Artificially Reprogrammed Macrophages as Tumor‐Tropic Immunosuppression‐Resistant Biologics to Realize Therapeutics Production and Immune Activation

To engineer patient‐derived cells into therapy‐purposed biologics is a promising solution to realize personalized treatments. Without using gene‐editing technology, a live cell‐typed therapeutic is engineered for tumor treatment by artificially reprogramming macrophages with hyaluronic acid‐decorated superparamagnetic iron oxide nanoparticles (HIONs). This nanoparticle‐assisted cell‐reprogramming strategy demonstrates profound advantages, due to the combined contributions from the biological regulation of HIONs and the intrinsic nature of macrophages. Firstly, the reprogrammed macrophages present a substantial improvement in their innate capabilities, such as more effective tumor targeting and more efficient generation of bioactive components (e.g., reactive oxygen species, bioactive cytokines) to suppress tumor growth. Furthermore, this cell therapeutic exhibits cytostatic/proapoptotic effects specific to cancer cells. Secondly, HIONs enable macrophages more resistant to the intratumoral immunosuppressive environment. Thirdly, the macrophages are endowed with a strong ability to prime in situ protumoral M2 macrophages into antitumor M1 phenotype in a paracrine‐like manner. Consequently, a synergistic tumor‐inhibition effect is achieved. This study shows that engineering nanomaterial‐reprogrammed live cells as therapeutic biologics may be a more preferable option to the commonly used approaches where nanomaterials are administrated to induce bioresponse of certain cells in vivo.     

Implantable Synthetic Immune Niche for Spatiotemporal Modulation of Tumor‐Derived Immunosuppression and Systemic Antitumor Immunity: Postoperative Immunotherapy

The development of biomaterial‐based immune niches that can modulate immunosuppressive factors in tumor microenvironment (TME) will be a key technology for improving current cancer immunotherapy. Here, implantable, engineered 3D porous scaffolds are designed to generate synergistic action between myeloid‐derived suppressor cell (MDSC)‐depleting agents, which can accommodate the establishment of a permissive immunogenic microenvironment to counteract tumor‐induced immunosuppression, and cancer vaccines consisting of whole tumor lysates and nanogel‐based adjuvants, which can generate tumor antigen‐specific T cell responses. The local peritumoral implantation of the synthetic immune niche (termed immuneCare‐DISC, iCD) as a postsurgical treatment in an advanced‐stage primary 4T1 breast tumor model generates systemic antitumor immunity and prevents tumor recurrence at the surgical site as well as the migration of residual tumor cells into the lungs, resulting in 100% survival. These therapeutic outcomes are achieved through the inhibition of immunosuppressive MDSCs in tumors and spleens by releasing gemcitabine and recruitment/activation of dendritic cells, enhanced population of CD4⁺ and CD8⁺ T cells, and increased IFN‐γ production by cancer vaccines from the iCD. This combined spatiotemporal modulation of tumor‐derived immunosuppression and vaccine‐induced immune stimulation through the iCD is expected to provide an immune niche for prevention of postoperative tumor recurrence and metastasis.     

乌贼墨对环磷酰胺致小鼠脾脏氧化性损伤的保护效应

探讨乌贼墨提取物对环磷酰胺致小鼠脾脏氧化性损伤拮抗作用。40 只昆明小鼠,随机分成4 组,雌雄各半,各组分别灌服生理盐水或不同剂量的乌贼墨提取物及腹腔注射生理盐水或环磷酰胺。观察各组小鼠脾脏器官指数,脾脏中MDA、SOD、CAT、GSH-Px 含量,以及外周血白细胞数量。与对照组比较,环磷酰胺能显著的降低正常小鼠的脾脏指数(p ＜ 0.05),能极显著的降低正常小鼠脾脏组织中SOD、CAT、GSH-Px 活力(p ＜ 0.01),显著的提高正常小鼠脾脏组织中MDA 含量(p ＜ 0.05),也能极其显著的降低正常小鼠外周血白细胞数量(p ＜ 0.01)。与模型组比较,适当浓度的乌贼墨提取物对环磷酰胺所致各项指标的变化均有不同程度的改善作用(p ＜ 0.05 或p ＜0.01),结果表明,较高浓度的乌贼墨提取物的改善作用反而不是很明显,相对于低剂量组,在一定程度上起到抑制作用。乌贼墨提取物对环磷酰胺所致的小鼠脾脏组织氧化性损伤进而导致的免疫抑制具有一定的改善和治疗作用,是一种有效的而且很有潜力的天然药物资源。     

他克莫司治疗特发性膜性肾病研究进展

他克莫司是一种钙调磷酸酶抑制剂,发挥免疫抑制作用。特发性膜性肾病是原发性肾病综合征最常见的病理类型。他克莫司的不良反应较其他免疫抑制剂小,疗效肯定,在特发性膜性肾病中的应用越来越广泛。近年来,关于他克莫司在特发性膜性肾病中的应用有较多研究及探索。本文总结了他克莫司在特发性膜性肾病中的治疗进展及个体化用药。     

魔芋甘露寡糖对酸奶免疫调节活性的影响

益生元用于发酵乳制品可改善其质构特性和感官品质,同时强化其健康功效。本研究采用环磷酰胺（cyclophosphomide,CTX）诱导BALB/C小鼠建立免疫抑制模型,评价功能性低聚糖类益生元——魔芋甘露寡糖（konjac mannanoligosaccharides,KMOS）的添加对于酸奶免疫调节活性的影响。结果表明,KMOS可强化酸奶对于CTX诱导小鼠免疫抑制的改善作用。KMOS添加量为0.5%（以鲜牛乳质量计）时酸奶对免疫抑制小鼠基本生理状态、腹腔巨噬细胞吞噬活性、脾淋巴细胞增殖率、血清中免疫球蛋白质量浓度以及腹腔巨噬细胞炎症因子的释放等均有显著改善作用,且添加KMOS的酸奶可提高免疫抑制小鼠肠道中非优势菌群的相对丰度,抑制梭菌属的增殖并增加有益菌数量,从而调节免疫抑制小鼠肠道菌群结构及组成。本研究可为基于功能性低聚糖的新型发酵乳制品开发提供借鉴。     

乳酸菌BC299的鉴定及其对免疫抑制小鼠肠道菌群的影响

以传统发酵泡菜中分离得到的乳酸菌BC299为研究对象,通过形态观察、生理生化、16S rDNA基因序列分析等方法对其进行鉴定,研究其耐酸、耐胆盐、耐抗生素能力,并以环磷酰胺（CTX）诱导免疫抑制小鼠,研究菌株BC299对小鼠粪便中肠道细菌的多样性和相对丰度的影响。结果表明,菌株BC299被鉴定为植物乳杆菌（Lactobacillus plantarum）,其对pH2.0和0.3%胆盐具有良好的耐受性;对常见抗生素敏感;能改善CTX诱导小鼠的小肠绒毛和组织形态的破坏,对免疫抑制小鼠的肠道菌群具有调节作用,能正向调节与免疫相关菌群的相对丰度,使小鼠肠道内毛螺菌科（Lachnospiraceae）和瘤胃球菌科（Ruminococcaceae）的相对丰度显著降低（P＜0.05）,拟杆菌科（Bacteroidaceae）的相对丰度显著增加（P＜0.05）。     

Effects of mastectomy on composition of peripheral blood mononuclear cell populations in periparturient dairy cows

There is an increased incidence of infectious disease in periparturient dairy cows. During the periparturient period there is a decline in T-lymphocyte cell subsets, which parallels a reduction in functional capacities of blood lymphocytes and neutrophils. Mechanisms responsible for these changes in immune function during the periparturient period are poorly characterized. Ten mastectomized and eight intact multiparous Jersey cows were used to determine whether the periparturient changes in peripheral blood mononuclear cell populations are the result of the physiological demands associated with the onset of lactation or whether they are a result of the act of parturition. Blood mononuclear cells were phenotyped with monoclonal antibodies against T-cell subsets, B-cells, and monocytes. Blood samples were taken frequently from before 4 to 4 wk after parturition. In intact cows, all T-cell subset populations (i.e., CD3-, CD4-, CD8-, and gamma-delta positive cells) decreased at the time of parturition, while the percentage of monocytes increased. Mastectomy eliminated the changes in leukocyte subset populations (CD3-, CD4-, and gamma-delta positive cells, and monocytes) observed in intact cows around parturition. These results indicate that the mammary gland and metabolic stresses associated with lactation influence the composition of peripheral blood mononuclear cell populations in dairy cows during the periparturient period.     

Effects of the mammary gland on functional capacities of blood mononuclear leukocyte populations from periparturient cows

The composition and functional capacity of peripheral blood mononuclear leukocyte populations from dairy cows are altered substantially during the peripartal period. These changes are associated with a heightened susceptibility of the mammary gland to infection. It has been postulated that the metabolic demands associated with lactogenesis may impact negatively leukocyte function during the periparturient period. In the present study, serum immunoglobulin G1 concentration and functional capacities of peripheral blood mononuclear leukocytes from intact (n = 6) and mastectomized (n = 6) periparturient Jersey cows were evaluated and compared. Cell function assessments included lymphocyte proliferation, immunoglobulin M secretion, and interferon-gamma secretion by unstimulated and pokeweed mitogen stimulated mononuclear leukocytes. Data were summarized as mean responses for 5-d periods beginning 21 d prepartum and concluding at 19 d postpartum. The progressive decrease in serum immunoglobulin G in intact but not mastectomized cows before parturition likely was attributable to the selective uptake of this isotype by the mammary gland. Lymphocyte proliferation and secretion of interferon-gamma and polyclonal IgM by mitogen-stimulated leukocytes from intact cows decreased during the 15-d period before calving, reaching a nadir at 0 to 4 d postpartum. From 5 to 19 d postpartum, these functions often were comparable to those observed 2 to 3 wk prepartum. Functions of leukocytes from mastectomized cows did not change during the study period, although they often were of lower magnitude than those of cells from nonlactating cows. These results reconfirm the occurrence of a generalized reduction in blood mononuclear leukocyte function during the periparturient period. They also suggest that the reduction in leukocyte function during the period may be, in part, due to the physiologic demands imposed on the dairy cow by the lactating mammary gland.     

金雀异黄素通过AMPK/SIRT1/PGC-1α信号通路缓解免疫抑制大鼠的疲劳作用

目的：探讨金雀异黄素（genistein,GEN）缓解免疫抑制大鼠的疲劳作用及其作用机制。方法：96 只雄性SD大鼠随机分为6 组（每组16 只）,分别为空白对照组、免疫抑制模型组与金雀异黄素低、中、高剂量组以及阳性对照组。除空白对照组外,其余组腹腔注射环磷酰胺40 mg/kg mb,连续3 d,建立免疫抑制大鼠模型。金雀异黄素低、中、高剂量组分别灌胃10、20、40 mg/kg mb金雀异黄素,阳性对照组灌胃贞芪扶正颗粒3.125 g/kg mb,空白对照组灌胃等量花生油。实验结束后,记录大鼠力竭游泳时间;采用比色法检测大鼠血清中肌酸激酶（creatine kinase,CK）、乳酸脱氢酶（lactate dehydrogenase,LDH）活力;酶联免疫吸附测定法检测大鼠血清中免疫球蛋白G（immunoglobulin G,IgG）、肿瘤坏死因子α（tumor necrosis factor α,TNF-α）质量浓度;采用实时荧光定量技术检测大鼠骨骼肌中腺苷酸活化蛋白激酶（adenosine monophosphate-activated protein kinase,AMPK）、沉默信息调节因子1（silent information regulator 1,SIRT1）、过氧化物酶增殖活化受体γ辅激活因子1α（peroxisome proliferator-activated receptor γ coactivator 1α,PGC-1α）和过氧化物酶体增殖物激活受体γ（peroxisome proliferators-activated receptor γ,PPARγ）mRNA表达水平;采用蛋白免疫印迹法检测大鼠骨骼肌中p-AMPK、SIRT1、PGC-1α和PPARγ的蛋白表达水平。结果：与免疫抑制模型组相比,补充GEN后极显著延长了大鼠力竭游泳时间（P＜0.01）;与免疫抑制模型相比,高剂量GEN能够显著降低血清中CK活力（P＜0.05）和LDH活力（P＜0.01）,极显著提高大鼠血清中IgG、TNF-α质量浓度（P＜0.01）,同时显著提高大鼠骨骼肌中p-AMPK、SIRT1、PGC-1α和PPARγ基因及蛋白表达水平（P＜0.05、P＜0.01）。结论：GEN具有缓解免疫低下大鼠疲劳的作用,其机制可能与激活骨骼肌AMPK/SIRT1/PGC-1α信号通路及改善大鼠运动耐力、能量产生及免疫调节能力有关。