Pierson R N, Pino-Chavez G, Young V K, Kaspar-Konig W, White D J, Wallwork J
Imutran Ltd., Thoracic Transplant Service, Papworth Hospital, Cambridge, United Kingdom.
J Heart Lung Transplant. 1997 Feb;16(2):231-9.
Hyperacute rejection currently prevents clinical application of discordant lung xenografts. Pigs transgenic for human regulators of complement activation offer one promising potential solution to this problem.
Using fresh human blood in an ex vivo lung perfusion model, we studied eight different strains of pigs transgenic for human decay accelerating factor. Survival (by blood flow and gas transfer criteria) were correlated with immunohistologic evidence of pulmonary human decay accelerating factor expression and complement activation.
With human blood perfusion, blood flow through the unmodified pig lung rapidly falls and is not restored by continuous infusion or high-dose bolus of prostacyclin. Airway pressure also rises rapidly and is followed promptly by loss of gas transfer. Four of the transgenic pig strains showed no difference from this pattern. Immunohistochemistry for human decay accelerating factor revealed low or no pulmonary expression in these lungs. In contrast, two of five transgenic pig lungs that had significant decay accelerating factor expression demonstrated recovery of pulmonary blood flow within 1 hour, and rejection was delayed, from less than 20 minutes in controls to about 1 hour. Complement activation, particularly the alternative pathway, was inhibited in lungs with high levels of endothelial decay accelerating factor expression.
Lungs from some strains of pig transgenic for human decay accelerating factor demonstrate incomplete physiologic and histologic protection from hyperacute rejection. Although complement-independent pathogenic mechanisms may present a formidable obstacle, pig lungs transgenic for human complement regulatory proteins may facilitate discordant lung transplantation in human beings.
超急性排斥反应目前阻碍了不匹配肺异种移植的临床应用。转人类补体激活调节因子基因的猪为解决这一问题提供了一种有前景的潜在方案。
在体外肺灌注模型中使用新鲜人血，我们研究了八种转人类衰变加速因子基因的猪品系。（根据血流和气体交换标准）存活情况与肺组织中人衰变加速因子表达及补体激活的免疫组织学证据相关。
用人血灌注时，未经修饰的猪肺血流迅速下降，持续输注或大剂量推注前列环素均无法恢复。气道压力也迅速升高，随后气体交换立即丧失。四种转基因猪品系的情况与这种模式无差异。对人衰变加速因子进行免疫组织化学检测发现，这些肺组织中的人衰变加速因子表达低或无表达。相比之下，五只有显著衰变加速因子表达的转基因猪肺中有两只在1小时内肺血流恢复，排斥反应延迟，从对照组的不到20分钟延长至约1小时。在具有高水平内皮衰变加速因子表达的肺中，补体激活，尤其是替代途径，受到抑制。
一些转人类衰变加速因子基因的猪品系的肺对超急性排斥反应的生理和组织学保护不完整。尽管不依赖补体的致病机制可能是一个巨大障碍，但转人类补体调节蛋白基因的猪肺可能有助于人类进行不匹配肺移植。
