第三方未成熟树突状细胞负载同种异体抗原诱导免疫耐受的研究

发布时间：2018-08-29 08:27

【摘要】： 建立针对供者抗原的特异性免疫耐受,是解决在同种异体皮肤移植中排斥反应的理想途径。树突状细胞(dendritic cell,DC)是体内功能最强的抗原呈递细胞(antigen-presenting cell,APC),在抗原递呈过程中,若共刺激分子(如CD80、CD86等)缺乏或被阻止,不能激活T淋巴细胞,反而诱导对该抗原的耐受,因此缺乏刺激分子表达的未成熟树突状细胞(immature dendritic cell,imDC)具有先天的免疫耐受性,能够明显地诱导移植免疫耐受。供者源imDC与皮肤联合移植能够明显延长异体皮存活时间,并且疗效肯定。结合目前烧伤外科临床情况,大面积深度特重度烧伤病人一般利用同种异体皮移植覆盖创面或行自体微粒皮+大张同种异体皮移植术,异体皮存活时间对稳定病情及微粒皮存活有很大影响。若加上供者imDC联合移植,可能会收到更好的效果,从而解决重度烧伤病人创面封闭难的问题。目前临床上供者皮肤主要来自死后捐赠者,但可以利用的imDC主要来自平时健康成人献血或骨髓,从中分离培养并备存,因此临床上可以利用的供者DC与皮肤并非来自同一个体,即称为“第三方模式”,由于第三方imDC不携带皮肤供者抗原,联合皮肤移植后,要发挥诱导免疫耐受的作用必须首先摄取、加工处理及递呈供者抗原,这样就使它的作用受到影响,很难直接产生针对移植皮肤的免疫耐受。因此我们需要改造第三方imDC,使其携带并表达异体皮供者抗原,才可能诱导该抗原特异性的免疫耐受。 imDC具有强大的抗原摄取能力,imDC能摄取并负载外来抗原已得到广泛认识,负载了细胞性抗原(如:吞噬凋亡细胞)的imDC能够诱导该抗原特异性外周性免疫耐受,而且imDC有可能让机体已经产生的效应性T细胞功能障碍。如果能通过转基因技术,将供者的主要组织相容性抗原基因转染骨髓干细胞,将明显诱导供者抗原特异性的免疫耐受,但是人的HLA基因复合体很大,约有几千个kb,具有高度多形性,等位基因类型多复杂,难以转染成功,部分等位基因转染又不能充分有效表达供者抗原。因此我们借鉴肿瘤免疫治疗中,用肿瘤细胞裂解物冲击DC方法,将同种异体淋
[Abstract]:The establishment of specific immune tolerance for donor antigens is an ideal way to solve the rejection in skin allograft. Dendritic cells (dendritic cell,DC) are the most potent antigen-presenting cells (antigen-presenting cell,APC) in vivo. In the process of antigen presentation, if costimulatory molecules (such as CD80,CD86) are absent or blocked, T lymphocytes can not be activated and tolerance to the antigen is induced. Therefore, immature dendritic cells (immature dendritic cell,imDC), which lack the expression of stimulating molecules, have innate immune tolerance and can induce transplantation tolerance. Donor imDC combined with skin transplantation can significantly prolong the survival time of allogeneic skin, and the therapeutic effect is positive. Combined with the clinical situation of burn surgery at present, patients with extensive deep and severe burn usually use allograft skin graft to cover the wound or to carry out autogenous microskin-large sheet allograft skin transplantation. The survival time of allogeneic skin has great influence on stable condition and microskin survival. If combined donor imDC transplantation is added, better results may be obtained, thus solving the problem of difficult wound sealing in severe burn patients. At present, donor skin mainly comes from postmortem donors, but the imDC that can be used is mainly from normal healthy adults to donate blood or bone marrow, separate and culture from it and keep it, so the donor DC that can be used clinically does not come from the same body as the skin. This is called the "third party model". Because third-party imDC does not carry skin donor antigen, in order to play the role of inducing immune tolerance after skin transplantation, the donor antigen must be first ingested, processed and presented. As a result, its role is affected and it is difficult to directly produce immune tolerance for the transplanted skin. So we need to modify the third party imDC, to carry and express allogeneic skin donor antigens. The ability of imDC to absorb and load foreign antigens has been widely recognized. ImDC loaded with cellular antigen (such as phagocytosis of apoptotic cells) can induce the specific peripheral immune tolerance of the antigen, and imDC may cause the dysfunction of T cells. If the donor's major histocompatibility antigen gene can be transfected into bone marrow stem cells by transgenic technology, it will obviously induce donor antigen-specific immune tolerance, but the human HLA gene complex is very large. About thousands of kb, have high polymorphism, complex allelic types, difficult to transfect successfully, and partial allelic transfection can not fully express donor antigen effectively. So we learn from the tumor immunotherapy, using tumor cell lysate to impact the DC method, the allogeneic Lymphocyte Lymphocyte
【学位授予单位】：第三军医大学
【学位级别】：硕士
【学位授予年份】：2006
【分类号】：R392.4

【相似文献】