Hale D A, Gottschalk R, Fukuzaki T, Wood M L, Maki T, Monaco A P
Department of Surgery, Deaconess Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
Transplantation. 1997 Feb 15;63(3):359-64. doi: 10.1097/00007890-199702150-00005.
Sirolimus is a potent immunosuppressive agent with great therapeutic potential. The objective of our study was to evaluate the efficacy of sirolimus versus cyclosporine in augmenting the unresponsiveness induced by an antilymphocyte serum (ALS)/donor-specific bone marrow (BM)-based regimen across three levels of histoincompatibility: class I and II disparate (DBA/2 to B6AF1), complete mismatch (AKR to C57BL/6), and xenograft (ACI rat to B6AF1).
Full-thickness skin grafts were taken from donors and placed on recipients in standard fashion. Seven groups of recipient mice (n=10-28) received various combinations of the following treatment protocols: sirolimus, 1.5 mg/kg (3.0 mg/kg for xenografts) every other day from day 0 to day 12; cyclosporine, 50 mg/kg every other day from day 10 through 22; ALS, 0.5 ml on days -1 and 2 for allografts and days -1, 2, and 4 for xenografts; and BM, 25 million donor-specific cells IV on day 7.
The administration of ALS or ALS/BM resulted in modest but significant prolongation of skin graft survival in all combinations tested. Cyclosporine combined with ALS or ALS/BM significantly extended allograft survival compared with ALS or ALS/BM alone (P<0.05) but had no effect on xenograft survival. In contrast, the combination of sirolimus with ALS or ALS/BM resulted in a two- to threefold increase in allograft survival and over a fourfold increase in xenograft survival when compared with the comparable cyclosporine-based regimen. Additionally, lymphocytes isolated from class I and II incompatible mice with skin grafts surviving >100 days demonstrated markedly reduced interleukin 2 and interferon-gamma secretion in response to irradiated donor-specific lymphocytes in culture.
In the regimens tested, sirolimus was superior to cyclosporine in augmenting donor BM-induced skin graft prolongation in ALS-treated mice across all levels of histoincompatibility.
西罗莫司是一种具有巨大治疗潜力的强效免疫抑制剂。我们研究的目的是评估西罗莫司与环孢素在增强抗淋巴细胞血清（ALS）/供体特异性骨髓（BM）方案诱导的无反应性方面的疗效，该方案涵盖三个组织相容性水平：I类和II类不相配（DBA/2至B6AF1）、完全不匹配（AKR至C57BL/6）以及异种移植（ACI大鼠至B6AF1）。
从供体获取全层皮肤移植物，并以标准方式移植到受体身上。七组受体小鼠（n = 10 - 28）接受以下治疗方案的不同组合：西罗莫司，从第0天至第12天每隔一天给予1.5 mg/kg（异种移植为3.0 mg/kg）；环孢素，从第10天至第22天每隔一天给予50 mg/kg；ALS，同种异体移植在第 - 1天和第2天给予0.5 ml，异种移植在第 - 1天、第2天和第4天给予0.5 ml；BM，在第7天静脉注射2500万个供体特异性细胞。
在所有测试组合中，给予ALS或ALS/BM均使皮肤移植物存活时间适度但显著延长。与单独使用ALS或ALS/BM相比，环孢素与ALS或ALS/BM联合使用显著延长了同种异体移植物的存活时间（P < 0.05），但对异种移植物存活时间无影响。相比之下，与基于环孢素的类似方案相比，西罗莫司与ALS或ALS/BM联合使用使同种异体移植物存活时间增加了两到三倍，异种移植物存活时间增加了四倍以上。此外，从皮肤移植物存活超过100天的I类和II类不相容小鼠中分离的淋巴细胞，在体外培养中对照射的供体特异性淋巴细胞反应时，白细胞介素2和干扰素 - γ分泌明显减少。
在测试的方案中，在所有组织相容性水平上，西罗莫司在增强ALS处理的小鼠中供体BM诱导的皮肤移植物延长方面优于环孢素。
