PDF(Pubmed)
Abstract：
The presence of donor-specific antibodies (DSA) are associated with graft failure either following human leukocyte antigen (HLA)-mismatched allogeneic stem cell transplantation or after organ transplantation. Although targeting B cells and plasma cells have been used for desensitization, there have been reports of failure. T-follicular helper (Tfh) cells assist B cells in differentiating into antibody-secreting plasma cells. We used haploidentical allograft as a platform to investigate the possibility of targeting Tfh cells to desensitize DSA. The quantities of circulating Tfh (cTfh) cell subsets in allograft candidates were abnormal, and these cells, including the cTfh2 and cTfhem cell subsets, were positively related to the production of anti-HLA antibodies. Ex vivo experiments showed that the cTfh cells of anti-HLA antibody-positive allograft candidates could induce B cells to differentiate into DSA-producing plasmablasts. The immune synapse could be involved in the assistance of cTfh cells to B cells in antibody production. In vitro experiments and in vivo clinical pilot studies indicated that targeting cTfh cells with sirolimus can inhibit their auxiliary function in assisting B cells. Ex vivo and in vivo studies demonstrated the effect of sirolimus and rituximab on DSA desensitization compared with either sirolimus or rituximab alone (60%, 43.75%, and 30%, respectively). Our findings provide new insight into the role of Tfh cells in the pathogenesis of DSA production in HLA-mismatched transplant candidates. Our data also indicate that targeting Tfh cells is a novel strategy for DSA desensitization and combination of sirolimus and rituximab might be a potential therapy. The prospective cohort of this study is registered at http://www.chictr.org.cn as #ChiCTR-OPC-15006672.
摘要：
供体特异性抗体（DSA）的存在与HLA错配的同种异体干细胞移植后或器官移植后的移植物衰竭有关。尽管靶向B细胞和浆细胞已用于脱敏，有失败的报道。T滤泡辅助细胞(Tfh)帮助B细胞分化成分泌抗体的浆细胞。我们使用单倍体同种异体移植物作为平台来研究靶向Tfh细胞对DSA脱敏的可能性。同种异体移植候选者中cTfh细胞亚群的数量异常，这些细胞，包括cTfh2和cTfhem细胞亚群，与抗HLA抗体的产生呈正相关。离体实验表明，抗HLA抗体阳性同种异体移植候选物的cTfh细胞可以诱导B细胞分化为产生DSA的成浆细胞。免疫突触可能参与cTfh细胞对B细胞产生抗体的辅助。体外实验和体内临床初步研究表明，西罗莫司靶向cTfh细胞可以抑制其辅助B细胞的辅助功能。离体和体内研究表明，与单独使用西罗莫司或利妥昔单抗相比，西罗莫司和利妥昔单抗对DSA脱敏的影响（60％，43.75%,30%,分别)。我们的发现为Tfh细胞在HLA不匹配的移植候选者中DSA产生的发病机理中的作用提供了新的见解。我们的数据还表明，靶向Tfh细胞是DSA脱敏的新策略，西罗莫司和利妥昔单抗的组合可能是一种潜在的治疗方法。
