Harmon J V, Gruessner A C, Nakhleh R E, Zhang K, Gruessner R W
University of Minnesota, Department of Surgery, MMC 90, 420 Delaware St SE, Minneapolis, MN 55455, USA.
Arch Surg. 2001 Jul;136(7):817-21. doi: 10.1001/archsurg.136.7.817.
We previously showed in a large animal pig model that unmodified donor-specific bone marrow infusion (DSBMI) did not facilitate total bowel engraftment; in contrast, it increased the risks of rejection, infection, and graft-vs-host disease (GVHD) posttransplant. We hypothesize that continuous immunosuppression, in combination with DSBMI, might contribute to-or even trigger-these unwarranted immune responses by both host and graft; therefore, discontinuing immunosuppression might decrease these risks and prolong survival.
Six groups of outbred, mixed lymphocyte culture-reactive pigs underwent a total (small and large) bowel transplant: group 1, nonimmunosuppressed control pigs (n = 5); group 2, nonimmunosuppressed DSBMI pigs (n = 6); group 3, tacrolimus (indefinite) pigs (n = 7); group 4, tacrolimus (indefinite) plus DSBMI pigs (n = 7); group 5, tacrolimus (10 days only) pigs (n = 5); and group 6, tacrolimus (10 days only) plus DSBMI pigs (n = 6).
The combination of short-term immunosuppression and DSBMI (group 6) significantly prolonged survival, compared with short-term immunosuppression only (group 5) or DSBMI only (group 2). Short-term immunosuppression and DSBMI (group 6) did not prolong overall survival, compared with indefinite immunosuppression with (group 4) or without (group 3) DSBMI: survival rates at 7, 14, and 28 days posttransplant were 100%, 100%, and 67% in group 6; 100%, 100%, and 71% in group 3; and 100%, 67%, and 47% in group 4 (P =.14). Short-term immunosuppression and DSBMI (group 6) increased the incidence of rejection, infection, and GVHD, compared with indefinite immunosuppression without (but not with) DSBMI.
Short-term immunosuppression and DSBMI did not prolong survival and did not reduce the incidence of death from rejection, infection, or GVHD, compared with indefinite immunosuppression without DSBMI. But short-term immunosuppression and DSBMI resulted in a lower incidence of death from infection and GVHD, compared with indefinite immunosuppression and DSBMI. When immunosuppression was discontinued 10 days posttransplant, the effect of DSBMI was insufficient to avert death from rejection.
The clinical results of bowel transplantation trail those of other solid organ transplants. It reduced the rates of infection and GVHD. Our study shows that systemically infused donor-specific bone marrow with short-term or indefinite immunosuppression does not improve outcome after bowel transplantation. It seems necessary to modify the time, dosing, routing, and/or composition of donor-specific bone marrow before it can be successfully used in clinical bowel transplantation.
我们之前在大型动物猪模型中表明，未修饰的供体特异性骨髓输注（DSBMI）并不能促进全肠移植；相反，它增加了移植后排斥反应、感染和移植物抗宿主病（GVHD）的风险。我们推测，持续免疫抑制与DSBMI相结合，可能会导致宿主和移植物出现这些不必要的免疫反应，甚至引发这些反应；因此，停止免疫抑制可能会降低这些风险并延长生存期。
六组远交、混合淋巴细胞培养反应性猪接受了全（小肠和大肠）肠移植：第1组，未免疫抑制的对照猪（n = 5）；第2组，未免疫抑制的DSBMI猪（n = 6）；第3组，使用他克莫司（不限期）的猪（n = 7）；第4组，使用他克莫司（不限期）加DSBMI的猪（n = 7）；第5组，仅使用他克莫司10天的猪（n = 5）；第6组，仅使用他克莫司10天加DSBMI的猪（n = 6）。
与仅短期免疫抑制（第5组）或仅DSBMI（第2组）相比，短期免疫抑制与DSBMI联合使用（第6组）显著延长了生存期。与使用（第4组）或不使用（第3组）DSBMI的不限期免疫抑制相比，短期免疫抑制与DSBMI（第6组）并未延长总体生存期：移植后7天、14天和28天的生存率在第6组中分别为100%、100%和67%；在第3组中分别为100%、100%和71%；在第4组中分别为100%、67%和47%（P = 0.14）。与不使用（但不是使用）DSBMI的不限期免疫抑制相比，短期免疫抑制与DSBMI（第6组）增加了排斥反应、感染和GVHD的发生率。
与不使用DSBMI的不限期免疫抑制相比，短期免疫抑制与DSBMI并未延长生存期，也未降低因排斥反应、感染或GVHD导致的死亡率。但与不限期免疫抑制和DSBMI相比，短期免疫抑制与DSBMI导致因感染和GVHD导致的死亡率较低。当移植后10天停止免疫抑制时，DSBMI的作用不足以避免因排斥反应导致的死亡。
肠移植的临床结果落后于其他实体器官移植。它降低了感染和GVHD的发生率。我们的研究表明，短期或不限期免疫抑制下全身输注供体特异性骨髓并不能改善肠移植后的结局。在其能够成功用于临床肠移植之前，似乎有必要对供体特异性骨髓的时间、剂量、途径和/或组成进行调整。
