Department of Surgery, University of Maryland School of Medicine, Baltimore, USA.
Am J Transplant. 2011 Aug;11(8):1599-609. doi: 10.1111/j.1600-6143.2011.03624.x. Epub 2011 Jul 12.
Selective blockade of CD28 is a promising therapy to inhibit pathogenic alloimmunity. However, evaluation of this approach in transplantation has been very limited. Using a novel nonactivating single-chain Fv-based reagent (α28scFv), we have investigated the role of CD28 and cytotoxic T lymphocyte antigen 4 (CTLA-4) in a murine cardiac transplant model. Blockade of CD28 for 2 weeks after engraftment promoted allograft survival, and significantly attenuated chronic rejection when combined with transient CD154-blockade or calcineurin inhibition. Graft acceptance was associated with decreased alloantibody production, increased proportion of early graft infiltration by regulatory T cells and increased expression of regulatory dendritic cell genes. Blockade of CTLA-4 during α28scFv-based treatments led to prompt rejection in all animals and inhibited expression of forkhead box P3 (Foxp3), programmed death (PD)-1 and 2,3-indoleamine dioxygenase (IDO) in the graft. These results show that CD28 signaling during the first weeks after transplant is a pivotal mediator of pathogenic alloimmunity, and that selective CD28 blockade prolongs graft acceptance by at least two immunomodulatory mechanisms. Selective CD28 inhibition while sparing CTLA-4 is thus a promising approach to inhibit pathogenic alloimmunity.
选择性阻断 CD28 是抑制致病性同种异体免疫的一种有前途的治疗方法。然而，这种方法在移植中的评估非常有限。我们使用一种新型的非激活单链 Fv 基试剂 (α28scFv)，研究了 CD28 和细胞毒性 T 淋巴细胞抗原 4 (CTLA-4) 在小鼠心脏移植模型中的作用。移植后 2 周阻断 CD28 可促进移植物存活，并与短暂的 CD154 阻断或钙调神经磷酸酶抑制联合使用时，可显著减轻慢性排斥反应。移植物接受与同种异体抗体产生减少、调节性 T 细胞早期浸润移植物的比例增加以及调节性树突状细胞基因表达增加有关。在基于 α28scFv 的治疗中阻断 CTLA-4 会导致所有动物的迅速排斥，并抑制移植物中叉头框 P3 (Foxp3)、程序性死亡 (PD)-1 和 2、吲哚胺 2,3-双加氧酶 (IDO)的表达。这些结果表明，移植后第一周内的 CD28 信号是致病性同种异体免疫的关键介质，选择性 CD28 阻断通过至少两种免疫调节机制延长移植物接受。因此，选择性 CD28 抑制而不抑制 CTLA-4 是抑制致病性同种异体免疫的一种有前途的方法。
