抗PD-1/PD-L1免疫检查点抑制剂的皮肤免疫相关不良反应的研究进展

随着免疫检查点抑制剂（immune checkpoint inhibitors，ICPI）在国内外临床试验和应用中的逐步推广，越来越多的患者从免疫治疗中获得显著的疗效。其中抗程序细胞死亡蛋白1（programmed death-1，PD-1）及其配体（PD-1 ligand，PD-L1）免疫检查点抑制剂已被美国食品药品管理局（FDA）批准用于恶性黑色素瘤、转移性鳞状非小细胞肺癌、晚期肾癌、头颈鳞状细胞癌、尿路上皮癌等肿瘤的治疗。但PD-1/PD-L1单抗也会引起免疫相关性皮肤、消化道、肝脏、内分泌、肺部等器官的不良反应，皮肤毒性如皮疹、白癜风、皮肤干燥症等是最常见也是最早发生的不良反应。     

激光照射对皮肤及机体免疫功能影响的研究

目的:探讨二氧化碳激光照射治疗对皮肤及机体免疫功能的影响。方法:将34只健康小白鼠和15只家兔随机分为照射组和对照组,实验采用波长10.6滋m二氧化碳激光。分别取血清测定免疫球蛋白G(IgG)含量,解剖后取出胸腺和脾脏称重;在背部注射植物血凝素(PHA)做皮试观察红斑反应,并进行皮肤切片作病理组织学检查。结果:激光照射后,血清IgG含量、胸腺和脾脏重量、PHA皮试反应均未见明显差异(P>0.05)。照射区皮肤切片病理组织学检查为一过性非特异性炎症反应,3天后即基本消退。结论:本实验提示所用的CO2激光剂量对实验动物的皮肤、体液免疫和细胞免疫等方面并无不良影响。     

Inhibition of T cell receptor signal transduction by tyrosine kinase-interacting protein of Herpesvirus saimiri

T cells play a central role in orchestrating immunity against pathogens, particularly viruses. Thus, impairing T cell activation is an important strategy employed by viruses to escape host immune control. The tyrosine kinase-interacting protein (Tip) of the T lymphotropic Herpesvirus saimiri (HVS) is constitutively present in lipid rafts and interacts with cellular Lck tyrosine kinase and p80 endosomal protein. Here we demonstrate that, due to the sequestration of Lck by HVS Tip, T cell receptor (TCR) stimulation fails to activate ZAP70 tyrosine kinase and to initiate downstream signaling events. TCR zeta chains in Tip-expressing T cells were initially phosphorylated to recruit ZAP70 molecule upon TCR stimulation, but the recruited ZAP70 kinase was not subsequently phosphorylated, resulting in TCR complexes that were stably associated with inactive ZAP70 kinase. Consequently, Tip expression not only markedly inhibited TCR-mediated intracellular signal transduction but also blocked TCR engagement with major histocompatibility complexes on the antigen-presenting cells and immunological synapse formation. These results demonstrate that a lymphotropic herpesvirus has evolved a novel mechanism to deregulate T cell activation to disarm host immune surveillance. This process contributes to the establishment and maintenance of viral latency.     

B7-H 3在神经胶质瘤免疫逃逸过程中的作用机制研究

目的：通过对不同级别的神经胶质瘤（glioma）组织中的刺激分子B7‐H3的检测,进一步探讨其在神经胶质瘤免疫逃逸过程中的作用机制,为神经胶质瘤临床免疫治疗提供理论基础和实验依据。方法：采用免疫组化法,检测58例脑神经胶质瘤患者瘤组织和9例正常脑组织中B7‐H3的表达,并分析其与神经胶质瘤生物学行为及预后之间的关系。结果：58例不同级别的胶质瘤组织均表达B7‐H3,9例正常脑组织中发现很少有B7‐H3的表达,低级别（1～2级）及高级别（3～4级）胶质瘤组与正常脑组织组之间B7‐H3的表达差异均有显著意义（ P＜0．05）,低级别（1～2级）胶质瘤组与高级别（3～4级）胶质瘤组之间有明显差异性（P＜0．05）,B7‐H3的表达与患者的年龄、性别无关,与病理级别及预后有关,生存期超过2年的神经胶质瘤患者B7‐H3阳性表达率显著高于生存期短于2年的胶质瘤患者（ P＜0．01）。结论：B7‐H3的表达与神经胶质瘤之间具有相关性,且随神经胶质瘤病理级别的增高而降低,在神经胶质瘤的免疫逃逸过程中有重要作用,可以作为反映神经胶质瘤生物学行为和患者预后的一个新的指标;并为神经胶质瘤免疫逃逸机制的进一步研究提供了线索,为临床制定合理的治疗方案、预后判断及疗效评定提供客观参考依据。     

当归不同有效部位对高原低氧模型小鼠免疫功能的影响

目的探讨当归不同有效部位对高原低氧模型小鼠免疫功能的干预作用。方法将SPF级小鼠采用随机数字表法分为对照组、模型组、红景天组及当归有效部位B、X、C组。灌胃给药,每日1次,连续21 d。除对照组外,第8日起各组小鼠每日灌胃30 min后于低氧舱中模拟高海拔环境进行低氧暴露。第22日出舱称重后眼球采血处死小鼠,制备脾淋巴细胞悬液。MTT法检测各组小鼠脾淋巴细胞增殖能力、转化能力及NK细胞杀伤活力。ELISA检测各组小鼠血清白细胞介素(IL)-2含量。结果与对照组比较,模型组小鼠在处死前体质量明显下降,脾淋巴细胞增殖能力、转化能力、刺激指数及NK细胞杀伤活性均明显下降,血清IL-2含量明显降低(P0.05,P0.01);与模型组比较,各给药组小鼠脾淋巴细胞增殖能力、转化能力及NK细胞杀伤活性均明显升高(P0.05,P0.01),当归有效部位X组刺激指数明显升高,当归有效部位X、C组血清IL-2含量均明显升高(P0.05,P0.01)。结论当归不同有效部位对低氧暴露下的小鼠免疫功能具有一定的增强作用。     

免疫干预对慢性阻塞性肺疾病患者急性加重期免疫功能及生活质量的影响

目的探讨免疫干预对慢性阻塞性肺疾病(COPD)患者急性加重期(AECOPD)免疫功能及生活质量的影响。方法82例AECOPD患者随机分为观察组40例和对照组42例,对照组给予常规治疗,观察组在此基础上加用胸腺五肽注射液,2组均连续治疗15 d。结果治疗后,观察组显效率显著高于对照组(P0.05);与治疗前比较,观察组CD3+、CD4+细胞、CD16+CD56+细胞比例及CD4+/CD8+升高(P0.05或P0.01),对照组仅CD16+CD56+细胞比例升高(P0.05);组间比较,观察组CD3+细胞、CD4+细胞、CD16+CD56+细胞比例,及CD4+/CD8+均高于对照组(P0.05或P0.01)。2组治疗后6个月的圣乔治呼吸问卷(SGRQ)各问卷得分及总分均显著下降(P0.01),观察组低于对照组(P0.01)。结论AECOPD患者采用胸腺五肽进行免疫干预治疗,可有效提高临床疗效,改善免疫功能及生活质量。     

Effects of 60-day bed rest with and without exercise on cellular and humoral immunological parameters

Exercise at regular intervals is assumed to have a positive effect on immune functions. Conversely, after spaceflight and under simulated weightlessness (e.g., bed rest), immune functions can be suppressed. We aimed to assess the effects of simulated weightlessness (Second Berlin BedRest Study; BBR2-2) on immunological parameters and to investigate the effect of exercise (resistive exercise with and without vibration) on these changes. Twenty-four physically and mentally healthy male volunteers (20–45 years) performed resistive vibration exercise (n=7), resistance exercise without vibration (n=8) or no exercise (n=9) within 60 days of bed rest. Blood samples were taken 2 days before bed rest, on days 19 and 60 of bed rest. Composition of immune cells was analyzed by flow cytometry. Cytokines and neuroendocrine parameters were analyzed by Luminex technology and ELISA/RIA in plasma. General changes over time were identified by paired t-test, and exercise-dependent effects by pairwise repeated measurements (analysis of variance (ANOVA)). With all subjects pooled, the number of granulocytes, natural killer T cells, hematopoietic stem cells and CD45RA and CD25 co-expressing T cells increased and the number of monocytes decreased significantly during the study; the concentration of eotaxin decreased significantly. Different impacts of exercise were seen for lymphocytes, B cells, especially the IgD⁺ subpopulation of B cells and the concentrations of IP-10, RANTES and DHEA-S. We conclude that prolonged bed rest significantly impacts immune cell populations and cytokine concentrations. Exercise was able to specifically influence different immunological parameters. In summary, our data fit the hypothesis of immunoprotection by exercise and may point toward even superior effects by resistive vibration exercise.