DONOR SPECIFIC HYPORESPONSIVENESS

供体特异性低反应

• 批准号: 5210317
• 负责人: Nancy Louise Reinsmoen
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5210317
• 关键词: T cell receptor; anergy; apoptosis; artificial immunosuppression; blood transfusion; cell mediated cytotoxicity; cyclosporines; histocompatibility; human subject; immune tolerance /unresponsiveness; interleukin 2; kidney transplantation; lymphocyte proliferation; mixed lymphocyte reaction test; radiation immunosuppression; tissue /cell culture

We plan to identify the immunogenetic, cellular and regulatory mechanisms involved in the immunologic adaptation of the recipient to donor HLA disparities. In human transplantation, the life-long use of immunosuppressive drugs has been necessary but is also associated with numerous side effects. Previous studies indicate some kidney recipients demonstrate specific proliferative unresponsiveness in MLC to donor cells posttransplant. Those patients who develop donor antigen-specific hyporeactivity may be candidates for withdrawal or reduction of maintenance immunosuppressive therapy. We will determine what proportion of CSA- treated recipients have developed in vitro donor antigen-specific hyporeactivity. Our preliminary studies, using a combination of donor cells and homozygous typing cells defining the HLA-Dw specificities of the donor cells (in MLR), have identified in vitro donor antigen-specific hyporeactivity for 34% of the CSA-treated haploidentical living related donor (LRD) recipients. This subgroup had lower serum creatinines at 1 and 2 years posttransplant and had fewer rejection episodes after 6 months than those recipients who did not demonstrate in vitro donor antigen-specific hyporeactivity. In addition, there have been no graft losses in the hyporesponsive group vs. 3 (11%) in the non-hyporesponsive group. The exact mechanisms involved in the development of donor antigen-specific hyporeactivity are not known. We will focus on the study of the cellular basis and mechanisms involved in the development of the donor antigen specific hyporeactivity. In our preliminary studies, we observed an increased percentage of HLA-DQ-directed clones in the patient anti-donor priming combinations of 2 patients who demonstrated in vitro donor antigen- specific hyporeactivity were consistent with increased suppressor cell phenotypes. Finally, we will determine whether the development of donor antigen-specific hyporeactivity predicts successful withdrawal or tapering of immunosuppression. Our goal is to reduce the side effects of immunosuppression by providing immunologically based-criteria for the selection of patients who can be successfully withdrawn or tapered from immunosuppression.

我们计划确定免疫遗传、细胞和调节机制 参与受者对供体人类白细胞抗原的免疫适应 差距。在人类移植中，终生使用 免疫抑制药物是必要的，但也与 很多副作用。先前的研究表明，一些肾移植受者 显示MLC对供体细胞的特异性增殖无反应性 移植后。那些出现供体抗原特异性的患者 低反应性可能是退出或减少维持的候选对象 免疫抑制疗法。我们将确定CsA的比例- 接受治疗的受者在体外培养出了供体抗原特异性 反应迟钝。我们的初步研究，使用了捐赠者的组合 定义人类白细胞抗原DW特异性的细胞和纯合子分型细胞 供体细胞(在MLR中)，已在体外鉴定供体抗原特异性 34%CsA治疗的单倍体相合活体亲属的低反应性 捐赠者(LRD)接受者。这一亚组的血清肌酐在1和 移植后2年，6个月后排斥反应发生率低于 那些没有在体外证明供者抗原特异性的受者 反应迟钝。此外，还没有发生贪污损失。 低反应组与非低反应组中3例(11%)。这个 与供体抗原特异性形成有关的确切机制 低反应性是未知的。我们将重点研究细胞 供体抗原形成的基础和机制 特定的低反应性。在我们的初步研究中，我们观察到 抗供者患者中人类白细胞抗原-DQ定向克隆百分率升高 两名在体外证明供体抗原- 特异性低反应性与抑制细胞的增加一致 表型。最后，我们将确定供体的发育是否 抗原特异性低反应性预测成功戒断或缩减 免疫抑制。我们的目标是减少 通过提供基于免疫学的标准来抑制免疫 选择可以成功退出或逐渐退出的患者 免疫抑制。