神经节苷脂对新生儿缺血缺氧性脑病的疗效及对血清肿瘤坏死因子-α及白介素-6的影响

目的:观察单唾液酸四己糖神经节苷脂(GMI)对新生儿缺血缺氧性脑病(HIE)的疗效及对血清肿瘤坏死因子-α(TNF-α)及白介素-6(IL-6)的影响。方法:HIE患儿70例,随机分为GMI组与对照组,各35例;在常规治疗基础上,GMI组给予GMI治疗,对照组给予胞二磷胆碱治疗。观察2组临床疗效、治疗后新生儿神经行为测定(NBNA)评分及治疗前后血清TNF-α、IL-6水平。结果:GMI组治疗有效率为97.14%,显著高于对照组的82.86%(P0.05)。NBNA评分结果显示,GMI组行为能力、被动肌张力、主动张力、原始反射及一般评估得分分别为(10.20±1.67)分、(8.28±1.60)分、(8.11±1.51)分、(4.57±1.97)分、(6.12±1.46)分,对照组得分分别为(9.32±1.51)分、(7.33±1.54)分、(7.14±0.98)分、(3.46±1.58)分、(5.05±1.35)分,差异均有统计学意义(P0.05)。治疗前,2组血清TNF-α、IL-6水平差异无显著性(P0.05);治疗后,GMI组血清TNF-α、IL-6水平为(85.56±10.36)pg/L、(97.36±17.59)pg/L,对照组为(124.35±12.49)pg/L、(155.56±16.20)pg/L,差异均有统计学意义(P0.05)。结论:GMI对HIE有较好的疗效,可降低患儿血清TNF-α、IL-6水平。     

An Essential Role for Tumor Necrosis Factor in Natural Killer Cell–mediated Tumor Rejection in the Peritoneum

Natural killer (NK) cells are thought to provide the first line of defence against tumors, particularly major histocompatibility complex (MHC) class I⁻ variants. We have confirmed in C57BL/6 (B6) mice lacking perforin that peritoneal growth of MHC class I⁻ RMA-S tumor cells in unprimed mice is controlled by perforin-dependent cytotoxicity mediated by CD3⁻ NK1.1⁺ cells. Furthermore, we demonstrate that B6 mice lacking tumor necrosis factor (TNF) are also significantly defective in their rejection of RMA-S, despite the fact that RMA-S is insensitive to TNF in vitro and that spleen NK cells from B6 and TNF-deficient mice are equally lytic towards RMA-S. NK cell recruitment into the peritoneum was abrogated in TNF-deficient mice challenged with RMA-S or RM-1, a B6 MHC class I⁻ prostate carcinoma, compared with B6 or perforin-deficient mice. The reduced NK cell migration to the peritoneum of TNF-deficient mice correlated with the defective NK cell response to tumor in these mice. By contrast, a lack of TNF did not affect peptide-specific cytotoxic T lymphocyte–mediated rejection of tumor from the peritoneum of preimmunized mice. Overall, these data show that NK cells delivering perforin are the major effectors of class I⁻ tumor rejection in the peritoneum, and that TNF is specifically critical for their recruitment to the peritoneum.     

Generation of Splenic Follicular Structure and B Cell Movement in Tumor Necrosis Factor–deficient Mice

Secondary lymphoid tissue organogenesis requires tumor necrosis factor (TNF) and lymphotoxin α (LTα). The role of TNF in B cell positioning and formation of follicular structure was studied by comparing the location of newly produced naive recirculating and antigen-stimulated B cells in TNF^−/− and TNF/LTα^−/− mice. By creating radiation bone marrow chimeras from wild-type and TNF^−/− mice, formation of normal splenic B cell follicles was shown to depend on TNF production by radiation-sensitive cells of hemopoietic origin. Reciprocal adoptive transfers of mature B cells between wild-type and knockout mice indicated that normal follicular tropism of recirculating naive B cells occurs independently of TNF derived from the recipient spleen. Moreover, soluble TNF receptor–IgG fusion protein administered in vivo failed to prevent B cell localization to the follicle or the germinal center reaction. Normal T zone tropism was observed when antigen-stimulated B cells were transferred into TNF^−/− recipients, but not into TNF/LTα^−/− recipients. This result appeared to account for the defect in isotype switching observed in intact TNF/LTα^−/− mice because TNF/LTα^−/− B cells, when stimulated in vitro, switched isotypes normally. Thus, TNF is necessary for creating the permissive environment for B cell movement and function, but is not itself responsible for these processes.     

Supraoptimal Peptide–Major Histocompatibility Complex Causes a Decrease in Bcl-2 Levels and Allows Tumor Necrosis Factor α Receptor II–mediated Apoptosis of Cytotoxic T Lymphocytes

Cytotoxic T lymphocytes (CTLs) are primary mediators of viral clearance, but high viral burden can result in deletion of antigen-specific CTLs. We previously reported a potential mechanism for this deletion: tumor necrosis factor (TNF)-α–mediated apoptosis resulting from stimulation with supraoptimal peptide–major histocompatibility complex. Here, we show that although death is mediated by TNF-α and its receptor (TNF-RII), surprisingly neither the antigen dose dependence of TNF-α production nor that of TNF-RII expression can account for the dose dependence of apoptosis. Rather, a previously unrecognized effect of supraoptimal antigen in markedly decreasing levels of the antiapoptotic protein Bcl-2 was discovered and is likely to account for the gain in susceptibility or competence to sustain the death signal through TNF-RII. This decrease requires a signal through the TCR, not just through TNF-RII. Although death mediated by TNF-RII is not as widely studied as that mediated by TNF-RI, we show here that it is also dependent on proteolytic cleavage by caspases and triggered by a brief initial encounter with antigen. These results suggest that determinant density can regulate the immune response by altering the sensitivity of CTLs to the apoptotic effects of TNF-α by decreasing Bcl-2 levels.     

急性胰腺炎早期患者IL-6,TNF,CD_4~ /CD_8~ 的变化及意义

目的揭示重型胰腺炎发病机制和早期监测指标。方法对 12例重型胰腺炎 (SAP) ,15例轻型胰腺炎 (MAP)病人和 13例正常人 (N )的外周血用ELISA法测定IL -6及TNF ;用间接免疫荧光法测定CD4 、CD8 细胞。结果SAP组IL-6水平明显高于MAP组及N组 (P <0 .0 1) ,但MAP组与N组比较无差异 (P >0 .0 5 )。IL -6大于 10 0 pg/ml时预测SAP的敏感性为83 .33 % ,特异性 93 .33 % ;三组间TNF检出率无差异 ;CD4 百分率在SAP组明显下降 (P <0 .0 1)。SAP组IL -6与CD4 百分率呈明显负相关 (r =-0 .6 196 ,P <0 .0 5 )。结论SAP早期IL -6升高和细胞免疫功能抑制可能属其早期反应 ,测定IL -6有助于轻、重型胰腺炎的鉴别     

Targeting Oxidative Injury and Cytokines' Activity in the Treatment with Anti‐Tumor Necrosis Factor‐α Antibody for Complex Regional Pain Syndrome 1

Cytokines and oxygen free radicals have been implicated in the potential pathogenic development of complex regional pain syndrome (CRPS). We aimed to analyze the relationship between clinical status, circulating levels of cytokines, and markers of oxidative damage during the treatment with anti‐TNFα antibodies. The patient chosen for treatment had not had improvement through a number of conventional therapies and fulfilled the current diagnostic criteria for CRPS‐1. We investigated the clinical variables before and after systemic administration of 1.4 mg/kg anti‐TNFα antibody (infliximab), repeated after 1 month in a dose of 3 mg/kg. Blood samples were collected before and after anti‐TNFα antibodies administration, and plasma was analyzed for 8‐isoprostane‐prostaglandin F2α (8‐iso‐PGF2α, a marker of oxidative injury) and cytokines (TNF‐α, IL‐4, IL‐6, IL‐7, IL‐8, IL‐10, IL‐17A). Plasma concentrations of 8‐iso‐PGF2α were measured with radioimmunoassay (RIA), and the kinetics of cytokines were detected in plasma by antibody‐based proximity ligation (PLA). Pathologically high levels of 8‐iso‐PGF2α were found in the patient. Immediately after each administration of infliximab, the levels of 8‐iso‐PGF2α decreased. Although the patient showed an improvement of the cutaneous dystrophic symptoms and diminished pain associated with these lesions, the levels of circulating TNFα increased after the administration of anti‐TNFα antibodies. In a patient with CRPS‐1 treated with anti‐TNFα antibodies, we report increased levels of circulating TNFα and a temporary mitigation of oxidative stress as measured by plasma F₂‐isoprostane. This case report provides evidence 2 supporting the indication of monitoring the oxidative stress biomarkers during treatment with anti‐TNFα antibodies in CRPS 1.