微囊化基因工程细胞移植的研究进展

微囊化基因工程细胞移植是将目的基因通过基因转染技术导入到靶细胞内,再将该细胞微囊化后植入受体体内,具有组织相容性好,避免了机体的排斥反应(免疫隔离),且微囊内的功能细胞可以长期存活,发挥其生物学效应。该技术使得异种组织细胞或基因工程细胞移植成为可能,在神经内分泌及代谢疾病等方面的研究取得了可喜的进展,具有广阔的应用前景。     

天然免疫细胞在急性器官移植免疫排斥中的作用

器官移植免疫排斥反应是一多分子、多细胞参与的复杂免疫应答过程.传统研究主要集中于适应性免疫细胞如T,B细胞在急性移植排斥反应中的作用.近年来,随着对天然免疫细胞亚群、功能及其异质性认识的不断深入,人们发现,除天然免疫细胞在移植免疫应答中的抗原提呈功能及炎性反应以外,其可以发挥直接效应功能,参与移植物的排斥.天然免疫细胞亚群在移植免疫排斥与耐受中的不同作用近来受到重视.本文对天然免疫细胞在急性器官移植免疫排斥和免疫耐受诱导过程中的作用作一简要综述.     

人羊膜上皮细胞和人羊膜间充质干细胞的研究进展

人羊膜上皮细胞和人羊膜间充质干细胞存在于人羊膜组织中,统称为人羊膜细胞.人羊膜细胞可塑性强,具有多向分化的潜能;并且免疫原性低,移植不会发生免疫排斥反应,成为近年来研究的热点.人羊膜上皮细胞和人羊膜间充质干细胞的生物学特性使其符合干细胞药物产品的标准,将其应用于诸多疾病的治疗,如心肌梗死、脑梗死和肾损伤等,均已取得良好...     

糖尿病治疗新进展——胰岛细胞移植

随着医学科学的发展和生物学技术的进步,胰岛细胞移植已经被认为是治疗1型糖尿病的一种有效方法。技术上首先要解决好移植物的来源、提取和储存。同时,将移植物导入体内的技术也在不断发展,介入放射学技术发挥了非常重要的作用。研究发现．移植后受体的高血糖明显降低,并能在较长时期保持在正常水平。但胰岛细胞移植后,同样面临移植排斥反应,而在应用免疫抑制剂后又可能引起肝小静脉病等不良反应。利用磁共振和光学成像对标记后的胰岛细胞进行显像,对移植后的胰岛细胞在活体内进行追踪．了解其分布和存活,对于长期监测其功能、改进移植技术和免疫调节方法也很重要。目前面临的问题终将逐一得到解决．胰岛细胞移植很有希望成为治愈糖尿病的方法。     

对血小板认识的进展

本文简要地描述血小板的超微结构;阐述血小板的粘附、聚集;血小板对血管活性胺等物质的吸收、贮存和释放;血小板对颗粒性物质的吞噬作用等多种细胞反应及其生物学意义。着重介绍血小板参与止血功能和血栓形成,维持血管内皮完整性、创伤愈合、动脉粥样硬化、炎症以及移植排斥等重要的生理和病理过程,从而说明血小板是一种多功能细胞。     

死亡分子受体介导凋亡信号的研究进展

死亡分子受体与死亡分子相互作用经发的细胞凋亡倍受人们关注。Ｆａｓ、ＴＮＦＲ、ＤＲ３／Ｗａｌ－１和ＣＡＲ４个死亡分子受体已被确定。它们参与免疫调节,ＣＴＬ杀伤活性、肿瘤消退、移植排斥反应等并发挥关重要的生物学作用。     

开发排斥反应的图像诊断法

美国麻省总医院心内科的矶部光章等开发了早期诊断移植脏器排斥反应的图像诊断技术。方法是使用放射性同位素标记的单克隆抗体从患者体内检测随着排斥而早期在移植脏器上诱导的组织适应抗原(MHC抗原)2级。代替了活检等方法。可进行排斥反应的非侵袭性诊断。矶部准备在循环器官系统的医学专门杂志Circulation,92年2月号上发表用小鼠进行的心脏移植的实验结果。打算与国内的大学协议在日本进行开发实验。移植脏器,发生排斥反应时在排斥的脏器侧诱导MHC抗原。MHC抗原是支持T细胞进行抗原识别反     

"细胞的分化、癌变和衰老"一节的教学设计

实验探究是生物学的重要部分。从某种意义上可以说 ,许多生物学热点问题就是探究性课题 ,现代生物学的发展就是研究性学习过程。因此在课堂教学中渗透研究性学习是适应生物学科发展的。“细胞的分化、癌变和衰老”这一节是新教材新增内容。这一节是在学生了解了细胞的结构、功能、增殖的基础上 ,向学生展现了当今细胞生物学的 3个重要课题——细胞的分化、癌变和衰老。本节涉及的知识点 ,如细胞的全能性 ,是细胞生物技术的主要基础 ,本节涉及的生物学热点问题 ,如植物组织培养技术、“多利”羊的克隆技术等 ,可以激发学生的求知欲 ,提高学生…     

细胞微囊化免疫隔离技术在移植医学中的应用

作为一种十分有效的免疫隔离技术,细胞微囊化可排除细胞移植中出现的宿主与移植物之间的双向排斥作用,从而使能分泌生物活性物质的细胞在移植后得以存活。目前报道的多种微囊材料中,以海藻酸钠一聚赖氨酸一海藻酸钠的应用最为广泛,可通过提高其生物相容性来减弱免疫排斥反应。细胞微囊化在医学治疗上正在发挥越来越大的作用,特别是基因修饰细胞日益成为研究的焦点。尽管该技术尚需改进,但它在异体和异种组织或细胞移植等方面有着广阔的应用前景。     

用补体控制因子阻止异种移植排斥反应

京都府立医科大学第2外科教授周隆宏、赤见敏和和东雪基础研究所小组确认表达人补体抑制因子CD59基因的小鼠细胞株可避免人淋巴细胞的攻击。如能抑制排斥反应,将使异种移植的实用化前进一大步。赤见等于9月在东京召开的日本移植学会上发表了这项成果。该小组将阻碍补体反应的终因子(C9因子)活化的人细胞表面分子CD59的cDNA导入小鼠细胞株(A31)。重组A31细胞与人血清反应时,由补体介导的细胞障碍随血清浓度不同(3～25％)而抑制程度不同(浓度8％时能抑制94％、浓度25％抑制47％)。异种移植的最大难关是超急性排斥反应。在移植患者的血液流入移植脏器血管的同时引起排斥反应。     

Gene therapy strategies to facilitate organ transplantation.

Organ transplantation is now the definitive therapy for many forms of end-organ disease, but chronic allograft rejection, the side effects of chronic immunosuppressive therapy and the severe donor organ shortage continue to limit its success. Gene therapy has the potential to prevent graft rejection by manipulating the immune response in the microenvironment of the graft or by facilitating the induction of tolerance. Genetic manipulation of stem cells to create transgenic and/or knockout animals that could serve as organ or cell donors could be combined with gene therapy approaches to overcome the problem of limited allogeneic donor organ supply.     

Clonotype analysis of human alloreactive T cells: a novel approach to studying peripheral tolerance in a transplant recipient

The recognition of allo-MHC and associated peptides on the surface of graft-derived APC by host T cells (direct pathway allorecognition) plays an important role in acute rejection after organ transplantation. However, the status of the direct pathway T cells in stable long term transplants remains unclear. To detect alloreactive T cell clones in PBL and the allograft during the transplant tolerance, we utilized RT-PCR instead of functional assays, which tend to underestimate their in vivo frequencies. We established alloreactive CD4+ and CD8+ T cell clones from peripheral blood sampled during the stable tolerance phase of a patient whose graft maintained good function for 9 years, 7 without immunosuppression. We analyzed the sequence of TCR Vbeta and Valpha genes and made clonotype-specific probes that allowed us to detect each clone in peripheral blood or biopsy specimens obtained during a 1-year period before and after the rapid onset of chronic rejection. We found an unexpectedly high level of donor HLA-specific T cell clonotype mRNA in peripheral blood during the late tolerance phase. Strong signals for two CD4+ clonotypes were detected in association with focal T cell infiltrates in the biopsy. Chronic rejection was associated with a reduction in direct pathway T cell clonotype mRNA in peripheral blood and the graft. Our data are inconsistent with the hypothesis that direct pathway T cells are involved only in early acute rejection events and suggest the possibility that some such T cells may contribute to the maintenance of peripheral tolerance to an allograft.     

Growing up to one's standard

Plant organs grow to characteristic sizes and shapes that are dictated by the plant's genotype and the identity of the organ. Significant progress has been made in identifying and characterizing regulatory factors that promote organ growth, which act either on cell proliferation or on cell expansion. Their activity is antagonized by repressors of growth that limit organ size. Although the way in which that genes determine the identity of an organ modify its growth patterns is still unclear, initial links between growth regulators and patterning activities are being uncovered. As for the differences in organ size and shape between plant species, studies of natural variation are beginning to shed light on the underlying molecular changes.     

Interleukin-2-producing helper T lymphocyte precursor frequency and rejection: a longitudinal cellular study after cardiac transplantation

Interleukin-2-producing helper T lymphocyte precursors (HTLp) in the recipient recognize donor alloantigen expressed by the transplanted organ. The frequency of these reactive cells in the peripheral blood was determined and correlated with rejection episodes. Endomyocardial biopsy is generally used to quantify cardiac allograft rejection and guide immunotherapy. While non-invasive techniques have been investigated, none of these has demonstrated sufficient sensitivity or specificity to replace myocardial biopsy. Twelve cardiac transplant recipients were assessed over a 1 year period using limiting dilution analysis, to determine the frequency of HTLp in response to cadaver donor splenocytes. The IL-2-dependent mouse cell line CTLL-2 was used to measure the IL-2 present and the precursor frequency was calculated using maximum likelihood estimation. In the months immediately post transplantation, six of the 12 recipients displayed an association with increases in HTLp frequency, which preceded histologically detectable rejection. The second six recipients had fewer rejection episodes and achieved 'acceptance' of their graft sooner. Once 'acceptance' was achieved, the association between IL-2 HTLp frequency and rejection was no longer apparent. The ability to identify two groups of patients on the basis of IL-2 HTLp frequency clearly highlights the heterogenous nature of the response to the graft and this emphasizes the need to monitor other cytokines, which may influence the functioning of effector T cells.     

Alloantibody-mediated class I signal transduction in endothelial cells and smooth muscle cells: enhancement by IFN-gamma and TNF-alpha.

Chronic rejection is the major limiting factor to long term survival of solid organ allografts. The hallmark of chronic rejection is transplant atherosclerosis, which is characterized by the intimal proliferation of smooth muscle cells, endothelial cells, and fibroblasts, leading to vessel obstruction, fibrosis, and eventual graft loss. The mechanism of chronic rejection is poorly understood, but it is suspected that the associated vascular changes are a result of anti-HLA Ab-mediated injury to the endothelium and smooth muscle of the graft. In this study we have investigated whether anti-HLA Abs, developed by transplant recipients following transplantation, are capable of transducing signals via HLA class I molecules, which stimulate cell proliferation. In this report we show that ligation of class I molecules with Abs to distinct HLA-A locus and HLA-B locus molecules results in increased tyrosine phosphorylation of intracellular proteins and induction of fibroblast growth factor receptor expression on endothelial and smooth muscle cells. Treatment of cells with IFN-gamma and TNF-alpha up-regulated MHC class I expression and potentiated anti-HLA Ab-induced fibroblast growth factor receptor expression. Engagement of class I molecules also stimulated enhanced proliferative responses to basic fibroblast growth factor, which augmented endothelial cell proliferation. These findings support a role for anti-HLA Abs and cytokines in the transduction of proliferative signals, which stimulate the development of myointimal hyperplasia associated with chronic rejection of human allografts.     

Molecular mechanisms of immunity in corneal allotransplantation and xenotransplantation

Corneal allotransplantation is the most common and successful form of solid organ transplantation in humans. In uncomplicated cases, the two-year graft survival rate is over 90%. This extraordinary success can be attributed in part to various features of the normal cornea and anterior segment that together account for their 'immune-privileged' status. However, despite this success, a significant number of corneal grafts fail and immunological rejection remains by far the leading cause of graft failure. Studies on animal models of corneal transplantation have yielded a wealth of information on the molecular and cellular features of graft rejection, and have established that this process is mediated primarily by CD4+ T cells of the T helper 1 (Th1) phenotype. In addition, studies have elucidated that certain facets of allosensitisation differ between corneal and other solid organ transplants. On the basis of these findings, novel experimental strategies selectively targeting the afferent or efferent arms of corneal alloimmunity have provided promising results in preventing corneal allograft rejection in the laboratory. Finally, because of the global shortage of human donor corneas, there is currently renewed interest in the possibility of using corneas from other species for transplantation into human eyes (xenotransplantation). Preliminary studies on animal models of corneal xenotransplantation have documented both antibody-mediated and cell-mediated responses that might play important roles in the accelerated rejection observed in corneal xenotransplants. This review synthesises the principal concepts emerging from studies of the molecular mechanisms in corneal transplant immunology.     

Mathematical analysis of haemopoietic grafted cell renewal and migration through the allogeneic or syngeneic mouse host

A mathematical analysis of results from kinetic studies of 125-iododeoxyuridine uptake and loss in almost all the lymphoid and non-lymphoid organs of mice is described. Applied to data gathered from a graft-versus-host reaction experiment, this analysis affords quantitative precision on the differential effects of organ alloantigens on the proliferating grafted cells. It is shown that, depending on the organ and the post-graft period, cell growth can be ascribed to alloantigen-driven cell renewal or to alloantigen-driven trapping or sequestration. Possible applications of the present approach in graft rejection monitoring are discussed.     

Mathematical Analysis of Haemopoietic Grafted Cell Renewal and Migration Through the Allogeneic Or Syngeneic Mouse Host

Abstract. A mathematical analysis of results from kinetic studies of 125-iododeoxyuri-dine uptake and loss in almost all the lymphoid and non-lymphoid organs of mice is described. Applied to data gathered from a graft- versus -host reaction experiment, this analysis affords quantitative precision on the differential effects of organ alloantigens on the proliferating grafted cells. It is shown that, depending on the organ and the post-graft period, cell growth can be ascribed to alloantigen-driven cell renewal or to alloantigen-driven trapping or sequestration. Possible applications of the present approach in graft rejection monitoring are discussed.     

Cytokines in clinical and experimental transplantation

Allograft rejection is a complex process, which requires interactions between different cell types and a variety of soluble factors, such as cytokines. In this review we discuss the role of cytokines in the induction and effector phases of the rejection process and in the induction and maintenance of allospecific graft tolerance. Furthermore, we discuss the feasibility of clinical graft function monitoring by measuring cytokines and the possibilities for intervention in the cytokine network in order to inhibit graft rejection and eventually obtain graft acceptance.