IMMUNE MECHANISMS OF CHRONIC ALLOGRAFT REJECTION

慢性同种异体移植排斥的免疫机制

• 批准号: 2005193
• 负责人: CHARLES B CARPENTER
• 金额: $ 18.61万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-12-01 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2005193
• 关键词: MHC class I antigen; MHC class II antigen; T cell receptor; antigen presenting cell; chemokine; chronic disease /disorder; clone cells; cytokine; gene expression; heart transplantation; helper T lymphocyte; homologous transplantation; immunocytochemistry; isoantibody; isoantigen; kidney transplantation; laboratory rat; leukocyte activation /transformation; monoclonal antibody; mutant; nucleic acid sequence; pathologic process; polymerase chain reaction; transplant rejection; transplantation immunology

Vascularized organ transplants frequently develop a progressive obliterative vasculopathy, interstitial fibrosis and, in the case of kidneys, glomerulosclerosis, that lead to organ failure within a few years, in spite of continuing immunosuppressive therapy. This 'chronic rejection' process is poorly understood, and although there is clear evidence that T cell recognition of alloantigen plays a key role in initiating early acute rejection, there is little direct evidence that an active alloimmune response is responsible for progression of chronic rejection. In an established rat model of kidney and heart transplants (F344 and LEW strains) in which the sequential morphological and immunohistologic features, with associated cytokine/chemokine gene activation patterns, are well defined, the MHC antigen-driven T cell and antibody responses will be studied. These strains differ only by a class II public antigen. The hypothesis is that an ongoing alloantigen-driven response initiated by T cells primed by the indirect pathway of allorecognition is responsible for mediating the chronic rejection process. The sequences of F344 will be obtained and peptides prepared which represent the difference(s) with LEW MHC class II in order to establish the presence of T cell priming to the indirect pathway during chronic rejection. Preparation of T cell clones for transfer to naive recipients of grafts, and the use of monoclonal antibodies to TCRV/Beta families to block recognition in vivo, will test the significance of priming to immunodominant epitopes in chronic rejection. Tolerance- inducing strategies using synthetic peptides after transplantation will then be applied to interrupt the ongoing process of T cell activation. The hypothesis is supported by preliminary data showing that a single injection of CTLA4Ig to block T cell costimulation via CD28-B7, in addition to preventing chronic rejection if given early, can interrupt progression of chronic rejection when given 8 weeks after transplantation. Further study using antibodies and CTLA4Ig mutants which distinguish between B7-1 and B7-2 pathways should further elucidate approaches to interrupting chronic rejection. The synthetic MHC peptide and costimulatory blockade protocols will be tested for synergistic interaction, and full MHC class I and II strain differences will be subsequently studied. The above studies should provide relevant information for development of novel strategies to prevent and possibly interrupt chronic allograft rejection in clinical transplantation.

带血管器官移植经常进展为进展性 闭塞性血管病，间质纤维化，在 肾脏，肾小球硬化，导致几个器官衰竭 数年，尽管仍在继续进行免疫抑制治疗。这是慢性的 人们对拒绝的过程知之甚少，尽管有明确的 有证据表明T细胞对同种异体抗原的识别在 引发早期急性排斥反应，几乎没有直接证据表明 活跃的同种异体免疫反应与慢性粒细胞白血病的进展有关 拒绝。在已建立的大鼠肾脏和心脏移植模型中 (F344和LEW菌株)，其中顺序形态和 免疫组织学特征与相关细胞因子/趋化因子基因 激活模式是明确的，MHC抗原驱动的T细胞和 将对抗体反应进行研究。这些菌株只有一个类别不同。 II公共抗原。假设是一个正在进行的同种异体抗原驱动 T细胞通过间接途径启动的免疫应答 同种异体识别在慢性排斥反应中的作用 进程。将获得F344的序列并制备多肽 它们代表了(S)与卢MHC II类的区别，以便 建立T细胞启动间接途径的存在 慢性排斥。移植给幼稚细胞的T细胞克隆的制备 移植物的接受者和抗TCRV/Beta的单抗的使用 阻断家族在体内的识别，将考验其意义 慢性排斥反应中免疫优势表位的启动。宽容-- 移植后使用合成肽的诱导策略将 然后应用于中断正在进行的T细胞激活过程。 这一假说得到了初步数据的支持，这些数据表明， 注射CTLA4Ig阻断CD28-B7介导的T细胞共刺激 除了预防慢性排斥反应外，如果及早给予，还可以中断 8周后给予慢性排斥反应的进展 移植。利用抗体和CTLA4Ig突变体进一步研究 B7-1和B7-2途径的哪些区别需要进一步阐明 阻断慢性排斥反应的方法。人工合成的MHC多肽 将测试共刺激封锁协议的协同性 相互作用，MHC I类和II类菌株的完全差异将是 随后对其进行了研究。上述研究应提供相关的 为制定新的战略提供信息，以预防和可能 阻断临床移植慢性排斥反应。