Chavez H, Beaudreuil S, Abbed K, Taoufic Y, Kriaa F, Charpentier B, Durrbach A
Unité d'Immunologie Biologique, Hôpital de Bicêtre, France.
Transpl Immunol. 2007 Jun;17(4):243-8. doi: 10.1016/j.trim.2007.01.005. Epub 2007 Jan 24.
Belatacept is a new recombinant molecule (CTLA4-Ig) that interferes with the second activation signal of T lymphocytes. CTLA4-Ig induced T cell allograft tolerance in rodents but not in primates. We examined the changes in peripheral lymphocyte subsets, including regulatory T cells, in renal transplant patients treated with Belatacept.
A cross-sectional immunological study was carried out 6 months after transplantation in 28 patients enrolled in the Belatacept phase II study. Eighteen patients received Belatacept, mycophenolate mofetil and steroids (Belatacept group), while the control group of 10 patients received cyclosporine, mycophenolate mofetil and steroids (CsA group). Lymphocyte subsets were examined by flow cytometry. Foxp3 mRNA expression was measured by quantitative PCR.
The number of T lymphocytes and the percentage of CD3+ T cells were similar in both groups. However, the percentage of CD3+ CD4+ T cells was lower in the Belatacept group than in the control CsA group (B=42.5%+/-13.7 vs CsA=52.9%+/-9, p<0.005), and the percentage of CD3+ CD8+ cells was higher in the Belatacept group than in the control (B=32.9%+/-6.7 vs CsA=19.5%+/-8.2, p<0.0002). The percentage of CD19+ cells was similar in both groups. Among CD56+cells, only the percentage of CD16+ cells was significantly higher in the Belatacept group than in the control (B=82%+/-12 vs CsA=59.7%+/-25, p=0.01). Among CD4 and CD8 T cells the percentage of activated lymphocytes expressing CTLA4, HLA-DR or CD40L was similar in both groups. The percentage of CD4+CD25+ T cells was higher in the CsA group. The percentage of regulatory CD4+CD25+ cells with bright CD25 staining was similar in both groups (B=3.6+/-2.3% vs CsA=4.7+/-1.9%, ns) as was the expression of FoxP3.
Our results indicated that Belatacept did not induce regulatory T cell expansion in vivo. We suggest that Belatacept treatment should be maintained after transplantation to allow graft acceptance.
贝拉西普是一种新型重组分子（CTLA4-Ig），可干扰T淋巴细胞的第二激活信号。CTLA4-Ig在啮齿动物中可诱导T细胞同种异体移植耐受，但在灵长类动物中则不然。我们研究了接受贝拉西普治疗的肾移植患者外周淋巴细胞亚群（包括调节性T细胞）的变化。
对参加贝拉西普II期研究的28例患者在移植后6个月进行了一项横断面免疫学研究。18例患者接受贝拉西普、霉酚酸酯和类固醇治疗（贝拉西普组），而10例患者的对照组接受环孢素、霉酚酸酯和类固醇治疗（环孢素A组）。通过流式细胞术检测淋巴细胞亚群。通过定量PCR测量Foxp3 mRNA表达。
两组的T淋巴细胞数量和CD3+ T细胞百分比相似。然而，贝拉西普组的CD3+ CD4+ T细胞百分比低于环孢素A对照组（贝拉西普组=42.5%±13.7，环孢素A组=52.9%±9，p<0.005），贝拉西普组的CD3+ CD8+细胞百分比高于对照组（贝拉西普组=32.9%±6.7，环孢素A组=19.5%±8.2，p<0.0002）。两组的CD19+细胞百分比相似。在CD56+细胞中，只有贝拉西普组的CD16+细胞百分比显著高于对照组（贝拉西普组=82%±12，环孢素A组=59.7%±25，p=0.01）。在CD4和CD8 T细胞中，表达CTLA4、HLA-DR或CD40L的活化淋巴细胞百分比在两组中相似。环孢素A组的CD4+CD25+ T细胞百分比更高。两组中CD25染色明亮的调节性CD4+CD25+细胞百分比相似（贝拉西普组=3.6±2.3%，环孢素A组=4.7±1.9%，无显著性差异），FoxP3的表达也相似。
我们的结果表明，贝拉西普在体内不会诱导调节性T细胞扩增。我们建议移植后应维持贝拉西普治疗以促进移植物接受。
