Weimer R, Melk A, Daniel V, Friemann S, Padberg W, Opelz G
Department of Internal Medicine, Giessen, Germany.
Hum Immunol. 2000 Sep;61(9):884-97. doi: 10.1016/s0198-8859(00)00152-x.
We showed previously that pretransplant CD4 helper defects and low in-vitro IL-10 responses predict a low risk of acute kidney graft rejection. To compare the effect of tacrolimus (Tacr) and cyclosporine A (CsA) on the humoral immune response we assessed T helper function, B cell/monocyte responses and in-vitro cytokine responses (TNF-alpha, GM-CSF, IL-1 beta, IL-2, IL-4, IL-6, IL-10) in 20 renal transplant recipients before and 3 months after they were switched from CsA to Tacr because of hyperlipoproteinemia, hirsutism, or gum hyperplasia. T helper function was assessed using a PWM-driven allogeneic coculture system of patient T cells together with control B cells. B cell/monocyte responses were determined using a PWM-stimulated allogeneic coculture system, SAC I-stimulated B-cell cultures and LPS-stimulated monocyte cultures. Immunoglobulin-secreting cell (ISC) responses were assessed in a reverse hemolytic plaque assay, and ELISA were used to determine cytokine secretion. Treatment with Tacr resulted in a decreased expression of costimulatory ligands and adhesion molecules (T cells: CD40L, p < 0.05; CD28 and CD54, p < or = 0.01; B cells: CD25, p = 0.05; CD40, p < 0.001; monocytes: CD40, p < 0.05), which coincided with decreased PHA-stimulated T cell IL-2 responses (398 +/- 153 versus 43 +/- 15 pg/ml, p < 0.05), impaired CD4 helper activity (117% +/- 22% versus 73% +/- 19%, p < 0.05) and increased CD4 suppressor activity (-120% +/- 28% versus -18% +/- 27%, p = 0.02). We observed enhanced CD4 IL-10 responses (p < 0.01) and LPS-stimulated monocyte responses (TNF-alpha, IL-1 beta, and IL-6, p < 0.005; IL-10, p < 0.05), indicating an increased humoral immune responsiveness under treatment with tacrolimus. Our data show that switching of immunosuppressive therapy from CsA to tacrolimus results in suppression of costimulatory ligands, adhesion molecules, Th1 responses and CD4 helper activity. However, enhanced humoral immune responses, Th2 and monokine responses, might have a negative impact on long-term graft function.
我们之前曾表明，移植前CD4辅助性细胞缺陷及体外白细胞介素-10反应低下预示着急性肾移植排斥反应的低风险。为比较他克莫司（Tacr）和环孢素A（CsA）对体液免疫反应的影响，我们评估了20例肾移植受者在因高脂蛋白血症、多毛症或牙龈增生从CsA转换为Tacr之前及之后3个月时的辅助性T细胞功能、B细胞/单核细胞反应及体外细胞因子反应（肿瘤坏死因子-α、粒细胞-巨噬细胞集落刺激因子、白细胞介素-1β、白细胞介素-2、白细胞介素-4、白细胞介素-6、白细胞介素-10）。使用患者T细胞与对照B细胞的PWM驱动的同种异体共培养系统评估辅助性T细胞功能。使用PWM刺激的同种异体共培养系统、SAC I刺激的B细胞培养物和LPS刺激的单核细胞培养物确定B细胞/单核细胞反应。在反向溶血斑试验中评估免疫球蛋白分泌细胞（ISC）反应，并使用酶联免疫吸附测定法测定细胞因子分泌。用Tacr治疗导致共刺激配体和黏附分子的表达降低（T细胞：CD40L，p<0.05；CD28和CD54，p≤0.01；B细胞：CD25，p = 0.05；CD40，p<0.001；单核细胞：CD40，p<0.05），这与PHA刺激的T细胞白细胞介素-2反应降低（398±153对43±15 pg/ml，p<0.05）、CD4辅助活性受损（117%±22%对73%±19%，p<0.05）及CD4抑制活性增加（-120%±28%对-18%±27%，p = 0.02）相一致。我们观察到CD4白细胞介素-10反应增强（p<0.01）及LPS刺激的单核细胞反应增强（肿瘤坏死因子-α、白细胞介素-1β和白细胞介素-6，p<0.005；白细胞介素-10，p<0.05），表明在用他克莫司治疗期间体液免疫反应性增加。我们的数据表明，免疫抑制治疗从CsA转换为他克莫司会导致共刺激配体、黏附分子、Th1反应和CD4辅助活性受到抑制。然而，增强的体液免疫反应、Th2和单核因子反应可能会对移植的长期功能产生负面影响。
