Erdmann Andreas A, Jung Unsu, Foley Jason E, Toda Yoko, Fowler Daniel H
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Biol Blood Marrow Transplant. 2004 Sep;10(9):604-13. doi: 10.1016/j.bbmt.2004.06.006.
CD3/CD28 co-stimulation activates T-cell cytokine and cytolytic effector function and therefore represents an approach to modulate donor T cells before allogeneic bone marrow transplantation (BMT). We hypothesized that co-stimulation of donor T cells under T2 conditions would generate CD4+ T-helper type 2 (Th2) and CD8+ Tc2 cells capable of abrogating marrow graft rejection with reduced graft-versus-host disease (GVHD). Relative to control co-stimulated Th1/Tc1 (T1) cells, co-stimulated T2 cells secreted reduced interleukin (IL)-2 and interferon-gamma and increased IL-4 and IL-10, expressed reduced fas ligand, and had similar total cytolytic capacity. In an F1-into-parent sublethal irradiation model, T2 cells potently abrogated rejection; this veto effect was partially attenuated if T2 cell infusion was delayed for 24 hours after BMT. Cell-tracking studies determined that T2 cells were quantitatively reduced after BMT when administered to hosts capable of mounting a host-versus-graft rejection response; both donor and host cytotoxic T lymphocytes may therefore have been deleted during Th2/Tc2 cell facilitation of engraftment. Donor T2 cells also abrogated rejection in an F1-into-parent model that used lethal host irradiation and subsequent host T-cell addback. Further experiments in a P1-into-P2 transplantation model demonstrated that donor T2 cells abrogated rejection with reduced GVHD in a transplant setting involving full major histocompatibility complex disparity in both the host-versus-graft and graft-versus-host directions. The capacity of T2 cells to abrogate rejection with reduced GVHD was a function of both the number of T2 cells infused and the number of T cells present after host preparation. Co-stimulation under T2 polarizing conditions therefore rapidly generates donor Th2/Tc2 cells that potently abrogate murine marrow rejection with reduced GVHD.
CD3/CD28共刺激可激活T细胞细胞因子和细胞溶解效应功能，因此是一种在异基因骨髓移植（BMT）前调节供体T细胞的方法。我们假设，在T2条件下对供体T细胞进行共刺激会产生能够消除骨髓移植排斥反应并减轻移植物抗宿主病（GVHD）的CD4+辅助性T2型（Th2）细胞和CD8+Tc2细胞。相对于对照共刺激的Th1/Tc1（T1）细胞，共刺激的T2细胞分泌的白细胞介素（IL）-2和干扰素-γ减少，IL-4和IL-10增加，Fas配体表达减少，且总细胞溶解能力相似。在F1到亲代的亚致死照射模型中，T2细胞能有效消除排斥反应；如果在BMT后24小时延迟输注T2细胞，这种否决效应会部分减弱。细胞追踪研究确定，当将T2细胞给予能够产生宿主抗移植物排斥反应的宿主时，BMT后T2细胞数量会定量减少；因此，在Th2/Tc2细胞促进植入过程中，供体和宿主细胞毒性T淋巴细胞可能都被清除了。供体T2细胞在使用致死性宿主照射和随后宿主T细胞回输的F1到亲代模型中也能消除排斥反应。在P1到P2移植模型中的进一步实验表明，在宿主抗移植物和移植物抗宿主方向上均存在完全主要组织相容性复合体差异的移植环境中，供体T2细胞能消除排斥反应并减轻GVHD。T2细胞以减轻GVHD的方式消除排斥反应的能力取决于输注的T2细胞数量和宿主预处理后存在的T细胞数量。因此，在T2极化条件下的共刺激能快速产生供体Th2/Tc2细胞，这些细胞能有效消除小鼠骨髓排斥反应并减轻GVHD。
