Sivasai K S, Mohanakumar T, Phelan D, Martin S, Anstey M E, Brennan D C
Department of Surgery and Pathology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Clin Exp Immunol. 2000 Mar;119(3):559-65. doi: 10.1046/j.1365-2249.2000.01138.x.
One of the important parameters for prolonged waiting time for potential renal transplant recipients is the presence of preformed antibodies to human leucocyte antigen (HLA) antigens, which is often caused by previous transplants, pregnancy or transfusions. In vivo administration of specific and unselected polyclonal intravenous immunoglobulin (IVIGs) preparations have been shown to inhibit anti-HLA alloantibodies in highly sensitized patients. We sought to determine whether Cytogam (Medimmune Inc., Gaithersburg, MD, USA), a hyperimmune anticytomegalovirus immunoglobulin would (1) effect either in vitro or in vivo alloreactivity, and (2) whether Cytogam therapy could reduce the titre of preformed anti-HLA antibodies in highly sensitized patients. Alloreactivity was assessed by mixed lymphocyte reaction (MLR) and cytotoxic T lymphocyte (CTL) assay. A complement dependent microlymphocytotoxicity assay was done to assess for panel reactive antibody (PRA) status and the presence of anti-idiotypic antibodies in the Cytogam preparation. The MLR was inhibited by Cytogam in vitro in a dose-dependent fashion ranging from 31-92%. Significant inhibition of the MLR responses was not observed in recipients who received Cytogam in vivo (50 mg/kg). This could be a result of adminstration of a low dose of IVIG. However, CTL activity against the alloantigens in all individuals assessed was significantly inhibited after in vivo administration of Cytogam. Three of five individuals experienced a decrease of 5-32% in the PRA status at 4 weeks post administration of Cytogam. Cytogam also blocked the anti-HLA antibody titres in a microlymphocytotoxicity assay, suggesting the presence of anti-idiotypic antibodies. Our study was based on a single prophylactic dose of Cytogam (50 mg/kg), however, higher dose administration could be feasible by removing more fluid at dialysis, but should be given intradialytically to avoid volume overload. Overall, our results suggest that Cytogam can modulate the in vivo and in vitro T cell responses against the alloantigens.
对于潜在的肾移植受者而言，等待时间延长的一个重要参数是存在针对人类白细胞抗原（HLA）抗原的预先形成的抗体，这通常是由先前的移植、怀孕或输血引起的。已证明在体内给予特异性且未经筛选的多克隆静脉注射免疫球蛋白（IVIG）制剂可抑制高度致敏患者体内的抗HLA同种抗体。我们试图确定超免疫抗巨细胞病毒免疫球蛋白Cytogam（美国马里兰州盖瑟斯堡的Medimmune公司生产）是否会（1）在体外或体内影响同种异体反应性，以及（2）Cytogam治疗是否能降低高度致敏患者体内预先形成的抗HLA抗体的滴度。通过混合淋巴细胞反应（MLR）和细胞毒性T淋巴细胞（CTL）试验评估同种异体反应性。进行补体依赖性微量淋巴细胞毒性试验以评估群体反应性抗体（PRA）状态以及Cytogam制剂中抗独特型抗体的存在情况。Cytogam在体外以31%至92%的剂量依赖性方式抑制MLR。在体内接受Cytogam（50mg/kg）治疗的受者中未观察到MLR反应的显著抑制。这可能是由于给予的IVIG剂量较低所致。然而，在体内给予Cytogam后，所有评估个体针对同种异体抗原的CTL活性均受到显著抑制。五名个体中有三名在给予Cytogam后4周时PRA状态下降了5%至32%。在微量淋巴细胞毒性试验中，Cytogam也阻断了抗HLA抗体滴度，提示存在抗独特型抗体。我们的研究基于单次预防性剂量的Cytogam（50mg/kg），然而，通过在透析时去除更多液体，给予更高剂量可能是可行的，但应在透析过程中给予以避免容量过载。总体而言，我们的结果表明Cytogam可调节体内和体外针对同种异体抗原的T细胞反应。
