Matsuyama Shinichi, Gunji Takashi, Ise Kazuya, Sato Yoshihiro, Saito Takuro, Gotoh Mitsukazu
Department of Surgery I, Fukushima Medical University, Fukushima, Japan.
Transplantation. 2003 Jul 15;76(1):65-71. doi: 10.1097/01.TP.0000069232.48055.03.
Mitomycin C (MMC) treatment produces genotoxic stress and exerts various biologic effects on cell function. This study determines the feasibility of MMC pretreatment of islet grafts as a sole immunomodulatory regimen to protect murine crude-digested islet allografts.
Collagenase-digested BALB/c (H-2d) islets were incubated for 30 min with MMC at different doses (0, 3.2, 10, 32, and 100 microg/mL; n=20, 15, 55, 15, 15, respectively), cultured for 20 hr, and transplanted into the renal subcapsular space of streptozotocin-induced diabetic C57BL/6 (B6; H-2b) mice.
All mice that received MMC-treated islets showed restoration of normoglycemia within 5 days postgrafting, which was maintained until rejection. All untreated islets were acutely rejected with a mean survival time of 15.1+/-3.5 days. Significant prolongation of graft survival was noted in mice undergoing transplantation with islets treated with 10 microg/mL MMC compared with untreated islets (58.9+/-37.7 days, P<0.01). Notably, the grafts of 24 of 55 animals (43%) that received islets treated with 10 microg/mL MMC survived more than 100 days without any other treatment. Furthermore, antigen-specific prolongation of graft survival of secondary untreated islets was observed in mice bearing long-term functioning islet grafts.
Our results indicate that pretreatment of islets with MMC alone protects the graft against rejection and produces long-term graft survival with normal blood glucose levels, and that pretreatment with MMC offers a new strategy for allogeneic islet transplantation.
丝裂霉素C（MMC）治疗会产生遗传毒性应激，并对细胞功能产生多种生物学效应。本研究确定MMC预处理胰岛移植作为一种单独的免疫调节方案来保护小鼠粗消化胰岛同种异体移植的可行性。
用胶原酶消化的BALB/c（H-2d）胰岛与不同剂量（0、3.2、10、32和100μg/mL；分别为n = 20、15、55、15、15）的MMC孵育30分钟，培养20小时，然后移植到链脲佐菌素诱导的糖尿病C57BL/6（B6；H-2b）小鼠的肾被膜下间隙。
所有接受MMC处理的胰岛移植的小鼠在移植后5天内血糖恢复正常，并维持到排斥反应发生。所有未处理的胰岛均被急性排斥，平均存活时间为15.1±3.5天。与未处理的胰岛相比，接受10μg/mL MMC处理的胰岛移植的小鼠移植存活时间显著延长（58.9±37.7天，P<0.01）。值得注意的是，55只接受10μg/mL MMC处理的胰岛移植的动物中有24只（43%）的移植在没有任何其他治疗的情况下存活超过100天。此外，在具有长期功能的胰岛移植的小鼠中观察到二次未处理的胰岛移植存活时间的抗原特异性延长。
我们的结果表明，单独用MMC预处理胰岛可保护移植免受排斥，并使移植长期存活且血糖水平正常，并且MMC预处理为同种异体胰岛移植提供了一种新策略。
