Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, 30625 Hannover, Germany.
Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany.
Sci Transl Med. 2024 Jul 17;16(756):eadi9548. doi: 10.1126/scitranslmed.adi9548.
Immune rejection remains the major obstacle to long-term survival of allogeneic lung transplants. The expression of major histocompatibility complex molecules and minor histocompatibility antigens triggers allogeneic immune responses that can lead to allograft rejection. Transplant outcomes therefore depend on long-term immunosuppression, which is associated with severe side effects. To address this problem, we investigated the effect of genetically engineered transplants with permanently down-regulated swine leukocyte antigen (SLA) expression to prevent rejection in a porcine allogeneic lung transplantation (LTx) model. Minipig donor lungs with unmodified SLA expression (control group, = 7) or with modified SLA expression (treatment group, = 7) were used to evaluate the effects of SLA knockdown on allograft survival and on the nature and strength of immune responses after terminating an initial 4-week period of immunosuppression after LTx. Genetic engineering to down-regulate SLA expression was achieved during ex vivo lung perfusion by lentiviral transduction of short hairpin RNAs targeting mRNAs encoding β2-microglobulin and class II transactivator. Whereas all grafts in the control group were rejected within 3 months, five of seven animals in the treatment group maintained graft survival without immunosuppression during the 2-year monitoring period. Compared with controls, SLA-silenced lung recipients had lower donor-specific antibodies and proinflammatory cytokine concentrations in the serum. Together, these data demonstrate a survival benefit of SLA-down-regulated lung transplants in the absence of immunosuppression.
免疫排斥仍然是同种异体肺移植长期存活的主要障碍。主要组织相容性复合体分子和次要组织相容性抗原的表达引发同种异体免疫反应，导致移植物排斥。因此，移植结果取决于长期免疫抑制，而长期免疫抑制与严重的副作用有关。为了解决这个问题，我们研究了通过基因工程使猪白细胞抗原（SLA）表达永久下调的移植对预防猪同种异体肺移植（LTx）模型排斥反应的影响。使用未经修饰 SLA 表达的小型猪供体肺（对照组，n=7）或修饰 SLA 表达的小型猪供体肺（实验组，n=7）来评估 SLA 敲低对移植物存活的影响，以及在 LTx 后结束最初 4 周免疫抑制期后，对免疫反应的性质和强度的影响。通过慢病毒转导针对编码β2-微球蛋白和 II 类转录激活物的 mRNA 的短发夹 RNA，在体外肺灌注过程中实现了 SLA 表达的基因下调。虽然对照组的所有移植物在 3 个月内被排斥，但实验组的 7 只动物中有 5 只在 2 年的监测期间在没有免疫抑制的情况下维持移植物存活。与对照组相比，沉默 SLA 的肺受者的血清中具有较低的供体特异性抗体和促炎细胞因子浓度。这些数据表明，SLA 下调的肺移植在没有免疫抑制的情况下具有生存优势。
