Macrophage priming and lipopolysaccharide-triggered release of tumor necrosis factor alpha during graft-versus-host disease

In this report we have investigated macrophage (M phi) activity and tumor necrosis factor alpha (TNF-alpha) production during graft-vs.-host disease (GVHD). TNF-alpha production by M phi requires two signals: priming of M phi by interferon followed by triggering of TNF-alpha production and release by lipopolysaccharide (LPS). The state of M phi activation was examined in nonirradiated B6AF1 recipient mice injected with either 60 x 10(6) (acute GVHD) or 30 x 10(6) (nonlethal GVHD) parental B6 lymphoid cells. During the early phase of acute GVHD, administration of normally sublethal amounts of LPS-triggered release of significant amounts of TNF-alpha into the serum resulting in death of the animals within 36 h. Normal animals treated with the same dose of LPS neither died nor produced detectable amounts of serum TNF-alpha. In vitro studies demonstrated that M phi were primed during GVHD. The level of M phi priming was greater during acute GVHD than nonlethal GVHD since 100-fold less LPS was required to trigger killing of a TNF-alpha-sensitive cell line by M phi from acute GVHD animals. The amount of TNF-alpha released into the serum after LPS injection increased during the course of the GVHD and was significantly greater in acute GVH-reactive mice. Endogenous LPS was detected in the serum of acute GVH-reactive animals coincident with the onset of mortality. The data provide evidence that during GVHD M phi are primed as a result of the allogeneic reaction and that endogenous LPS therefore triggers M phi production of TNF-alpha resulting in the symptoms characteristic of acute GVHD.     

早期生长反应基因1对巨噬细胞分泌肿瘤坏死因子α的影响

背景：体内外研究已证实肺巨噬细胞合成和分泌肿瘤坏死因子α 等参与肺组织局部损伤和炎症反应，但具体发生机制仍不明确。 目的：观察核转录因子早期生长反应基因1对巨噬细胞分泌肿瘤坏死因子α的影响。设计、时间及地点：随机分组设计，于2004-06／2006—12在湘雅医学院病理学系完成。材料：标准石英粉尘（SiO2）为Sigma公司产品：早期生长反应基因1抗体为Santa Cruz公司产品：小鼠巨噬细胞系RAW264．7购自中科院上海生物细胞研究所细胞库。方法：实验将巨噬细胞分为正常对照组、二氧化硅刺激组、Egr-1＋二氧化硅组和IgG＋二氧化硅组，前两组加无血清培养基，后两组分别加入5，10，20mg／L不同浓度的Egr-1和IgG抗体干预。 主要观察指标：酶联免疫吸附实验检测各组细胞上清中肿瘤坏死因子α蛋白的水平；反转录-聚合酶链反应检测细胞内肿瘤坏死因子amRNA的表达。结果：①与二氧化硅刺激组相比，不同浓度Egr-1＋二氧化硅组细胞上清中肿瘤坏死因子α蛋白水平均下降（P〈0．01），且10mg／L组与5，20mg／L组相比，差异有显著性意义（P〈0．05）。不同浓度IgG＋二氧化硅组相比，上清液中肿瘤坏死因子α蛋白水平差异无显著性意义（F=1．008，P=0．438）。②二氧化硅刺激组肿瘤坏死因子ⅡmRNA表达高于正常对照组（P〈0．01），而Egr-1＋二氧化硅组mRNA表达低于二氧化硅刺激组和IgG＋二氧化硅组（P〈0．01）。结论：二氧化硅致巨噬细胞分泌肿瘤坏死因子α增加可能通过激活核转录因子早期生长反应基因1介导的信号通路而实现。     

Adeno-associated virus production of soluble tumor necrosis factor receptor neutralizes tumor necrosis factor alpha and reduces arthritis

The major limitation of adenovirus is its association with induction of an inflammatory response and relatively short-term production of the gene therapy transgene product. Adeno-associated virus (AAV) is a 4.68-kb single-strand DNA virus that contains ITRs for viral replication and a packaging signal, and also has been engineered to contain therapeutic genes up to 5 kb in length. Transduction of recombinant AAV (rAAV) results in low inflammatory response and long-term expression. We have cloned a low-immunogenic form of human sTNFRI (sTNFRI2.6D) into AAV (rAAVsTNFRI). This vector was analyzed for its ability to transfect and neutralize the effect of TNF-alpha on primary rheumatoid arthritis synovial fibroblast (RASFs). The rAAVsTNFRI was transduced into the cells at 1.8 x 10(1), 1.8 x 10(2), and 1.8 x 10(3) viral particles per cell. There was greater than 90% neutralization of TNF-alpha at 1.8 x 10(3) viral particles/cell. There was a significant decrease in the synovial cell hyperplasia and cartilage and bone destruction in human TNF-alpha transgenic mice treated intraarticularly with rAAVsTNFRI. These results indicate that the low-immunogenic and long-term expressing vector, rAAVsTNFRI, can be used to deliver the soluble TNF-alpha in vitro and in vivo and effectively reduce the severity of arthritis.     

Tumor suppression after tumor cell-targeted tumor necrosis factor alpha gene transfer

The tumor necrosis factor alpha (TNF-alpha) gene was introduced by retroviral gene transfer into the TNF-alpha-insensitive tumor cell line J558L. Production of 40 pg/ml TNF-alpha by clone J2T12 consistently did not change the growth rate in vitro, but drastically suppressed tumor growth when injected into syngeneic BALB/c mice. Within 2 wk, 90% of the mice inoculated with J558L cells developed a tumor, but none of the mice injected with J2T12 did so. Within the observation period (greater than 3 mo), 60% of the mice inoculated with J2T12 did not develop a tumor. In the other 40% of the mice, tumor manifestation was significantly delayed. Mice injected simultaneously with J2T12 cells and an anti-TNF-alpha monoclonal antibody developed tumors similar to parental J558L cells. Similarly, the tumor-suppressive effects of TNF-alpha were abolished, e.g., by injection of an anti-type 3 complement receptor (CR3) monoclonal antibody that is known to prevent migration of inflammatory cells. These results and the observation of tumor-infiltrating macrophages suggest that lack of tumorigenicity of J2T12 cells is due to the TNF-alpha secretion by the tumor cells and that TNF-alpha acts indirectly by a mechanism that involves chemotactic recruitment and activation of cells, predominantly of macrophages. In contrast, the tumor growth was not affected when, instead of TNF-alpha, interleukin 6 was expressed by J558L cells. Together, our results support the concept of tumor cell-targeted cytokine gene transfer as a tool for cancer treatment, and particularly demonstrate that extremely low doses of TNF-alpha produced by tumor cells are sufficient to inhibit tumor growth without detectable side effects.     

Lipopolysaccharide-induced selective priming effects on tumor necrosis factor alpha and nitric oxide production in mouse peritoneal macrophages

Preculture of thioglycollate-elicited C3HeB/FeJ mouse peritoneal macrophages in vitro with subthreshold stimulatory concentrations of lipopolysaccharide (LPS) can induce hyporesponsiveness (desensitization) to both tumor necrosis factor alpha (TNF-alpha) and nitric oxide (NO) production when these cells are subsequently stimulated with 100 ng/ml of LPS. We have established, however, that the primary dose of LPS required for inducing downregulation of NO production is significantly lower than that required for inducing downregulation of TNF-alpha production. Further, when LPS-pretreated macrophages become refractory to subsequent LPS stimulation for NO production, the secondary LPS-stimulated TNF-alpha production is markedly enhanced, and vice versa. These results indicate that LPS- induced TNF-alpha and NO production by macrophages are differentially regulated, and that the observed desensitization process may not reflect a state in which macrophages are totally refractory to subsequent LPS stimulation. Rather, our data suggest that LPS- pretreated macrophages become selectively primed for differential responses to LPS. The LPS-induced selective priming effects are not restricted to LPS stimulation, but extend as well to stimuli such as zymosan, Staphylococcus aureus, and heat-killed Listeria monocytogenes.     

五种生物材料对大鼠巨噬细胞肿瘤坏死因子α和白细胞介素1 β表达的影响

背景：生物材料的免疫学研究主要包括免疫球蛋白、血清总补体及补体降解产物的血生化定量测定等方面，主要通过细胞学和组织学的检测手段，其评价指标比较单一，无特异性。 目的：以细胞因子（肿瘤坏死因子α和白细胞介素1β）为研究对象，从mRNA水平上对5种生物材料介导的炎症反应进行相关免疫学评价。 设计、时间及地点：对比观察实验，于2004—01／2005—03在上海生物材料研究测试中心完成。 材料：清洁级SD大鼠3只用于原代培养大鼠巨噬细胞。阳性材料：含8％有机锡的聚氟乙烯。阴性材料：聚苯乙烯。实验材料：美国NPG黄合金块、β-磷酸三钙、固化的磷酸钙骨水泥、聚丙交酯乙交酯及聚四氟乙烯。 方法：参照ISO 10993-12标准，用RPMI—1640按1g／5mL比例，37℃72h制备材料的浸提液。将大鼠腹腔巨噬细胞分别给予脂多糖刺激和无脂多糖刺激，脂多糖的终浓度为1．0mg／L，再用不同生物材料的浸提液予以刺激，作用2h后收集细胞，进行反转录-聚合酶链反应检测。 主要观察指标：大鼠巨噬细胞肿瘤坏死因子α和白细胞介素1β的表达强度。 结果：未经脂多糖诱导的大鼠腹腔巨噬细胞与阳性材料及聚四氟乙烯、NPG接触后肿瘤坏死因子α和白细胞介素1β的表达均高于阴性材料，差异均有非常显著性意义（P〈0．05）；聚丙交酯乙交酯中肿瘤坏死因子α的表达与阴性材料相比无明显升高（P〉0．05），白细胞介素1β的表达高于阴性材料，差异有显著性意义（P〈0．05）；β-磷酸三钙和固化的磷酸钙骨水泥中肿瘤坏死因子α和白细胞介素1β的表达与阴性材料比较差异无显著性意义（P〉0．05）。经脂多糖诱导的大鼠腹腔巨噬细胞与阳性材料及聚四氟乙烯、NPG、聚丙交酯乙交酯、β-磷酸三钙及固化的磷酸钙骨水泥接触后肿瘤坏死因子α和白细胞介素1β的表达均高于阴性材料，差异均有非常显著性意义（P〈0．01）。 结论：肿瘤坏死因子α、白细胞介素1β是在分子水平上衡量不同生物材料诱导免疫刺激反应的理想指标。聚四氟乙烯和NPG的生物相容性程度较差，β-磷酸三钙和固化的磷酸钙骨水泥的相容性较好，尤其是固化的磷酸钙骨水泥。     

Fungal infections complicating tumor necrosis factor alpha blockade therapy

Tumor necrosis factor a (TNF-alpha) blockade has emerged as a useful therapy for collagen vascular diseases or graft-vs-host disease. Fungal infections complicating such therapy have been reported sporadically. MEDLINE and PubMed databases (from January 1, 1966, to June 1, 2007) were searched for reports of invasive fungal infections (IFIs) associated with the 3 available anti-TNF- alpha agents, ie, infliximab, etanercept, and adalimumab. Of the 281 cases of IFI associated with TNF-alpha inhibition, 226 (80%) were associated with infliximab, 44 (16%) with etanercept, and 11 (4%) with adalimumab. Fungal infections associated with infliximab occurred a median of 55 days (interquartile range [IQR], 15-140 days) after initiation of therapy and 3 infusions of the medication (IQR, 2-5), whereas those associated with etanercept occurred a median of 144 days (IQR, 46-240 days) after initiation of therapy. The median age of patients was 58 years (IQR, 44-68 years), and 62% were male. Use of at least 1 other immunosuppressant medication, typically a systemic corticosteroid, was reported during the course of the fungal infection in 102 (98%) of the 104 patients for whom data were available. The most prevalent IFIs were histoplasmosis (n=84 [30%]), candidiasis (n=64 [23%]), and aspergillosis (n equals 64 [23%]). Pneumonia was the most common pattern of infection. Of the 90 (32%) of 281 cases for which outcome information was available, 29 fatalities (32%) were recorded. Tumor necrosis factor a blockade is associated with IFI across a range of host groups. A high index of suspicion in patients treated with TNF-alpha antagonists is recommended because the course of such infections can be serious or fulminant, and rapid access to health care should be provided. Surveillance of IFIs complicating TNF-alpha blockade and other biologic therapies is warranted through well-organized prospective patient registries.     

Dehydroepiandrosterone protects mice from endotoxin toxicity and reduces tumor necrosis factor production.

Recent reports have demonstrated an immunomodulating activity of dehydroepiandrosterone (DHEA) different from that described for glucocorticoids. The present study was designed to test DHEA's activity in endotoxic shock and to investigate its effect on endotoxin-induced production of tumor necrosis factor (TNF). Mortality of CD-1 mice exposed to a lethal dose of lipopolysaccharide (LPS; 800 micrograms per mouse) was reduced from 95 to 24% by treatment with a single dose of DHEA, given 5 min before LPS. LPS administration resulted in high levels of TNF, a response that was significantly blocked by DHEA, both in vivo and in vitro. DHEA treatment also reduced LPS-induced increments in serum corticosterone levels, a parameter considered not to be mediated by TNF. In another experimental model, mice sensitized with D-galactosamine, followed by administration of recombinant human TNF, were subjected to 89% mortality rate, which was reduced to 55% in DHEA-treated mice. These data show that DHEA protects mice from endotoxin lethality. The protective effect is probably mediated by reduction of TNF production as well as by effecting both TNF-induced and non-TNF-induced phenomena.     

Reduction of no synthase expression and tumor necrosis factor alpha production in macrophages by amphotericin B lipid carriers

The present study compared the abilities of different lipid carriers of amphotericin B (AMB) to activate murine peritoneal macrophages, as assessed by their capacities to produce nitric oxide (NO) and tumor necrosis factor alpha (TNF-alpha). Although AMB alone did not induce NO production, synergy was observed with gamma interferon but not with lipopolysaccharide. This synergy could not be explained by the mobilization of the nuclear activation factor NF-kappaB by AMB. On the other hand, AMB induced TNF-alpha production without a costimulator and no synergy was observed. Anti-TNF-alpha antibodies did not influence NO production, and an inhibitor of NO synthase did not affect TNF-alpha production, indicating that the production of one of these effector molecules was independent of that of the other. The incorporation of AMB into lipid carriers reduced NO and TNF-alpha production with all formulations but more so with liposomes than with lipid complexes. NO production was correlated with the induction of NO synthase II, revealed by Western blotting. The extent of association of AMB with macrophages depended on the formulation, especially on the AMB/lipids ratio: the higher the ratio was, the greater the AMB association with macrophages. However, there was no clear correlation between AMB association with macrophages, whether internalized or bound to the membrane, and immunostimulating effects. These results may explain the reduced toxicities of lipid-based formulations of AMB.     

肿瘤坏死因子诱导肿瘤细胞凋亡及其调节机制的研究

背景肿瘤坏死因子(TNF)在体外能诱导某些正常细胞和大多数肿瘤细胞株(包括Hela细胞株)凋亡,其凋亡发生机制与细胞周期的关系中尚有许多问题需要探讨.目的研究细胞周期时相对TNF诱导Hela细胞凋亡的影响.设计非随机非对照实验研究.地点和对象实验在广东医学院生物化学与分子生物学研究所完成,对象为重组人肿瘤坏死因子-α(rhTNF-α,Sigma产品),Hela细胞株引自中国科学院上海细胞生物研究所.干预通过胸腺嘧啶核苷酸(TdR)阻断法阻滞Hela细胞的细胞周期,采用MTT法、流式细胞术和荧光染色分析TdR阻滞细胞和周期化的Hela细胞对TNF诱导凋亡的敏感性.主要观察指标TNF诱导TdR阻滞和周期化Hela细胞凋亡数.结果TdR阻滞细胞周期较周期化的Hela细胞对TNF诱导凋亡的敏感性降低.结论TNF诱导Hela细胞凋亡与细胞周期有关.     

Passive immunization against tumor necrosis factor partially abrogates interleukin 2 toxicity

Passive immunization against TNF allowed non-tumor-bearing C3H/HEN mice and tumor-bearing C57BL/6 mice to tolerate significantly more doses of IL-2 before death (p less than 0.005 and p less than 0.001, respectively). The antitumor effect of IL-2 against both 3-d and 10-d pulmonary metastases was maintained in mice treated concurrently with neutralizing antibodies to TNF. In one experiment with 10-d pulmonary metastases, increased administration of IL-2 made possible by passive immunization against TNF significantly improved the antitumor response compared to equitoxic doses of IL-2 and control antibody. The results indicate that TNF is a mediator of IL-2 toxicity but contributes minimally to the antitumor effects of IL-2. Strategies to inhibit TNF may improve the therapeutic index of IL-2 as a neoplastic agent.     

肿瘤坏死因子α诱导人成骨细胞和人成骨细胞系HOS-8603凋亡的作用

目的:观察不同浓度重组肿瘤坏死因子α对于培养的人原代成骨细胞和人成骨细胞系HOS-8603的凋亡作用,并分析浓度效应。方法:实验于1998-04/2000-04在第二军医大学卫生毒理学教研室完成。在人成骨细胞和人成骨细胞系HOS-8603中,实验组加浓度为1,10,100,1000ng/L的肿瘤坏死因子α,对照组加等量的无肿瘤坏死因子培养基,培养后检测细胞活力应用噻唑兰法,检测细胞凋亡情况应用DNA梯形条带和透射电镜等方法。结果:①肿瘤坏死因子α对培养成骨细胞和HOS-8603细胞的作用(噻唑兰法):肿瘤坏死因子α浓度为100和1000ng/L实验组均高于对照组犤成骨细胞:(0.14±0.006),(0.10±0.010),(0.27±0.013)ng/L;HOS-8603细胞:(0.15±0.012),(0.09±0.015),(0.27±0.013)ng/L,P<0.05犦。②DNA梯形条带结果:凋亡细胞使DNA在核小体外降解,形成180～200bp或与之成倍的DNA片段。在琼脂糖凝胶电泳时呈现梯形结果。在肿瘤坏死因子α浓度为1000ng/L时,成骨细胞可检测到典型DNA梯形条带。③成骨细胞的凋亡情况:应用透射电镜检查,浓度为1000ng/L实验组较浓度为100ng/L实验组凋亡细胞多。肿瘤坏死因子α同样可以诱导HOS-8603的凋亡,未加肿瘤坏死因子α时,凋亡很少,加入100ng/L及1000ng/L肿瘤坏死因子α时,凋亡细胞数量明显增加。结论:肿瘤坏死因子α质量浓度达到100g/L时,可以引起体外培养的成骨细胞和成骨细胞系HOS-8603细胞凋亡,并随浓度加大出现凋亡细胞增多的剂量-效应关系,结果验证了肿瘤坏死因子能刺激成骨细胞凋亡的假说。     

Inhibition of cytotoxic T cell development by transforming growth factor beta and reversal by recombinant tumor necrosis factor alpha

The immunoregulatory effects of transforming growth factor beta (TGF-beta) and recombinant murine tumor necrosis factor alpha (rMuTNF-alpha) on CTL generation and activity were examined. The results demonstrate that TGF-beta, in a dose-dependent manner, inhibited CTL generation but not CTL activity. The inhibitory effects were detected only when TGF-beta was added within the first 48 h of the MLC. Little activity was seen when it was added thereafter, including the addition of TGF-beta to the cytotoxicity assay. The production of TNF-alpha, which occurs during early phases of the MLC and which is inhibited in the presence of TGF-beta, appears to have an important regulatory role, as altering the levels of TNF-alpha in an MLC can significantly influence CTL development. The inhibitory effects of TGF-beta on the MLC can be significantly reversed by the addition of rMuTNF-alpha to the cultures. These results demonstrate that TGF-beta can inhibit MLC and subsequent CTL generation at early stages of the reaction, and such inhibition may involve the suppression of TNF-alpha production.     

肿瘤坏死因子α诱导人成骨细胞和人成骨细胞系HOS-8603凋亡的作用

目的：观察不同浓度重组肿瘤坏死因子α对于培养的人原代成骨细胞和人成骨细胞系HOS-8603的凋亡作用，并分析浓度效应。方法：实验于1998-04／2000—04在第二军医大学卫生毒理学教研室完成。在人成骨细胞和人成骨细胞系HOS-8603中，实验组加浓度为1，10，100，1000ng／L的肿瘤坏死因子α，对照组加等量的无肿瘤坏死因子培养基，培养后检测细胞活力应用噻唑兰法，检测细胞凋亡情况应用DNA梯形条带和透射电镜等方法。结果：①肿瘤坏死因子α对培养成骨细胞和HOS-8603细胞的作用（噻唑兰法）：肿瘤坏死因子α浓度为100和1000ng／L实验组均高于对照组[成骨细胞：（0．14&;#177;0．006），（0．10&;#177;0．010），（0．27&;#177;0．013）ng／L：HOS-8603细胞：（0．15&;#177;0．012），（0．09&;#177;0．015），（0．27&;#177;0．013）ng／L,P〈0．05]。②DNA梯形条带结果：凋亡细胞使DNA在核小体外降解。形成180～200bp或与之成倍的DNA片段。在琼脂糖凝胶电泳时呈现梯形结果。在肿瘤坏死因子α浓度为1000ng／L时，成骨细胞可检测到典型DNA梯形条带。③成骨细胞的凋亡情况：应用透射电镜检查。浓度为1000ng／L实验组较浓度为100ng／L实验组凋亡细胞多。肿瘤坏死因子α同样可以诱导HOS-8603的凋亡，未加肿瘤坏死因子α时，凋亡很少。加入100ng／L及1000ng／L肿瘤坏死因子α时，凋亡细胞数量明显增加。结论：肿瘤坏死因子α质量浓度达到100g／L时，可以引起体外培养的成骨细胞和成骨细胞系HOS-8603细胞凋亡，并随浓度加大出现凋亡细胞增多的剂量-效应关系，结果验证了肿瘤坏死因子能刺激成骨细胞凋亡的假说。     

Circadian dynamics of tumor necrosis factor alpha (cachectin) lethality

Recombinant human tumor necrosis factor-alpha (TNF-alpha) has demonstrable antitumor activity in transplantable murine tumor models and patients with cancer but is highly toxic to both animals and human beings. The narrow therapeutic index of TNF-alpha has limited its anticancer utility. Toxicity associated with many standard anticancer drugs is highly dependent upon the circadian timing of their administration. The effect of time of day of TNF-alpha administration on lethal toxicity was examined in 238 BALB/c female mice in two studies. Each mouse received a single intravenous injection of human TNF-alpha at one of six equispaced times within the first contiguous 24- h cycle. The probability of dying across all times of day of TNF-alpha treatment was not equal (p < 0.01) and varied up to ninefold. Significant time of day dependence of TNF-alpha toxicity was present over a full order of magnitude of TNF-alpha dose. The frequency of TNF- alpha-induced lethality was greatest and the time to death was most brief when TNF-alpha was administered just before awakening. The survival probability was highest when TNF-alpha was administered in the second half of the daily activity span corresponding roughly to late afternoon and evening hours for human beings. The optimization of TNF- alpha administration timing is a strategy that warrants further investigation for improving the toxic/therapeutic ratio of this important cytokine. From a more fundamental perspective, these data may be essential for achieving a fuller understanding of TNF-alpha in vivo biology.     

腰椎间盘突出程度与间盘组织肿瘤坏死因子α水平的关系

背景：腰椎间盘突出的过程不仅表现为形态学上的变化，同时也伴随有椎间盘的组织学与生化性质的一系列改变，细胞因子在椎间盘退行性变的病理过程中及由此所引起的临床症状中可能发挥着重要的调控作用。目的：分析腰椎间盘突出类型与肿瘤坏死因子α产生之间的关系。设计、时间及地点：试验于2005—03／10在河北医科大学第三医院骨科研究所完成。对象：选择河北医科大学附属第三医院脊柱科及小儿骨科收治的经手术证实腰椎间盘突出患者之髓核纤维环和邻近突出髓核的组织，共51例作为实验组，其中纤维环完整者即膨出者16例，突出者21例，脱出者14例。对照组标本取自本科和小儿骨科共7例患者15个间盘组织。方法：手术摘除椎间箍标本制作石蜡切片，采用免疫组织化学染色法对实验组和对照组标本进行测定。主要观察指标：各组标本肿瘤坏死因子CI的水平。结果：对照组中未检测到肿瘤坏死因子CI，而实验组中各标举均可检测到，两者相比，差异有显著性意义（P〈0．01）；实验组纤维环突出者及脱出间盘样本中肿瘤坏死因子α水平分别为66．7％和78．5％，与纤维环完整者25％相比，差异有显著性意义（P〈0．05）；纤维环完整者和突出及脱出者组织化学积分分别为1．00，5．76分和8．28分，3者相比，差异有显著性意义（P〈0．05）。结论：腰椎间盘突出程度及纤维环撕裂程度越重时肿瘤坏死因子CI的产生越多。     

Infliximab(chimeric monoclonal antibody to tumor necrosis factor alpha)

In rheumatoid arthritis and inflammatory bowel disease, such as Crohn's disease, certain immunological abnormalities are considered as its cause, but the fundamental mechanism remains unclear. However, recent researches revealed that inflammatory cytokines, such as TNF-alpha, IL-1 and IL-6, are greatly involved in these immunological abnormalities. This led to the development of anti-cytokine therapy using monoclonal antibodies to these cytokines. Among them, Infliximab, a chimeric monoclonal antibodies to TNF-alpha, is most clinically applied and marked therapeutic effect is seen in various diseases.