Ueda H, Hancock W W, Cheung Y C, Tanaka K, Kupiec-Weglinski J W, Tilney N L
Surgical Research Laboratory, Harvard Medical School, Boston, Massachusetts 02115.
Transplantation. 1990 Jun;49(6):1124-9. doi: 10.1097/00007890-199006000-00019.
ART-18, a mouse antirat IL-2R mAb inhibits IL-2 binding and IL-2-dependent T cell growth. Although both (LEW x BN)F1 kidney and heart allografts survive ca. 3 weeks in ART-18-treated LEW rats (acute rejection occurs within 10 days, P less than 0.001), the host responses against the two organs vary. In the heart model, the splenic CD4:CD8 ratio as determined by FMF was similar both in untreated and treated animals, but decreased significantly in kidney recipients conditioned with ART-18. In both mAb-modulated animal groups, splenocytes inhibited test MLR and prolonged test cardiac allograft survival in a donor-specific fashion upon adoptive transfer, suggesting that ART-18 mediates "sparing" of Ts. However, both CD4+ and CD8+ cells from kidney-grafted hosts conferred suppression in vivo; only the CD8+ subset was effective in the heart model. Immunohistologically, IL-2R+ cells were absent in the heart grafts of treated hosts; a significant proportion of the kidney cell infiltrate remained IL-2R+ despite continuous mAb administration. Although ART-18 therapy prolonged renal graft survival significantly, function was poor and the rats remained uremic. However, when one of the native kidneys was retained and the rat continued to enjoy normal renal function, IL-2R+ cells were abolished from the graft infiltrate, as shown by FMF and immunohistology. Thus, ART-18 treatment influences host responses differentially against kidney and heart allografts (modulation and depletion of IL-2R+ cells, respectively) despite increasing their survival comparably. The uremic state in the kidney model prevents elimination of infiltrating IL-2R+ mononuclear cells by a mAb directed specifically against them.
ART-18是一种小鼠抗大鼠IL-2R单克隆抗体，可抑制IL-2结合及IL-2依赖的T细胞生长。尽管在接受ART-18治疗的LEW大鼠中，（LEW×BN）F1肾和心脏同种异体移植均可存活约3周（急性排斥反应在10天内发生，P<0.001），但宿主对这两种器官的反应有所不同。在心脏模型中，通过荧光激活细胞分选术（FACS）测定的未治疗和治疗动物的脾脏CD4:CD8比值相似，但在接受ART-18预处理的肾移植受体中该比值显著降低。在两个单克隆抗体调节的动物组中，脾细胞在过继转移后均以供体特异性方式抑制试验性混合淋巴细胞反应（MLR）并延长试验性心脏同种异体移植的存活时间，提示ART-18介导了抑制性T细胞（Ts）的“保留”。然而，来自肾移植宿主的CD4+和CD8+细胞在体内均具有抑制作用；只有CD8+亚群在心脏模型中有效。免疫组织学检查显示，治疗宿主的心脏移植物中不存在IL-2R+细胞；尽管持续给予单克隆抗体，肾细胞浸润中仍有相当比例的细胞为IL-2R+。尽管ART-18治疗显著延长了肾移植的存活时间，但肾功能较差，大鼠仍处于尿毒症状态。然而，当保留一个天然肾且大鼠继续享有正常肾功能时，如FACS和免疫组织学所示，移植浸润中的IL-2R+细胞被清除。因此，尽管ART-18治疗同等程度地延长了肾和心脏同种异体移植的存活时间，但对宿主针对肾和心脏同种异体移植的反应有不同影响（分别为调节和清除IL-2R+细胞）。肾模型中的尿毒症状态阻止了通过特异性针对浸润的IL-2R+单核细胞的单克隆抗体将其清除。
