Cellular strategies to induce immune tolerance after liver transplantation:Clinical perspectives

Liver transplantation(LT)has become the most efficient treatment for pediatric and adult end-stage liver disease and the survival time after transplantation is becoming longer due to the development of surgical techniques and perioperative management.However,long-term side-effects of immunosuppressants,like infection,metabolic disorders and malignant tumor are gaining more attention.Immune tolerance is the status in which LT recipients no longer need to take any immunosuppressants,but the liver function and intrahepatic histology maintain normal.The approaches to achieve immune tolerance after transplantation include spontaneous,operational and induced tolerance.The first two means require no specific intervention but withdrawing immunosuppressant gradually during follow-up.No clinical factors or biomarkers so far could accurately predict who are suitable for immunosuppressant withdraw after transplantation.With the understanding to the underlying mechanisms of immune tolerance,many strategies have been developed to induce tolerance in LT recipients.Cellular strategy is one of the most promising methods for immune tolerance induction,including chimerism induced by hematopoietic stem cells and adoptive transfer of regulatory immune cells.The safety and efficacy of various cell products have been evaluated by prospective preclinical and clinical trials,while obstacles still exist before translating into clinical practice.Here,we will summarize the latest perspectives and concerns on the clinical application of cellular strategies in LT recipients.

执行器部分失效的鲁棒模糊容错切换控制

针对一类具有不确定性、外部扰动和执行器部分失效的非线性工业过程,提出一种鲁棒模糊容错切换控制方法。首先,构建新型多自由度T-S模糊状态空间模型,在此基础上,结合执行器部分失效的情况设计控制律。其次,给出基于线性矩阵不等式(LMI)的容错切换条件和系统稳定条件,并通过当前系统状态和稳定性条件求取其子模型的控制律及相应权值。最后,通过对连续搅拌釜式反应器的仿真研究来验证该文方法的有效性。

卵巢癌微环境调控调节性T细胞的研究进展

卵巢癌是导致女性癌症死亡的主要原因之一。虽然免疫治疗方法已用于卵巢癌的临床治疗,但有效率较低。肿瘤微环境中存在免疫抑制因素,提示免疫系统失衡与卵巢癌进展密切相关。调节性T细胞(Treg)是一群发挥抑制效应的T细胞亚群,作为维持自身免疫耐受的重要组成部分,是肿瘤免疫、自身免疫和维持机体免疫稳态的关键。Treg在卵巢癌微环境中发挥重要作用,参与介导免疫耐受,影响卵巢癌的进展和预后。文章对卵巢癌微环境调控Treg的研究进展进行总结。

Preliminary report of coseismic surface rupture(part)of Türkiye's M_(W)7.8 earthquake by remote sensing interpretation

Both M_(W) 7.8 and M_(W) 7.5 earthquakes occurred in southeastern Türkiye on February 6,2023,resulting in numerous buildings collapsing and serious casualties.Understanding the distribution of coseismic surface ruptures and secondary disasters surrounding the epicentral area is important for post-earthquake emergency and disaster assessments.High-resolution Maxar and GF-2 satellite data were used after the events to extract the location of the rupture surrounding the first epicentral area.The results show that the length of the interpreted surface rupture zone(part of)is approximately 75 km,with a coseismic sinistral dislocation of 2-3 m near the epicenter;however,this reduced to zero at the tip of the southwest section of the East Anatolia Fault Zone.Moreover,dense soil liquefaction pits were triggered along the rupture trace.These events are in the western region of the Eurasian Seismic Belt and result from the subduction and collision of the Arabian and African Plates toward the Eurasian Plate.The western region of the Chinese mainland and its adjacent areas are in the eastern section of the Eurasian Seismic Belt,where seismic activity is controlled by the collision of the Indian and Eurasian Plates.Both China and Türkiye have independent tectonic histories.

TGF-β对膀胱癌组织中巨噬细胞来源肿瘤相关成纤维细胞的影响及其机制

目的探讨TGF-β对膀胱癌组织中巨噬细胞来源肿瘤相关成纤维细胞(CAF)的影响及其机制。方法采用Kaplan-Meier法分析膀胱癌组织中α-SMA^(+)CD68^(+)CAF表达水平与患者的总生存率(OS)的关系;采用免疫荧光技术检测α-SMA^(+)CD68^(+)CAF在膀胱癌组织中的浸润情况;采用Western blot实验检测TGF-β对α-SMA^(+)CD68^(+)CAF体外诱导作用。同时构建膀胱癌小鼠模型,采用免疫荧光技术和免疫组化法检测TGF-β对膀胱癌小鼠体内α-SMA^(+)CD68^(+)CAF的诱导作用及对CD8^(+)T细胞浸润的影响。结果膀胱癌组织中α-SMA与CD68的表达呈正相关,且α-SMA^(+)CD68^(+)CAF高表达的患者预后更差(χ^(2)=9.05,P<0.05)。免疫荧光技术检测结果显示,膀胱癌组织中存在α-SMA^(+)CD68^(+)CAF。Western blot实验检测结果显示,TGF-β可显著促进α-SMA^(+)CD68^(+)CAF的生成。膀胱癌小鼠模型体内实验显示,TGF-β可促进膀胱癌组织中α-SMA^(+)CD68^(+)CAF的生成,从而抑制CD8^(+)T细胞的浸润。结论TGF-β可显著促进膀胱癌组织中巨噬细胞来源CAF的生成,从而抑制CD8^(+)T细胞的浸润。

从转向到演化:W.J.T.米歇尔图像学研究的理论进路

自20世纪90年代始,视觉媒介技术逐渐完成了从电子技术向数字技术的转换,与此同时,学界也兴起一股以“图像转向”为主题的视觉文化研究热潮,W.J.T.米歇尔无疑是其中的领军人物。近年来,虚拟影像技术、大数据算法、生成式人工智能等新型数字技术系统的不断突破,再一次激发了人们对未来视觉呈现的想象。此刻,回看米歇尔对现代图像学的理论构想和阶段阐述,不难发现米歇尔在该研究领域的前瞻性,他关于生控复制及生命图像的隐喻,以及关于形象科学的系统性论释,打通了符号学、媒介学与图像学的边界,在完善从转向到演化的自身理论框架的同时,为当下诸多图像新样态和视觉新现象提供了重要的理论论证支撑,实现了现代图像学从认识论到本体论的体系建构。

两种不同钢锭试制的Cr12W冷作模具钢大块碳化物研究

采用细高型710kg和粗矮型1.2t两种不同钢锭试制了Cr12W冷作模具钢(2~2.3%C、11~13%Cr、0.6~0.8%W),通过低倍、碳含量、金相分析,对其钢坯和钢材的大块碳化物进行了研究,结果表明:710kg钢锭的大块碳化物比1.2t钢锭严重,710kg钢锭的大块碳化物分布在锭身中部至头部的中心,最严重部位在距头部的1/4处,1.2t钢锭的大块碳化物分布在锭身中上部至头部的中心,最严重部位在距头部的1/8处;两种钢锭试制的∮32mm钢材的大块碳化物按JB/T7713标准评定,710kg钢锭的为5级,1.2t钢锭的为3级,采用1.2t钢锭试制可以满足≤3级供货要求。

Tolerance in liver transplantation: Biomarkers and clinical relevance

Transplantation is the optimal treatment for end-stage organ failure,and modern immunosuppression has allowed important progress in short-term outcomes. However,immunosuppression poorly influences chronic rejection and elicits chronic toxicity in current clinical practice. Thus,a major goal in transplantation is to understand and induce tolerance. It is well established that human regulatory T cells expressing the transcription factor Fox P3 play important roles in the maintenance of immunological self-tolerance and immune homeostasis. The major regulatory T cell subsets and mechanisms of expansion that are critical for induction and long-term maintenance of graft tolerance and survival are being actively investigated. Likewise,other immune cells,such as dendritic cells,monocyte/macrophages or natural killer cells,have been described as part of the process known as "operational tolerance". However,translation of these results towards clinical practice needs solid tools to identify accurately and reliably patients who are going to be tolerant. In this way,a plethora of genetic and cellular biomarkers is raising and being validated worldwide in large multicenter clinical trials. Few of the studies performed so far have provided a detailed analysis of the impact of immunosuppression withdrawal on pre-existing complications derived from the long-term administration of immunosuppressive drugs and the side effects associated with them. The future of liver transplantation is aimed to develop new therapies which increase the actual low tolerant vs non-tolerant recipients ratio.

Establishment of Nasal Tolerance to Heat Shock Protein-60 Alleviates Atherosclerosis by Inducing TGF-β-dependent Regulatory T Cells

Mounting evidence supports that a newly identified regulatory T cell (Treg),CD4+LAP+ Treg,is associated with oral tolerance induction and following inhibition of atherosclerosis,but little is described about whether nasal tolerance to antigen likewise induces the novel Tregs production and the relevant antiatherosclerotic benefit.We investigated the effect of nasal administration of heat shock protein-60 (HSP60) on atherogenesis.HSP60 or phosphate buffer solution (PBS) was nasally adminis-tered to six-week-old male ApoE-/-mice.At the 10th week after the nasal administration,there was a significant decrease in atherosclerotic plaque areas of aortic roots in the HSP60-treated mice as com-pared with those in the PBS-treated mice.Atherosclerosis suppression was accompanied with a signifi-cant increase in CD4+LAP+ and CD4+CD25+Foxp3+ Tregs and a concurrently increased production of TGF-β in the HSP60-treated mice.The protective effect of HSP60 was offset by injection of anti-TGF-βantibody.It is concluded that nasal administration of HSP60 can inhibit atherosclerotic formation through immune tolerance which is established by Tregs depending on the induction of anti-inflammatory cytokine TGF-β.Immune tolerance induced by nasal administration of HSP60 may provide an alternative therapeutic method for atherosclerosis.

Regulating regulatory T cells to achieve transplant tolerance

BACKGROUND:Regulatory T cells(Tregs) play crucial roles in both induction and maintenance of tolerance. This active immune regulation may contribute not only to the control of immune responses to self-antigens and thereby prevent autoimmune diseases,but also the control of responses to non-self molecules in adaptive immunity. Numerous experimental and clinical studies indicate that manipulating the balance between regulatory and responder T cells is an effective strategy to control immune responsiveness after transplantation. DATA SOURCES:Literature search was conducted using PubMed on the related subjects. Part of the material was based on the most recent work in the authors’ laboratory. RESULTS:We propose some new strategies to achieve transplant tolerance in rodent animals via manipulating Treg function,including using histone deacetylase(HDAC) inhibitor to regulate Foxp3 transcription and enhance Treg suppression,induction of Treg-sparing apoptosis via Nur77,and identification of the co-inhibitory molecule herpes virus entry mediator(HVEM) as an effector molecule for Treg function. CONCLUSION:Regulation of Treg function will definitely provide us very promising tools to achieve clinical tolerance in the future.

A new protoberberine alkaloid from Corydalis yanhusuo W.T.Wang

A new protoberberine alkaloid, named 5,6-dihydro- 10-hydroxy-2,3,9-trimethoxy- 13-methyldibenzo[α,g]quinoliziniurn （1） was isolated from the 60% ethanol extract of the tubers of Corydalis yanhusuo W. T. Wang, together with a new natural product, 13methylpalmatrubine （2）. Their structures were established by spectroscopic methods. 2009 Xin Sheng Yao. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All fights reserved.

Role of T cell death in maintaining immune tolerance during persistent viral hepatitis

Virus-specific T cells play an important role in the resolution of hepatic infection. However, during chronic hepatitis infection these cells lack their effector functions and fail to control the virus. Hepatitis B virus and hepatitis C virus have developed several mechanisms to generate immune tolerance. One of these strategies is the depletion of virus-specific T cells by apoptosis. The immunotolerogenic liver has unique property to retain and activate na ve T cell to avoid the over reactivation of immune response against antigens which is exploited by hepatotropic viruses to persist. The deletion of the virus-specific T cells occurs by intrinsic (passive) apoptotic mechanism. The pro-apoptotic molecule Bcl-2 interacting mediator (Bim) has attracted increasing attention as a pivotal involvement in apoptosis, as a regulator of tissue homeostasis and an enhancer for the viral persistence. Here, we reviewed our current knowledge on the evidence showing critical role of Bim in viral-specific T cell death by apoptotic pathways and helps in the immune tolerance.

Oral tolerance is inducible during active dextran sulfate sodium-induced colitis

AIM:To investigate whether oral tolerance is inducible during the active phase of dextran sulfate sodium(DSS)-induced colitis.METHODS:Colitis was induced in 6-to 8-wk-old female BALB/c mice by the administration of 2%DSS.To induce oral tolerance,mice that received water with DSS[DSS(+)]and mice that received autoclaved water[DSS(-)]were intragastrically(i.g.)administered ovalbumin(OVA)as a tolerogen before systemic challenge with OVA.Following this,serum levels of OVA-specific Ig E antibodies were measured.In mice with activecolitis,CD4+CD25+Foxp3+cell and B10 cell frequencies were evaluated using flow cytometry.Cytokine m RNA expression profiles were evaluated by reverse transcription real-time polymerase chain reaction.RESULTS:Regardless of the presence of DSS colitis,OVA-specific immunoglobulin E concentrations were significantly reduced in mice that were i.g.administered OVA compared to mice that were i.g.administered PBS[DSS(+):4.4(4.2-9.5)ng/m L vs 83.9(66.1-123.2)ng/m L,P<0.01;DSS(-):27.7(0.1-54.5)ng/m L vs116.5(80.6-213.6)ng/m L,P<0.01].These results demonstrated that oral tolerance was induced in both the presence and absence of colitis.In the spleen and mesenteric lymph nodes(MLN),the frequencies of CD4+CD25+Foxp3+cells and B10 cells,both of which are associated with oral tolerance,did not significantly change.In the spleen,interferon-γm RNA expression significantly decreased in mice with colitis[DSS(+):0.42(0.31-0.53)vs DSS(-):1.00(0.84-1.39),P<0.01].The expression levels of other cytokines did not significantly change.CONCLUSION:Oral tolerance is inducible during active DSS colitis.The stability of regulatory cell populations in the spleen and MLN in colitis might correlate with these results.

Maintaining immunological tolerance with Foxp3

在胸腺的中央忍耐是为删除汽车的主要机制反应 T 房间。尽管有这，进圆周的自我反应的 T 淋巴细胞的逃跑揭示汽车免疫的威胁。补偿它的瑕疵，胸腺也与镇压功能生产 Foxp3+CD4+CD25+ 规章的 T 房间的一个自然地发生的子集，能够控制汽车反应房间。Foxp3 (叉头框 P3 ) ，为房间的这个子集的系特定的标记，对他们的 thymic 开发和外部功能关键，并且还 Foxp3 驾驶的 transcriptional 程序直到现在大部分未定义。新兴的证据提供了卓见进它的角色：从 Foxp3 到的能力与象 NFAT 那样的另外的抄写因素合作，到目标的染色体宽的描述，基因直接由 Foxp3 跳了并且调整。这里，我们讨论自然地发生的规章的 T 房间的发现 - 他们的显型，发展，维护，和功能 - 大部分当他们被系特定的标记定义， Foxp3。

Type 1 diabetes mellitus and its oral tolerance therapy

As a T cell-mediated autoimmune disease,type 1 diabetes mellitus(T1DM)is marked by insulin defect resulting from the destruction of pancreaticβ-cells.The understanding of various aspects of T1DM,such as its epidemiology,pathobiology,pathogenesis,clinical manifestations,and complications,has been greatly promoted by valuable research performed during the past decades.However,these findings have not been translated into an effective treatment.The ideal treatment should safely repair the destroyed immune balance in a longlasting manner,preventing or stopping the destruction ofβ-cells.As a type of immune hypo-responsiveness to the orally administrated antigen,oral tolerance may be induced by enhancement of regulatory T cells(Tregs)or by anergy/deletion of T cells,depending on the dosage of orally administrated antigen.Acting as an antigen-specific immunotherapy,oral tolerance therapy for T1DM has been mainly performed using animal models and some clinical trials have been completed or are still ongoing.Based on the review of the proposed mechanism of the development of T1DM and oral tolerance,we give a current overview of oral tolerance therapy for T1DM conducted in both animal models and clinical trials.

Can the W.T.O. Change Russia?

If Vladimir Put in returns as planned to the presidency in 2012,he will once again face the challenge of modernizing the Russian economy. This is something both he and his seat-warmer, Dmitri Medvedev,have failed to achieve during three consecutive presidential terms. A

Tolerance protocol of living kidney transplant for developing countries through basic strategy of lymphocyte depletion

End-stage kidney failure(ESKD)is a global issue where kidney replacement therapy imposes enormous economic burden to people of developing countries,in addition to the severe limitations to the availability of hemodialysis and peritoneal dialysis technique.The best option of kidney transplantation also requires lifelong combination immunosuppressive medicines,the cost of which is equally comparable to lifelong dialysis.A strategy of achieving transplant tolerance that requires minimum immunosuppressive medicines,although in experimental stage,also requires state-of-art technology with costly medicines and interventions.This is evidently beyond the reach of ESKD patients of developing countries.Hence,globally in developing countries,a need for an innovative but cost-effective tolerance protocol is a burning need for a successful transplant program.In brief,transplant tolerance is defined as a state of donorspecific unresponsiveness to the allograft antigens without the need for ongoing pharmacologic immunosuppression or with a minimal need.Current state-of-art techniques involves:(1)A state of hematological chimera,for complete tolerance;(2)Prope or partial tolerance where immune-reactive T-lymphocytes are inhibited using monoclonal antibodies;and(3)Chimeric antigen receptor for T-regulatory(T-reg)cell therapy using genetically engineered T-reg cells targeting specific Tlymphocyte receptors for inducing anergy.From our real-world experience in transplant management in post-transplant lympho-proliferative disorders(PTLD),we noticed frequently a drastic reduction in the need of immunosuppressive medicines following lympho-ablative therapy for PTLD.We recently published a case study on a real-world experience transplant case where we explained a partial or prope tolerance that developed after lymphocyte ablation therapy,following which the allograft was maintained with low dose dual standard immunosuppressive medicines.Based on this publication,we propose here an innovative tolerance protocol for living related low risk kidney transplantation for developing countries,in this opinion review.

Russia Clears Last Hurdle for W.T.O. Membership

Russia on November 10 cleared the last major obstacle in its 18-year effort to join the World Trade Organization in what the head of the institution called a milestone for global trade. "It’s a victory for Russia, a victory for W.T.O. members, and a victory

ASTM 2015年度W.T.卡瓦诺纪念奖首次在中国征集

W.T.卡瓦诺纪念奖是ASTM董事会为纪念William T.卡瓦诺于1987年设立的奖项,W.T.卡瓦诺是自愿性标准制定和传播领域的世界级领袖,从1970年至1985年去世前,一直担任ASTM总裁。W.T.卡瓦诺纪念奖设立的目的是,对在国家和国际自愿标准方面广泛公认的杰出个人或做出了卓越贡献的个人进行嘉奖。