Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA, USA; Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA, USA; Division of Plastic Surgery and Hand Surgery, University Hospital Zurich, Zurich, ZH, Switzerland.
Transpl Immunol. 2022 Dec;75:101696. doi: 10.1016/j.trim.2022.101696. Epub 2022 Aug 18.
We evaluated the outcome of vertical rectus abdominus myocutaneous flap (VRAM) allotransplantation in a mini-pig model, using a combined co-stimulation blockade (Co-SB) and mechanistic target of rapamycin inhibition (mTORi)-based regimen, with or without preceding calcineurin inhibition (CNI).
VRAM allotransplants were performed between SLA-mismatched MGH miniature swine. Group A (n = 2) was treated continuously with the mTOR inhibitor rapamycin from day -1 in combination with the Co-SB agent cytotoxic T lymphocyte antigen 4-Ig (CTLA4-Ig) from post-operative day (POD) 0. In group B (n = 3), animals received tacrolimus daily from POD 0 to POD 13, followed by rapamycin daily from POD 7 and CTLA4-Ig weekly from POD 7-28. Graft rejection was determined by Banff criteria and host cellular and humoral immunity monitored.
In group A, allografts developed grade-I acute rejection by POD 2 and POD 7, and reached grade-IV by POD 17 and POD 20, respectively. By contrast, in group B, two allografts demonstrated grade-I rejection on POD 30 and grade-IV on POD 74, while the third exhibited grade-I rejection starting on POD 50, though this animal had to be euthanized on POD 58 due to Pneumocystis jirovecii infection. Time-to-event incidence of grade-I rejection was significantly lower in group A compared to group B. During the first 3 weeks post-transplant, no significant differences in anti-donor immunity were observed between the groups.
A short course of CNI, followed by combined Co-SB and mTORi significantly delays acute rejection of VRAM allografts in SLA-mismatched miniature swine.
我们评估了在小型猪模型中，使用联合共刺激阻断（Co-SB）和雷帕霉素机制靶点（mTORi）抑制，以及是否存在钙调神经磷酸酶抑制（CNI）的情况下，垂直腹直肌肌皮瓣（VRAM）同种异体移植的结果。
VRAM 同种异体移植在 SLA 错配的 MGH 小型猪之间进行。A 组（n=2）从-1 天开始连续使用 mTOR 抑制剂雷帕霉素，并在术后第 0 天（POD）开始使用共刺激阻断剂 CTLA4-Ig。B 组（n=3）从 POD 0 开始每天给予他克莫司，持续 13 天，然后从 POD 7 开始每天给予雷帕霉素，并从 POD 7-28 开始每周给予 CTLA4-Ig。排斥反应通过 Banff 标准确定，并监测宿主细胞和体液免疫。
在 A 组中，所有移植物在 POD 2 和 POD 7 时出现 I 级急性排斥反应，在 POD 17 和 POD 20 时分别达到 IV 级。相比之下，在 B 组中，两个移植物在 POD 30 时表现出 I 级排斥反应，在 POD 74 时表现出 IV 级排斥反应，而第三个移植物在 POD 50 时开始表现出 I 级排斥反应，但该动物因卡氏肺孢子虫感染而在 POD 58 时被安乐死。A 组中 I 级排斥反应的时间事件发生率明显低于 B 组。在移植后前 3 周，两组之间没有观察到抗供体免疫的显著差异。
CNI 的短期疗程，随后联合 Co-SB 和 mTORi 可显著延迟 SLA 错配小型猪 VRAM 同种异体移植物的急性排斥反应。
