Ar'Rajab A, Harris R B, Khair-el-Din T A, Sentementes J T, Lu C, Dawidson I J
Department of Surgery, University of Texas Southwestern Medical Center, Dallas 75235-9031, USA.
Cell Transplant. 1995 May-Jun;4(3):315-21. doi: 10.1177/096368979500400310.
Adenosine deaminase (ADA) is an important enzyme for proper function of lymphocytes and congenital absence of ADA results in a form of severe combined immunodeficiency syndrome. 2'-Deoxycoformycin (Pentostatin, DCF) irreversibly inhibits ADA and therefore has been suggested as an immunosuppressive drug. The present study evaluated the immunosuppressive effect of DCF for islet allotransplantation in rats. Isolated islets (1,500 islets) from Lewis rats were transplanted into the kidney subcapsular space of streptozotocin-induced diabetic Wistar-Furth rats. DCF was administered IP either as a single injection at 1 mg/kg/wk, 1 mg/kg twice weekly, 5 mg/kg/twice weekly or 1 mg/kg/day, or as a continuous infusion at 0.8 or 1 mg/kg/day. Daily administration of DCF at 0.8 mg/kg in both methods, single daily injection or continuous infusion, resulted in a lymphopenia and a decrease in concanavalin A stimulation of splenic lymphocytes. However, DCF (in all doses) was not effective in preventing islet allograft rejection as evaluated by measuring the duration of normoglycemia following islet transplantation and by microscopic examination of the islet grafts. In fact, the duration of normoglycemia following islet transplantation was 7.5 +/- 0.9 and 9.0 +/- 1.0 days in rats receiving DCF in single daily injection or continuous infusion, respectively. This was not significantly different from control nontreated transplanted rats (8.5 +/- 0.7 days). Increasing the dose of DCF to 1 mg/kg, administered by continuous infusion, resulted in 100% mortality. For comparison, cyclosporine A (20 mg/kg, IP daily injection for 14 days) prolonged islet allograft survival to 27.3 +/- 1.5 days (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
腺苷脱氨酶（ADA）是淋巴细胞正常功能所必需的一种重要酶，先天性ADA缺乏会导致一种严重联合免疫缺陷综合征。2'-脱氧助间型霉素（喷司他丁，DCF）可不可逆地抑制ADA，因此被提议作为一种免疫抑制药物。本研究评估了DCF对大鼠胰岛同种异体移植的免疫抑制作用。将来自Lewis大鼠的分离胰岛（1500个胰岛）移植到链脲佐菌素诱导的糖尿病Wistar-Furth大鼠的肾被膜下间隙。DCF通过腹腔注射给药，剂量分别为1 mg/kg/周单次注射、1 mg/kg每周两次、5 mg/kg每周两次或1 mg/kg/天，或通过持续输注给药，剂量为0.8或1 mg/kg/天。两种给药方式（单次每日注射或持续输注）中，每日以0.8 mg/kg的剂量给予DCF，均导致淋巴细胞减少以及脾淋巴细胞对刀豆球蛋白A刺激的反应降低。然而，通过测量胰岛移植后血糖正常的持续时间以及对胰岛移植物进行显微镜检查评估，DCF（所有剂量）在预防胰岛同种异体移植排斥方面均无效。事实上，在接受DCF单次每日注射或持续输注的大鼠中，胰岛移植后血糖正常的持续时间分别为7.5±0.9天和9.0±1.0天。这与未治疗的对照移植大鼠（8.5±0.7天）无显著差异。通过持续输注将DCF剂量增加至1 mg/kg，导致100%的死亡率。作为对照，环孢素A（20 mg/kg，腹腔注射每日一次，共14天）将胰岛同种异体移植存活时间延长至27.3±1.5天（p<0.001）。（摘要截选至250字）
