Veterans Affairs Palo Alto Health Care System/Stanford University School of Medicine, CA 94304, USA.
Circ Res. 2011 Nov 11;109(11):1290-301. doi: 10.1161/CIRCRESAHA.111.250167. Epub 2011 Oct 13.
While microvascular injury is associated with chronic rejection, the cause of tissue ischemia during alloimmune injury is not yet elucidated.
We investigated the contribution of T lymphocytes and complement to microvascular injury-associated ischemia during acute rejection of mouse tracheal transplants.
Using novel techniques to assess microvascular integrity and function, we evaluated how lymphocyte subsets and complement specifically affect microvascular perfusion and tissue oxygenation in MHC-mismatched transplants. To characterize T cell effects on microvessel loss and recovery, we transplanted functional airway grafts in the presence and absence of CD4(+) and CD8(+) T cells. To establish the contribution of complement-mediated injury to the allograft microcirculation, we transplanted C3-deficient and C3-inhibited recipients. We demonstrated that CD4(+) T cells and complement are independently sufficient to cause graft ischemia. CD8(+) T cells were required for airway neovascularization to occur following CD4-mediated rejection. Activation of antibody-dependent complement pathways mediated tissue ischemia even in the absence of cellular rejection. Complement inhibition by CR2-Crry attenuated graft hypoxia, complement/antibody deposition on vascular endothelium and promoted vascular perfusion by enhanced angiogenesis. Finally, there was a clear relationship between the burden of tissue hypoxia (ischemia×time duration) and the development of subsequent airway remodeling.
These studies demonstrated that CD4(+) T cells and complement operate independently to cause transplant ischemia during acute rejection and that sustained ischemia is a precursor to chronic rejection.
微血管损伤与慢性排斥反应有关，但同种免疫损伤导致组织缺血的原因尚不清楚。
我们研究了 T 淋巴细胞和补体在同种异体气管移植急性排斥反应中引起微血管损伤相关缺血的作用。
我们使用评估微血管完整性和功能的新技术，评估了淋巴细胞亚群和补体如何特异性影响 MHC 错配移植中的微血管灌注和组织氧合。为了研究 T 细胞对微血管丢失和恢复的影响，我们在存在和不存在 CD4+和 CD8+T 细胞的情况下移植了功能性气道移植物。为了确定补体介导的损伤对同种异体微循环的贡献，我们移植了 C3 缺陷和 C3 抑制的受者。我们证明 CD4+T 细胞和补体独立足以引起移植物缺血。CD8+T 细胞是 CD4 介导的排斥反应后气道新生血管发生所必需的。即使在没有细胞排斥的情况下，抗体依赖性补体途径的激活也介导组织缺血。CR2-Crry 抑制补体减轻了移植物缺氧、补体/抗体在血管内皮上的沉积，并通过促进血管生成促进了血管灌注。最后，组织缺氧的负担（缺血×时间持续时间）与随后的气道重塑的发展之间存在明显的关系。
这些研究表明，CD4+T 细胞和补体在急性排斥反应中独立作用引起移植缺血，持续缺血是慢性排斥反应的前兆。
