Emory Transplant Center, Atlanta, GA.
Am J Transplant. 2018 Jan;18(1):89-101. doi: 10.1111/ajt.14400. Epub 2017 Aug 14.
Donor-specific antibodies (DSAs) are a barrier to improved long-term outcomes after kidney transplantation. Costimulation blockade with CTLA4-Ig has shown promise as a potential therapeutic strategy to control DSAs. T follicular helper (Tfh) cells, a subset of CD4 T cells required for optimal antibody production, are reliant on the CD28 costimulatory pathway. We have previously shown that selective CD28 blockade leads to superior allograft survival through improved control of CD8 T cells relative to CTLA4-Ig, but the impact of CD28-specific blockade on CD4 Tfh cells is unknown. Thus, we identified and characterized donor-reactive Tfh cells in a murine skin transplant model and then used this model to evaluate the impact of selective CD28 blockade with an anti-CD28 domain antibody (dAb) on the donor-specific Tfh cell-mediated immune response. We observed that the anti-CD28 dAb led to superior inhibition of donor-reactive CXCR5 PD-1 Tfh cells, CD95 GL7 germinal center B cells and DSA formation compared with CTLA4-Ig. Interestingly, donor-reactive Tfh cells differentially upregulated CTLA4 expression, suggesting an important role for CTLA4 in mediating the superior inhibition observed with the anti-CD28 dAb. Therefore, selective CD28 blockade as a novel approach to control Tfh cell responses and prevent DSA after kidney transplantation warrants further study.
供体特异性抗体（DSA）是肾移植后改善长期预后的障碍。CTLA4-Ig 的共刺激阻断已显示出作为控制 DSA 的潜在治疗策略的前景。滤泡辅助性 T 细胞（Tfh）是产生最佳抗体所需的 CD4 T 细胞的一个亚群，依赖于 CD28 共刺激途径。我们之前已经表明，与 CTLA4-Ig 相比，选择性 CD28 阻断通过改善 CD8 T 细胞的控制，导致更好的同种异体移植物存活，但 CD28 特异性阻断对 CD4 Tfh 细胞的影响尚不清楚。因此，我们在小鼠皮肤移植模型中鉴定并表征了供体反应性 Tfh 细胞，然后使用该模型评估了用抗 CD28 结构域抗体（dAb）进行选择性 CD28 阻断对供体特异性 Tfh 细胞介导的免疫反应的影响。我们观察到，与 CTLA4-Ig 相比，抗 CD28 dAb 导致对供体反应性 CXCR5 PD-1 Tfh 细胞、CD95 GL7 生发中心 B 细胞和 DSA 形成的抑制作用更好。有趣的是，供体反应性 Tfh 细胞差异地上调 CTLA4 的表达，这表明 CTLA4 在介导抗 CD28 dAb 观察到的更好抑制中起重要作用。因此，作为一种控制 Tfh 细胞反应和预防肾移植后 DSA 的新方法，选择性 CD28 阻断值得进一步研究。
