肾移植后需要长期使用免疫抑制剂避免移植物排斥反应的发生。两类常用的免疫抑制剂他克莫司（FK506）以及雷帕霉素（RAPA）的作用靶点不同，我们课题组的前期研究发现使用FK506的肾移植受者存在Th17/Tregs细胞的失衡。近期研究发现TFH在参与B细胞的分化以及抗体相关的慢性移植物失功（CAD）中起到了重要作用。本课题主要从体液免疫的角度研究不同免疫抑制剂FK506以及RAPA对Tregs/TFH细胞的调节机制。推测FK506通过IL-2/STAT5/Blimp-1途径抑制Tregs，促进TFH，辅助B细胞产生抗体，与体内失衡的细胞免疫一起引发CAD；推测RAPA通过抑制ICOS-PI3K/Akt/mTOR通路，促进Tregs的增殖，抑制TFH的分化，有效的防止CAD的发生。本课题从细胞及体液免疫两个方面阐述不同免疫抑制剂作用下移植受者体内免疫状态的差异以及移植后CAD发病的机制。

Renal recipients need long-term immunosuppressant to prevent from allograft rejection. Tacrolimus (FK506) and rapamycin (RAPA)are two common immunosuppressant, each of which has different targets. Our group previously found that the imbalance of Th17/Tregs existed in renal recipients taking FK506 and in such patients, the occurrence rate of CAD is much higher. Recent studies found that follicular T helper cell (TFH) played pivotal role in B cell differentiation and antibody related CAD. Our current project aims to explore the mechanisms of FK506 and Rapamycin regulating Tregs/TFH balance from the perspective of humoral immunity. We postulate that FK506 suppresses Tregs through IL-2/STAT5/Blimp-1 signaling pathway and promotes skewed Tfh differentiation. The Tfh cell would help B cell produce donor-specific antibody and incur the onset of CAD in renal recipients, which is detrimental to the development and maintenance of immune tolerance. Additionally, we speculate that RAPA promotes the proliferation of Tregs through suppressing ICOS-PI3K/Akt/mTOR, and inhibits the differentiation of Tfh, rendering the balance skewing toward Tregs secretion. Accordingly, immune tolerance can be well induced and CAD can be effectively prevented. Therefore, current project aims to clarify the difference of immune tolerance between the two immunosuppressants and the pathogenesis of CAD after transplantation, from both cellular and humoral immunity perspectives.