DONOR SPECIFIC HYPORESPONSIVENESS

我们计划确定免疫遗传学，细胞和调节机制， 参与受体对供体HLA的免疫适应 差距。 在人类移植中，终身使用 免疫抑制药物是必需的，但也与 很多副作用 先前的研究表明一些肾脏接受者 显示MLC对供体细胞的特异性增殖无反应性 移植后 发生供体抗原特异性 低反应性可能是撤销或减少维持的候选者 免疫抑制治疗 我们将决定CSA的比例- 接受治疗的受者在体外产生了供体抗原特异性 低反应性 我们的初步研究，使用捐赠者的组合 细胞和纯合子分型细胞定义的HLA-Dw特异性， 供体细胞（在MLR中），已经在体外鉴定出供体抗原特异性 34%的CSA治疗的单倍体相合活体相关的低反应性 供体（LRD）受体。 该亚组在1和2小时血清肌酐较低， 移植后2年，6个月后的排斥反应发生率低于 那些没有证明体外供体抗原特异性的受体 低反应性 此外，没有移植损失， 低反应组vs非低反应组3例（11%）。 的 参与供体抗原特异性抗体形成的确切机制 低反应性是未知。 我们将重点研究细胞的 供体抗原开发的基础和机制 特异性低反应性 在初步研究中，我们观察到 患者抗供体中HLA-DQ定向克隆的百分比增加 2例患者的预激组合，这些患者在体外证明供体抗原- 特异性低反应性与抑制细胞增加一致 表型 最后，我们将确定是否发展捐助者 抗原特异性低反应性预示成功戒断或减量 免疫抑制。 我们的目标是减少 通过提供免疫学基础的标准， 选择可以成功退出或逐渐减少的患者 免疫抑制

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.