Soleimani Behzad, Wieczorek Grazyna, Katopodis Andreas, Zenke Gerhard, George Andrew J T, Hornick Philip I, Weitz-Schmidt Gabriele
Department of Cardiac Surgery, National Heart and Lung Institute, London, UK.
J Heart Lung Transplant. 2007 Jul;26(7):724-31. doi: 10.1016/j.healun.2007.04.007.
Cardiac allograft vasculopathy (CAV) is the pre-eminent cause of late cardiac allograft failure. It is characterized by a concentric intimal hyperplasia, which we designate transplant intimal hyperplasia (TIH). To date, blockade of the adhesion molecule lymphocyte function-associated antigen-1 (LFA-1) has been shown to be effective in preventing TIH in experimental models of transplantation, but only when combined with other immunosuppressants. In this study we explored the impact of monotherapy against LFA-1 in a carotid artery allograft model of TIH.
B10A(2R) (H-2(h2)) mice were used as donors and C57BL/6 (H-2(b)) mice used as recipients. The recipients were treated with a monoclonal antibody against LFA-1alpha (M17/4) or isotype-matched control immunoglobulin. Grafts were harvested after 35 days and analyzed by histomorphometry and immunohistochemistry. Blood samples were taken and analyzed by differential cell count and alloantibody levels.
We found that treatment with M17/4 resulted in a significant reduction in TIH compared with controls. Immunostaining revealed that LFA-1alpha blockade inhibited CD45+ leukocyte infiltration, prevented intimal smooth muscle cell (SMC) proliferation, and preserved the medial SMC population. Finally, we demonstrated a reduction in the serum alloantibody titer in the group treated with anti-LFA-1alpha when compared with controls.
We have demonstrated for the first time that LFA-1alpha blockade on its own can prevent development of TIH in an experimental model. The concept of modulating LFA-1alpha-mediated leukocyte migration and T-cell activation may therefore be of relevance to clinical cardiac transplantation and, as such, represents a potential target for therapeutic intervention against clinical CAV.
心脏移植血管病变（CAV）是心脏移植晚期失败的首要原因。其特征为同心性内膜增生，我们将其称为移植内膜增生（TIH）。迄今为止，在移植实验模型中，已证明阻断黏附分子淋巴细胞功能相关抗原-1（LFA-1）可有效预防TIH，但仅在与其他免疫抑制剂联合使用时有效。在本研究中，我们探讨了在TIH的颈动脉移植模型中单独使用抗LFA-1疗法的影响。
使用B10A(2R)（H-2(h2)）小鼠作为供体，C57BL/6（H-2(b)）小鼠作为受体。受体用抗LFA-1α单克隆抗体（M17/4）或同型对照免疫球蛋白治疗。35天后采集移植物，通过组织形态计量学和免疫组织化学进行分析。采集血样并通过细胞分类计数和同种异体抗体水平进行分析。
我们发现，与对照组相比，用M17/4治疗可使TIH显著减少。免疫染色显示，LFA-1α阻断可抑制CD45+白细胞浸润，防止内膜平滑肌细胞（SMC）增殖，并保留中层SMC群体。最后，我们证明与对照组相比，抗LFA-1α治疗组的血清同种异体抗体滴度降低。
我们首次证明，单独阻断LFA-1α可在实验模型中预防TIH的发生。因此，调节LFA-1α介导的白细胞迁移和T细胞活化的概念可能与临床心脏移植相关，并且代表了针对临床CAV进行治疗干预的潜在靶点。
