Modulation of alpha 1-acid glycoprotein (AGP) gene induction following honey bee venom administration to adjuvant arthritic (AA) rats; possible role of AGP on AA development.

Honey bee venom (HBV) administration to adjuvant arthritic (AA) rats resulted in a significant suppression of arthritis and in suppression of the hepatic acute phase alpha 1-acid glycoprotein (AGP) gene induction at the early stages of disease development. AGP administration in AA rats resulted in acceleration of arthritis development and in increase of severity and duration of the disease. IL-1, IL-6, tumour necrosis factor (TNF) and glucocorticoids alone are not responsible for the HBV-mediated AGP gene down-regulation. These results indicate that AGP gene expression in AA and HBV-treated AA rats involves the interaction of several factors, and that AGP plays a role for AA development in rats.     

Anti-CD2 (OX34) MoAb treatment of adjuvant arthritic rats: attenuation of established arthritis, selective depletion of CD4+ T cells, and CD2 down-modulation

Anti-CD2 MoAbs have previously been shown to induce tolerance and to block B cell differentiation, T cell and monocyte activation. Since these immune functions are important in joint inflammation, we asked whether administration of the anti-CD2 MoAb OX34 has a beneficial effect on established rat adjuvant arthritis, a model of human rheumatoid arthritis, and how it affects CD2-bearing leucocyte subsets. Female Lewis rats with established adjuvant arthritis received a total of 5 mg OX34 or isotype-matched control MoAb starting on day 15 after adjuvant injection. Weight and arthritis score (AS) were measured in a blinded fashion. Peripheral blood cells were analysed for numbers of leucocyte subsets at various time points. Animals were killed on day 30 and lymphatic organs were processed for immunohistology. Clinically, OX34 treatment led to increased body weight and reduced AS. Although OX34 binds to CD4⁺ and CD8⁺ T cells in a comparable fashion, OX34 treatment reduced CD4⁺ T cells, but not CD8⁺ T cells. Among CD4⁺ T cells CD45RC⁺ (‘naive’) T cells virtually disappeared; CD45RC⁻ (‘recently activated’) T cells were slightly reduced. A reduction of CD4⁺ T cells was also found in the lung, liver, bone marrow, spleen and lymph nodes. Down-modulation of the CD2 molecule by OX34, again, affected CD4⁺ T cells, suggesting a specific signal for CD4⁺ but not CD8⁺ T cells. In conclusion, the anti-CD2 MoAb OX34 attenuates established rat adjuvant arthritis. In spite of similar binding to CD4⁺ and CD8⁺ T cells, OX34 depletes only CD4⁺ T cells and down-modulates the CD2 molecule on these cells. These results suggest a therapeutic benefit from CD2-directed therapy for chronic types of arthritis.     

Efficient generation of respiratory syncytial virus (RSV)-neutralizing human MoAbs via human peripheral blood lymphocyte (hu-PBL)-SCID mice and scFv phage display libraries

RSV is one of the major causes of pneumonia and bronchiolitis in infants and young children and is associated with high mortality. RSV neutralizing human antibody (hu-Ab) is known to mediate resistance to viral infection as well as to be an effective treatment for severe lower respiratory tract RSV infection. We have previously demonstrated that human primary and secondary immune responses can be established in severe combined immunodeficient mice engrafted with human peripheral blood lymphocytes (hu-PBL-SCID). By combining this animal model with the single-chain Fv antibody (scFv) phage display library technique, we were able to investigate further its clinical potential by generating a panel of human scFvs that exhibit both high F glycoprotein (RSV-F) binding affinities ( approximately 108 M(-1)) and strong neutralizing activities against RSV infection in vitro. Sequencing analysis of the randomly isolated anti-RSV-F scFv clones revealed that they were derived from different VH families with mutations in the complementarity-determining region 1 (CDR1). The results suggest that: (i) RSV-F-specific human immune responses and affinity maturation can be induced in hu-PBL-SCID mice; and (ii) this approach can be applied to generate large numbers of human scFvs with therapeutic potential. Despite the fact that hu-PBL-SCID mouse and human scFv phage display library have individually been established, our approach contributes a simple and significant step toward the generalization of antigen-specific human monoclonal antibody (hu-MoAb) production and their clinical applications.     

Endogenous Immune Response to Glutamic Acid Decarboxylase (GAD67) in NOD Mice is Modulated by Adjuvant Immunotherapy

We have shown that immunization of non-obese diabetic (NOD) mice with adjuvants (CFA or BCG) prevents the onset of diabetes by induction of regulatory cells. Since autoimmune responses to glutamic acid decarboxylase (GAD) are up-regulated in insulin-dependent diabetes mellitus (IDDM), in this study GAD67-specific antibody, T cell proliferation and lymphokine production patterns were analysed in the adjuvant-treated mice to characterize the regulatory mechanisms underlying the protection. We used both spontaneous diabetes and syngeneic islet transplantation models in NOD mice. Protection against spontaneous diabetes and prevention of syngeneic islet graft rejection by CFA or BCG treatment was found to be accompanied by the production of long lasting and high titre anti-GAD67 antibody of IgG1 isotype in the sera. Uponin vitrostimulation with GAD67, draining lymph node and spleen cells from CFA-immunized NOD mice or syngeneic islet-grafted and BCG-protected NOD mice produced much more IL-4, whereas there was no significant change in IFN-γ production. The strong early T cell proliferative response to GAD67 in CFA or BCG-immunized NOD mice was followed by a low or unresponsiveness state. Taken together, these results suggest a shift in Th1/Th2 balance in the GAD67-specific endogenous immune response to a change in Th2 levels after adjuvant treatment. We postulate that the protective effect of CFA or BCG is due to the diversion of GAD-specific endogenous cellular immune response to a non-pathogenic humoral response.     

Evidence for Classically Conditioned Fatigue Responses in Patients Receiving Chemotherapy Treatment for Breast Cancer

Fatigue is the most common side effect of chemotherapy for cancer. Not yet explored is the possibility that patients may develop conditioned fatigue responses to clinic cues as a result of the repeated pairing of the clinic environment (conditioned stimulus) with infusions of chemotherapy (unconditioned stimulus) that cause fatigue (unconditioned response). As a first critical test of this possibility, breast cancer patients (N = 82) were studied across their first four cycles of chemotherapy. Consistent with conditioning: (1) fatigue levels in the clinic environment significantly increased with repeated pairings of the clinic environment and chemotherapy administration; (2) fatigue responses in the clinic environment prior to the fourth infusion (CR) were predicted by patients’ previous experiences of post-infusion fatigue (UR) above and beyond effects of concurrent emotional distress. These results provide the first evidence in the literature that fatigue can be conditioned. Additional research is warranted to determine the clinical importance of this source of fatigue in chemotherapy patients.     

单侧外周伤害性刺激诱发大鼠脊髓中转录因子CREB的双侧磷酸化(英文)

c AMP反应成分结合蛋白 (c AMP response elem ent-binding protein,CREB)是一种转录因子 ,它在磷酸化之后可调节靶基因的转录。 CREB在 13 3位置的丝氨酸的磷酸化 ,与脊髓中伤害性传入的处理有关 ,本文作者等用特殊抗体对此进行了免疫细胞化学研究。在正常大鼠 ,虽然几乎所有脊髓神经元的核中都可见 CREB的轻度着色 ,但磷酸化的 CREB仅见于双侧腰段脊髓的 ～ 层 (75± 15 vs60± 18)和 层 (9± 3 )。用福尔马林注射引起一侧后脚掌出现炎症时 ,可在双侧腰段脊髓看到磷酸化CREB细胞核的快速 (小于 5 min)和节段性的显著增多 ;它们主要分布在双侧背角表层 ～ 层 (2 5 4± 2 0 vs 2 62± 2 3 )、 层(115± 13 )和双侧 ～ 层 (3 46± 2 0 vs3 2 8± 2 6) ;而在对照和炎症组大鼠的胸段脊髓中均未见磷酸化 CREB的增加。在注射CFA诱发一侧炎症或切断一侧坐骨神经的实验组大鼠 ,也可看到至少延续到第三天的强而双侧性的 CREB的磷酸化。这种由一侧后肢伤害性传入引致腰段脊髓中镜像式双侧 CREB磷酸化的出现 ,与一般看到的损伤传入只在同侧脊髓背角引起某些神经化学改变的结果不同 ,可能是人神经损伤后或在实验动物中出现对侧镜像式疼痛过敏现象的基础     

The adjuvant monophosphoryl lipid A increases the function of antigen-presenting cells

The induction of immune responses in vivo is typically performed with antigens administered in external adjuvants, like alum, complete Freund's adjuvant, LPS and, more recently, monophosphoryl lipid A (MPL). However, the role of the adjuvant is still poorly defined. The aim of this study was to test whether the MPL affects the function of antigen-presenting cells (APC) in vitro and in vivo. Antigen-pulsed APC [including macrophages, B cells and dendritic cells (DC)] were incubated or not with MPL, and their ability to sensitize naive T cells was tested in vitro and in vivo. The data show that MPL enhances the ability of macrophages and B cells to sensitize naive T cells, and confers to them the capacity to induce the development of T(h)1 and T(h)2. Administration of MPL i.v. in mice results in the redistribution of fully mature DC in the T cell area of the spleen. These observations suggest that MPL may induce an antigen-specific primary immune response by provoking the migration and maturation of DC that are the physiological adjuvant of the immune system.     

顺铂和替加氟联合放疗治疗中晚期食管癌疗效观察

目的观察顺铂和替加氟联合放疗治疗食管癌的临床疗效及其毒副反应。方法2003年1月至2006年2月对60例食管癌患者采取顺铂20mg·m-2·d,替加氟750mg·m-2·d,连用5天,序贯放疗60~70Gy/6~7周。结果60例患者中,CR24例,PR18例,SD9例,PD9例,RR(CR+PR)为70·0%,主要毒副作用为骨髓抑制、恶心呕吐。肝肾功损害及口腔炎、静脉炎等较轻。结论顺铂和替加氟联合放疗治疗食管癌疗效好,耐受性好值得推广应用。     

紫杉醇联合草酸铂、卡培他滨三药方案治疗晚期转移性鼻咽癌的临床研究

目的探讨紫杉醇联合草酸铂、卡培他滨三药方案治疗晚期转移性鼻咽癌的疗效及不良反应。方法2002年1月至2005年1月，110例晚期转移性鼻咽癌病人入组：试验组55例患者．第1天应用紫杉醇135mg／m^2、草酸铂130mg／m。静脉滴注，口服卡培他滨1650mg／m^2／d，连服l-14d，每3周为一个周期，连用2-4个周期；对照组55例患者，第1-5天应用DDP 20mg／m^2、5-Fu 0．5g／m^2静脉注射，3周为一个周期，连用2-4个周期；治疗结束2-4周后评价疗效。结果试验组疗效可评价55例，对照组疗效可评价53例。试验组与对照组有效率分别为（CR＋PR）50．9％（28例）和32．1％（17例），两者差异有统计学意义（P〈0．05）。试验组和对照组中位生存时间为10．6个月和8．6个月，两者差异有统计学意义（t〈0．05）。安全性方面：试验组Ⅳ反应主要为手足综合征8例（14．5％）、骨髓抑制2例（3．6％）和消化道毒性4例（7.3％）；对照组Ⅳ反应主要为消化道毒性8例（15.1％）、骨髓抑制2例（3.8％）。结论紫杉醇联合草酸铂、卡培他滨三药方案对晚期转移性鼻咽癌的疗效较DDP＋5-Fu有优势，且不良反应可以耐受。     

Recognition of a novel naturally processed, A2 restricted, HCV-NS4 epitope triggers IFN-gamma release in absence of detectable cytopathicity

Using short term CTL lines derived from HLA A2/K^b transgenic mice and IFN-gamma release assays we demonstrate that the NS4.1769 epitope, is generated from natural processing of the NS4 antigen, and presented in the context of the A2/K^b molecules. Interestingly, T cell recognition of the naturally processed form of the NS4.1769 epitope was associated with significant IFN-gamma release, but no direct cytolytic activity. Epitopes of this phenotype might be of interest, in terms of therapy of chronic HCV infection by associating the benefit of localized lymphokine release with low or absent direct cytopathicity.