 and PRI-1901 were active only at higher concentrations. Furthermore, 1,25-dihydroxyvitamin D3 (50 and 500 nM) and PRI-2191 (500 but not 50 nM) reversed the staurosporine-evoked decrease in mitochondrial membrane potential. Hoechst and calcein staining confirmed the neuroprotective effects of the secosteroids under study. Further study revealed that a selective inhibitor of phosphatidylinositol 3-kinase (PI3-K), wortmannin, at concentration of 100 nM antagonized the effect of 1,25-dihydroxyvitamin D3 and PRI-2191 on staurosporine-induced caspase-3 activation. These data indicate that 1,25-dihydroxyvitamin D3 and its low-calcemic analogues at nanomolar concentrations inhibited mitochondrial pathway of apoptosis in SH-SY5Y neuronal cells, though with different potency. Moreover, the activation of PI3-K/Akt signaling pathway appears to play a role in anti-apoptotic effects of the secosteroids.