DONOR SPECIFIC HYPORESPONSIVENESS

供体特异性低反应

• 批准号: 2780164
• 金额: $ 4.81万
• 依托单位: UNIVERSITY OF MINNESOTA
• 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/2780164
• 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学、细胞和调控机制 参与受体对供体 HLA 的免疫适应 差异。 在人体移植中，终生使用 免疫抑制药物是必要的，但也与 许多副作用。 先前的研究表明一些肾脏接受者 证明 MLC 对供体细胞有特异性增殖无反应 移植后。 那些出现供体抗原特异性的患者 反应低下可能是退出或减少维持治疗的候选者 免疫抑制治疗。 我们将确定 CSA 的比例 接受治疗的受者在体外已形成供体抗原特异性 反应性低下。 我们的初步研究结合了捐赠者 定义HLA-Dw特异性的细胞和纯合分型细胞 供体细胞（在 MLR 中），已在体外鉴定出供体抗原特异性 34% 经 CSA 治疗的半相合活体相关性低反应性 捐赠者（LRD）接受者。 该亚组在 1 和 1 时血清肌酐较低 移植后 2 年，6 个月后排斥反应发生率低于 那些没有在体外表现出供体抗原特异性的受者 反应性低下。 此外，还没有发生移植物损失。 低反应组与非低反应组 3 人（11%）相比。 这 参与供体抗原特异性发展的确切机制 低反应性尚不清楚。 我们将重点研究细胞 供体抗原发育的基础和机制 特异性低反应性。 在我们的初步研究中，我们观察到 患者抗供体中 HLA-DQ 定向克隆的百分比增加 2名患者的启动组合在体外证明了供体抗原- 特异性低反应性与抑制细胞增加一致 表型。 最后，我们将确定捐助者是否发展 抗原特异性低反应性预示成功戒断或逐渐减量 的免疫抑制。 我们的目标是减少副作用 通过提供基于免疫学的标准来进行免疫抑制 选择可以成功退出或逐渐减量的患者 免疫抑制。