Shockcor Nicole, Buckingham Evan B, Hassanein Wessam, Dhru Urmil, Khalifeh Ali, Uluer Mehmet, Woodall Jhade, Brazio Philip, Drachenberg Cynthia, Nam Arthur J, Barth Rolf N
University of Maryland School of Medicine, Baltimore, MD.
Department of Surgery, University of Chicago, Chicago, IL.
Transplant Direct. 2021 Jan 26;7(2):e659. doi: 10.1097/TXD.0000000000001107. eCollection 2021 Feb.
Vascularized composite allografts (VCA) have demonstrated good clinical outcomes dependent on chronic immunosuppression. Previous work by our group and others supports that cotransplanted vascularized bone marrow (VBM) as a component of VCA offers immunologic protection to prolong graft survival. We aimed to characterize the requirements and potential mechanisms of VBM-mediated protection of VCA by modifying grafts through various strategies.
Experimental groups of mismatched cynomolgus macaque recipients received VCA transplants modified by the following approaches: heterotopic separation of the VCA and VBM components; T-cell depletion of either donor or recipient; irradiation of donor VCA; and infusion of donor bone marrow. All groups received standard immunosuppression with tacrolimus and mycophenolate mofetil.
Experimental modifications to donor, recipient, or graft all demonstrated short-graft survivals (31 d). Chimerism levels without bone marrow infusion were transient and minimal when detected and were not associated with prolonged survival. Donor bone marrow infusion increased levels of chimerism but resulted in alloantibody production and did not improve graft survival.
VCA graft survival is significantly reduced compared with previously reported VCA with VBM transplants (348 d; = 0.01) when the hematopoietic niche is removed, altered, or destroyed via irradiation, depletion, or topographical rearrangement. These experimental manipulations resulted in similar outcomes to VCA grafts without cotransplanted VBM (25 d). These data support the presence of a radiosensitive, T-cell population within the VBM compartment not reconstituted by reinfusion of bone marrow cells.
血管化复合异体移植（VCA）已显示出依赖慢性免疫抑制的良好临床效果。我们团队及其他研究人员之前的工作支持，作为VCA组成部分的共移植血管化骨髓（VBM）可提供免疫保护以延长移植物存活时间。我们旨在通过各种策略对移植物进行改造，以明确VBM介导的VCA保护的要求和潜在机制。
不匹配的食蟹猴受体实验组接受通过以下方法改造的VCA移植：VCA和VBM成分的异位分离；供体或受体的T细胞清除；供体VCA的照射；以及供体骨髓输注。所有组均接受他克莫司和霉酚酸酯的标准免疫抑制治疗。
对供体、受体或移植物的实验性改造均显示移植物存活时间较短（31天）。未进行骨髓输注时，嵌合水平短暂且检测到的水平极低，且与存活时间延长无关。供体骨髓输注增加了嵌合水平，但导致同种抗体产生，并未改善移植物存活。
当通过照射、清除或拓扑重排去除、改变或破坏造血微环境时，与先前报道的VBM移植的VCA相比，VCA移植物存活时间显著缩短（348天；P = 0.01）。这些实验操作导致的结果与未共移植VBM的VCA移植物（25天）相似。这些数据支持VBM隔室内存在对辐射敏感的T细胞群体，骨髓细胞再输注无法对其进行重建。
