Role of sphingosine 1-phosphate receptor type 1 in lymphocyte egress from secondary lymphoid tissues and thymus

Circulation of mature lymphocytes between blood and secondary lymphoid tissues plays a central role in the immune system. Homing of lymphocytes from blood into secondary lymphoid tissues beyond high endothelial venules is highly dependent on the interaction between the chemokines CCL19, CCL21, CXCL12, and CXCL13, and their receptors CCR7, CXCR4 and CXCR5. However, the molecular mechanism（s） of lymphocyte egress from secondary lymphoid tissues to lymph remained unclear. We have found a new class of immunomodulator, FTY720 by chemical modification of vegetative wasp-derived natural product, ISP-I （myriocin）. FTY720 has been shown to be highly effective in experimental allograft and autoimmune disease models. A striking feature of FTY720 is the induction of a marked decrease in peripheral blood lymphocytes at doses that show immunomodulating activity in these models. The reduction of circulating lymphocytes by FTY720 is caused by sequestration of lymphocytes into secondary lymphoid tissues and thymus. FTY720 is rapidly converted to （S）-enantiomer of FTY720-phosphate [（S）-FTY720-P] by sphingosine kinase 2 in vivo. （S）-FTY720-P acting as a potent agonist of S1P receptor type 1 （S1P1）, induces long-term down-regulation of S1P1 on lymphocytes, and thereby inhibits the migration of lymphocytes toward S1P. Thus, it is presumed that FTY720-induced lymphocyte sequestration is due to the inhibition of S1P/S1P1-dependent lymphocyte egress from secondary lymphoid tissues and thymus by its active metabolite （S）-FTY720-P. Throughout the analysis of the mechanism of action of FTY720, it is clarified that S1P/S1P1 interaction plays an important role for lymphocyte egress from secondary lymphoid tissues and thymus.     

E‐PTFE (Gore‐Tex®) implant with or without low‐dosage mitomycin‐C as an adjuvant in penetrating glaucoma surgery: 2 year randomized clinical trial

Purpose: To test the expanded polytetrafluoroethylene (ePTFE) as a new adjuvant in trabeculectomy. Methods: Consecutive glaucoma surgical inpatients were observed at the Department of Ophthalmology of Palermo University. Sixty patients (60 eyes) were randomly assigned to undergo trabeculectomy (T), trabeculectomy with mitomycin‐C (TMMC), with ePTFE (TG) or with mitomycin‐C and ePTFE (TGMMC). Postoperative visits were scheduled at 24 hr, 7 days, 1, 3, 6, 12, 18 and 24 months. Complete success and qualified success were assessed at two target intraocular pressure (IOP) levels –≤21 and ≤17 mmHg – by Kaplan–Meier curves. Results: The postoperative IOP reduction was significant (P < 0.01) at the endpoint in all groups, with a mean IOP of 16.9 (±2.9), 16.2 (±2.7), 15.3 (±3.4) and 15.2 (±4.3) mmHg in T, TMMC, TG and TGMMC eyes, respectively. No intergroup difference was found at either IOP targets. The Kaplan–Meier curves relating to either the ≤21 mmHg or the ≤17 mmHg target IOP did not show significant intergroup differences for complete and qualified success rate. When ePTFE was used, a trend favouring the medium‐term survival rate was noted. No adverse reaction to the ePTFE was present, and no membrane extrusion or conjuctival erosion were noted in any cases. Hypotony was significantly more frequent (P = 0.035) in groups without ePTFE. Moreover, the late MMC‐related complications were more frequent when MMC was applied. Conclusion: Expanded polytetrafluoroethylene implant in trabeculectomy is well tolerated and could act as a filtration modulating device. Therefore, it is useful in reducing early hypotony‐related complications and contributes to attaining medium‐term IOP control that is comparable to the low‐dosage MMC.     

Enhancement of in vitro nonspecific immune functions by African plant extracts

The in vitro immunomodulatory activities of extracts from African medicinal plants have been studied. Certain extracts exerted enhancing effects in a concentration dependent manner on immune cells from three different strains of mice. Among these were an enhancement of phagocytic activity of peritoneal macrophages and tumoricidal potential of macrophages, and stimulation of the oxidative burst of macrophages and granulocytes. In contrast, the proliferative capacity of lymphocytes was only marginally affected. Enhanced macrophage and granulocyte activation was also detected using leucocytes of the LPS nonresponder strain C3H/HeJ. From the latter it can be concluded that the observed stimulatory effects of the plant extracts in vitro were not due to contamination with lipopolysaccharides.     

白介素－2的Ⅱ期临床试验报告

共１５９例各种类型的恶性肿瘤病人进入了Ⅱ期临床试验。２５例病人接受了白介素－２（ＩＬ－２）单独全身治疗（静脉或皮下注射）；６０例病人接受了ＩＬ－２＋ＬＡＫ细胞全身性治疗；４１例癌性胸水病人接受了ＩＬ－２胸腔内灌注；６例癌性腹水病人接受了ＩＬ－２腹腔灌注；２７例病人接受了ＩＬ－２瘤内注射。单用ＩＬ－２全身治疗的病人没有病例获得临床缓解，２３晚期肾癌接受了ＩＬ－２＋ＬＡＫ细胞治疗，５例获得部分缓解，有效率２２％：癌件胸水和腹水的有效率分别为６８％和６７％：ＩＬ－２瘤内注射的有效率为３０％。Ｔ４／Ｔ８比值、ＮＫ细胞活性和ＬＡＫ细胞活性在全身性ＩＬ－２治疗后均有显著升高，并有统计学意义。病人接受本试验所用的ＩＬ－剂量后的毒副反应主要为发热、畏寒或寒战、疲乏，全组病人均无发生严重低血压、液体潴留等毛细血管渗漏现象。     

Recent Advances in Vaccine Adjuvants

New generation vaccines, particularly those based on recombinant proteins and DNA, are likely to be less reactogenic than traditional vaccines but are also less immunogenic. Therefore, there is an urgent need for the development of new and improved vaccine adjuvants. Adjuvants can be broadly separated into two classes based on their principal mechanisms of action: vaccine delivery systems and immunostimulatory adjuvants. Vaccine-delivery systems generally are particulate (e.g., emulsions, microparticles, iscoms, and liposomes)and function mainly to target associated antigens into antigen-resenting cells. In contrast, immunostimulatory adjuvants are derived predominantly from pathogens and often represent pathogen-ssociated molecular patterns (e.g., lipopolysaccaride, monophosphoryl lipid A, CpG DNA), which activate cells of the innate immune system. Recent progress in innate immunity is beginning to yield insight into the initiation of immune responses and the ways in which immunostimulatory adjuvants may enhance this process. The discovery of more potent adjuvants may allow the development of prophylactic and therapeutic vaccines against cancers and chronic infectious diseases. In addition, new adjuvants may also allow vaccines to be delivered mucosally.     

The immunomodulatory properties of in vitro immunoglobulins are dose-dependent

OBJECTIVES: The mechanism by which intravenous immunoglobulins (immunoglobulin G, IgG) exert their beneficial effect on multiple sclerosis (MS) is unknown. Furthermore, there is uncertainty about the optimal dosage of IgG. Therefore, we investigated the influence of different IgG dosages on cytokine production in MS. MATERIALS AND METHODS: Twenty-five MS patients and 15 healthy controls were enrolled. We measured the production of interferon gamma (IFN-gamma), tumour necrosis factor alpha (TNF) and interleukin 10 (IL-10) in peripheral blood lymphocytes by flowcytometry after stimulation without and with IgG in different doses (1, 5 and 10 mg/ml). RESULTS: IFN-gamma and TNF were decreased significantly (P = 0.001) in the untreated and interferon beta (IFN-beta) treated patients after stimulation with IgG. In contrast, IL-10 production was significantly enhanced (P = 0.001) at least in the untreated patient group. The reduction of the pro-inflammatory cytokines IFN-gamma and TNF after stimulation with different IgG doses was clearly dose-dependent in all groups. CONCLUSION: Besides a suppression of the pro-inflammatory cytokines IFN-gamma and TNF, IgG enhances the anti-inflammatory cytokine IL-10. This effect is dose-dependent, speaking in favour of higher IgG doses in the treatment of MS.     

Characterization of a recombinant immunomodulatory protein from the salivary glands of Dermacentor andersoni

The gene encoding a 36‐kDa (p36) immunomodulatory protein present in saliva of Dermacentor andersoni was cloned in prokaryotic and eukaryotic expression vectors. A polymerase chain reaction (PCR)‐generated cDNA lacking signal peptide was cloned into the Escherichia coli expression vector pET28 and a similar sequence was cloned into pIB/V5‐His‐TOPO expression vector for stable transfection of insect cells, High 5?. The 26‐kDa molecular mass of p36 expressed by bacteria is in agreement with that predicted from the translated full‐length cDNA sequence. Eukaryotic‐cell‐expressed p36 consisted of multiple forms with molecular masses between 34 and 36 kDa. These multiple forms were attributed to differences in post‐translational modifications. N‐linked mannose was detected on insect‐cell‐expressed and tick‐derived p36. Multiple bands remained after endoglycosidase removal of N‐linked sugars, indicating the presence of other modifications. Both bacterial‐ and insect‐cell‐expressed p36 reacted on immunoblots with polyclonal antibodies raised against tick‐derived p36. Insect‐cell‐expressed p36 suppressed T‐lymphocyte‐mitogen‐driven in vitro proliferation of splenocytes from tick‐naïve mice in a dose‐dependent manner. Bacterial‐cell‐expressed p36 lacked immunomodulatory activity.     

人肺来源的间充质干细胞对T淋巴细胞增殖的影响

目的探讨来源于人肺的间充质干细胞(MSCs)是否具有免疫调控能力。方法采用流式细胞术鉴定其免疫表型,用淋巴母细胞转化实验观察其是否具有免疫调控能力。结果①MSCs不表达引起免疫反应的细胞表面分子HLA- DR、CD86、CD80等;②随MSCs细胞量增多,抑制T细胞增殖能力越强。结论人肺来源的间充质干细胞具有免疫调控能力。     

围手术期应用西米替丁对结直肠癌TIL浸润及HLA-DR表达的影响

目的研究表明西米替丁(CIM)能增强胃肠癌患者机体的免疫力,本实验探讨了CIM对结直肠癌(CRC)肿瘤浸润淋巴细胞(TIL) 及肿瘤间质细胞HLA-DR表达的影响,以了解CIM在CRC局部免疫中的作用。方法将49例CRC随机分为治疗组与对照组,治疗组25例术前1周开始口服CIM；对照组进行常规治疗,不服用CIM；手术前后比较肿瘤间质TIL浸润程度及HLA-DR表达的变化。结果 CIM治疗组手术前后TIL的明显反应,由治疗前的32％(8／25)上升到治疗后的76％(19／25),差别有显著性(P＜0.005)；而对照组仅由治疗前的25％(6／24)上升至33％(8／24),无显著统计学差异。治疗组HLA-DR的高表达由治疗前的36％(9／25)上升到治疗后的72％(18／25),有显著差异性,而对照组由41.7％(10／24)上升至45.8％(11／24),无显著差异(P＞0.50)。结论术前应用CIM能增加CRC患者肿瘤组织TIL的浸润及增强间质细胞HLA-DR的表达,表明CIM能增加CRC患者的局部抗肿瘤免疫力。