Teachey David T, Obzut Dana A, Axsom Kelly, Choi John K, Goldsmith Kelly C, Hall Junior, Hulitt Jessica, Manno Catherine S, Maris John M, Rhodin Nicholas, Sullivan Kathleen E, Brown Valerie I, Grupp Stephan A
Divisions of Oncology and Hematology, Children's Hospital of Philadelphia, ARC 902, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA.
Blood. 2006 Sep 15;108(6):1965-71. doi: 10.1182/blood-2006-01-010124. Epub 2006 Jun 6.
Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by defective Fas-mediated apoptosis, leading to lymphadenopathy, hepatosplenomegaly, and an increased number of double-negative T cells (DNTs). Treatment options for patients with ALPS are limited. Rapamycin has been shown to induce apoptosis in normal and malignant lymphocytes. Since ALPS is caused by defective lymphocyte apoptosis, we hypothesized that rapamycin would be effective in treating ALPS. We tested this hypothesis using rapamycin in murine models of ALPS. We followed treatment response with serial assessment of DNTs by flow cytometry in blood and lymphoid tissue, by serial monitoring of lymph node and spleen size with ultrasonography, and by enzyme-linked immunosorbent assay (ELISA) for anti-double-stranded DNA (dsDNA) antibodies. Three-dimensional ultrasound measurements in the mice correlated to actual tissue measurements at death (r = .9648). We found a dramatic and statistically significant decrease in DNTs, lymphadenopathy, splenomegaly, and autoantibodies after only 4 weeks when comparing rapamycin-treated mice with controls. Rapamycin induced apoptosis through the intrinsic mitochondrial pathway. We compared rapamycin to mycophenolate mofetil, a second-line agent used to treat ALPS, and found rapamycin's control of lymphoproliferation was superior. We conclude that rapamycin is an effective treatment for murine ALPS and should be explored as treatment for affected humans.
自身免疫性淋巴细胞增生综合征（ALPS）是一种由Fas介导的凋亡缺陷导致淋巴细胞异常存活的疾病，可引起淋巴结病、肝脾肿大以及双阴性T细胞（DNT）数量增加。ALPS患者的治疗选择有限。雷帕霉素已被证明可诱导正常和恶性淋巴细胞凋亡。由于ALPS是由淋巴细胞凋亡缺陷引起的，我们推测雷帕霉素对治疗ALPS有效。我们在ALPS小鼠模型中使用雷帕霉素验证了这一假设。我们通过流式细胞术对血液和淋巴组织中的DNT进行系列评估、通过超声对淋巴结和脾脏大小进行系列监测以及通过酶联免疫吸附测定（ELISA）检测抗双链DNA（dsDNA）抗体来跟踪治疗反应。小鼠的三维超声测量结果与死亡时的实际组织测量结果相关（r = 0.9648）。与对照组相比，我们发现仅在4周后，雷帕霉素治疗的小鼠的DNT、淋巴结病、脾肿大和自身抗体就有显著且具有统计学意义的下降。雷帕霉素通过内在线粒体途径诱导凋亡。我们将雷帕霉素与用于治疗ALPS的二线药物霉酚酸酯进行比较，发现雷帕霉素对淋巴细胞增殖的控制效果更佳。我们得出结论，雷帕霉素是治疗小鼠ALPS的有效药物，应探索其作为人类患者治疗药物的可能性。
