Gao Wenda, Demirci Gülçin, Strom Terry B, Li Xian Chang
Department of Medicine, Harvard Medical School, Division of Immunology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Transplantation. 2003 Sep 27;76(6):994-9. doi: 10.1097/01.TP.0000085010.39567.FB.
A balanced network of positive and negative T-cell co-stimulatory signals is important in regulating T-cell activation. Blocking CD28, CD154 (CD40L), or both co-stimulatory molecules has been efficacious in preventing acute allograft rejection in certain but not all transplantation models. In the present study, the authors tested the hypothesis that stimulating programmed death 1 (PD-1)-triggered negative signals concurrent with blocking CD154 co-stimulatory signals would facilitate islet allograft tolerance.
The authors used a dimeric PD-L1 immunoglobulin (Ig) fusion protein to stimulate the inhibitory receptor PD-1, and a monoclonal antibody to block CD154. The effects of PD-1 engagement and CD154 blockade on lymphocyte activation were determined by cell proliferation, flow cytometry, and a model of islet transplantation.
PD-L1Ig inhibited the proliferation of both CD4+ and CD8+ T cells stimulated by anti-CD3. The inhibitory effect of PD-L1Ig was enhanced by concurrent blockade of CD154 co-stimulatory signals, as demonstrated by T-cell proliferation and expression of cell surface activation markers. PD-L1Ig and anti-CD154 also synergistically blocked the activation and maturation of antigen-presenting cells. In an islet transplantation model, treatment of recipient C57BL/6 (H-2b) mice with PD-L1Ig and anti-CD154 induced long-term survival of DBA/2 (H-2d) islet allografts, whereas treatment with each reagent alone failed to prevent islet allograft rejection.
These results suggest that engaging the negative receptor PD-1 exhibits critical immunoregulatory effects in the allograft response, and blocking positive co-stimulatory molecules with active delivery of inhibitory signals may represent a novel therapeutic strategy in transplantation.
正负性T细胞共刺激信号的平衡网络在调节T细胞活化中起重要作用。在某些但并非所有移植模型中，阻断CD28、CD154（CD40L）或这两种共刺激分子已被证明可有效预防急性同种异体移植排斥反应。在本研究中，作者测试了这样一种假设，即刺激程序性死亡1（PD-1）触发的负性信号并同时阻断CD154共刺激信号将促进胰岛同种异体移植耐受。
作者使用二聚体PD-L1免疫球蛋白（Ig）融合蛋白刺激抑制性受体PD-1，并使用单克隆抗体阻断CD154。通过细胞增殖、流式细胞术和胰岛移植模型确定PD-1激活和CD154阻断对淋巴细胞活化的影响。
PD-L1Ig抑制抗CD3刺激的CD4+和CD8+T细胞的增殖。如T细胞增殖和细胞表面活化标志物的表达所示，CD154共刺激信号的同时阻断增强了PD-L1Ig的抑制作用。PD-L1Ig和抗CD154还协同阻断抗原呈递细胞的活化和成熟。在胰岛移植模型中，用PD-L1Ig和抗CD154治疗受体C57BL/6（H-2b）小鼠可诱导DBA/2（H-2d）胰岛同种异体移植的长期存活，而单独使用每种试剂治疗未能预防胰岛同种异体移植排斥反应。
这些结果表明，激活负性受体PD-1在同种异体移植反应中具有关键的免疫调节作用，通过主动传递抑制信号来阻断正性共刺激分子可能代表了一种新的移植治疗策略。
