Mastroianni Melissa, Ng Zhi Yang, Goyal Ritu, Mallard Christopher, Farkash Evan A, Leonard David A, Albritton Alexander, Shanmugarajah Kumaran, Kurtz Josef M, Sachs David H, Macri Lauren K, Kohn Joachim, Cetrulo Curtis L
Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Division of Plastic and Reconstructive Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
J Burn Care Res. 2018 Apr 20;39(3):363-373. doi: 10.1097/BCR.0000000000000597.
Cadaveric skin allograft is the current standard of treatment for temporary coverage of large burn wounds. Porcine xenografts are viable alternatives but undergo α-1,3-galactose (Gal)-mediated hyperacute rejection and are lost by post-operative day (POD) 3 because of naturally occurring antibodies to Gal in primate recipients. Using baboons, we previously demonstrated that xenografts from GalT-KO swine (lacking Gal) provided wound coverage comparable with allografts with systemic immunosuppression. In this study, we investigate topical immunosuppression as an alternative to prolong xenograft survival. Full-thickness wounds in baboons were created and covered with xenogeneic and allogeneic split-thickness skin grafts (STSGs). Animals were treated with slow-release (TyroSphere-encapsulated) topical formulations (cyclosporine-A [CSA] or Tacrolimus) applied 1) directly to the STSGs only, or 2) additionally to the wound bed before STSG and 1). Topical CSA did not improve either xenograft or allograft survival (median: treated grafts = 12.5 days, control = 14 days; P = 0.27) with similar results when topical Tacrolimus was used. Pretreatment of wound beds resulted in a significant reduction of xenograft survival compared with controls (10 vs 14 days; P = 0.0002), with comparable results observed in allografts. This observation was associated with marked reduction of inflammation on histology with Tacrolimus and not CSA. Prolongation of allograft and xenograft survival after application to full-thickness wound beds was not achieved with the current formulation of topical immunosuppressants. Modulation of inflammation within the wound bed was effective with Tacrolimus pretreatment before STSG application and may serve as a treatment strategy in related fields.
尸体皮肤同种异体移植是目前大面积烧伤创面临时覆盖治疗的标准方法。猪异种移植物是可行的替代方案，但会经历α-1,3-半乳糖（Gal）介导的超急性排斥反应，并且由于灵长类动物受体中天然存在针对Gal的抗体，在术后第3天就会失去作用。我们之前使用狒狒证明，来自GalT-KO猪（缺乏Gal）的异种移植物在全身免疫抑制的情况下提供的伤口覆盖效果与同种异体移植物相当。在本研究中，我们研究局部免疫抑制作为延长异种移植物存活时间的替代方法。在狒狒身上制造全层伤口，并用异种和同种异体中厚皮片（STSG）覆盖。动物接受缓释（酪氨酸包封）局部制剂（环孢素A [CSA]或他克莫司）治疗，给药方式为：1）仅直接应用于STSG；或2）在应用STSG之前额外应用于伤口床以及1）所述的STSG。局部应用CSA并没有提高异种移植物或同种异体移植物的存活率（中位数：治疗组移植物 = 12.5天，对照组 = 14天；P = 0.27），使用局部他克莫司时结果相似。与对照组相比，伤口床预处理导致异种移植物存活率显著降低（10天对14天；P = 0.0002），同种异体移植物也观察到类似结果。这一观察结果与他克莫司而非CSA导致的组织学炎症明显减轻有关。目前的局部免疫抑制剂制剂未能实现应用于全层伤口床后延长同种异体移植物和异种移植物存活时间的目的。在应用STSG之前用他克莫司预处理对伤口床内炎症的调节是有效的，并且可能作为相关领域的一种治疗策略。
