Department of Applied Immunology, Nagoya University School of Medicine, Nagoya, Japan.
Transplantation. 2012 Feb 27;93(4):390-7. doi: 10.1097/TP.0b013e3182424df3.
Recent development of immunosuppressive therapy has provided a platform for clinical human leukocyte antigen (HLA)- and ABO-incompatible kidney transplantation. However, the prognosis seems to be different between the two. Accommodation, the condition of no injury even in the presence of antidonor antibody, is one of the key factors for successful transplantation with antidonor antibody. The purpose of this study was to compare signal transduction between anti-A/B and anti-HLA antibody reaction and to elucidate the mechanisms underlying accommodation.
Blood type A- or B-transferase gene was transfected into human EA.hy926 endothelial cells. After cell sorting, A- or B-expressing cells at high levels were obtained. The effects of anti-HLA and anti-A/B antibody binding on complement-mediated cytotoxicity and signal transduction were examined.
Preincubation with anti-HLA antibodies only at low levels (<10% of saturation level) or anti-A/B antibodies at high levels (even at near saturation levels) for 24 hr resulted in resistance to complement-mediated cytotoxicity. Anti-A/B antibody ligation inactivated ERK1/2 pathway and increased complement regulatory proteins such as CD55 and CD59, whereas anti-HLA ligation activated PI3K/AKT pathway and increased cytoprotective genes such as hemeoxygenase-1 and ferritin H.
Complement inhibition by upregulation of CD55 and CD59 through ERK1/2 inactivation might play a substantial role in accommodation after ABO-incompatible transplantation, which could also explain the intriguing finding of C4d deposition in the graft without rejection.
最近免疫抑制疗法的发展为临床人类白细胞抗原（HLA）和 ABO 不相容的肾移植提供了平台。然而，这两种情况的预后似乎有所不同。容纳，即使存在抗供体抗体也没有损伤的情况，是成功进行具有抗供体抗体移植的关键因素之一。本研究的目的是比较抗-A/B 和抗-HLA 抗体反应之间的信号转导，并阐明容纳的机制。
将血型 A 或 B-转移酶基因转染到人 EA.hy926 内皮细胞中。经过细胞分选，获得高表达 A 或 B 的细胞。检查了抗-HLA 和抗-A/B 抗体结合对补体介导的细胞毒性和信号转导的影响。
在 24 小时内预孵育低水平（<10%饱和水平）的抗-HLA 抗体或高水平（甚至接近饱和水平）的抗-A/B 抗体仅导致对补体介导的细胞毒性的抗性。抗-A/B 抗体结合使 ERK1/2 通路失活，并增加了补体调节蛋白，如 CD55 和 CD59，而抗-HLA 结合激活了 PI3K/AKT 通路，并增加了细胞保护基因，如血红素加氧酶-1 和铁蛋白 H。
通过 ERK1/2 失活上调 CD55 和 CD59 抑制补体可能在 ABO 不相容移植后容纳中起重要作用，这也可以解释在没有排斥的情况下在移植物中沉积 C4d 的令人费解的发现。
