Emory Transplant Center, Emory University, Atlanta, GA, USA.
Am J Transplant. 2011 Jan;11(1):22-33. doi: 10.1111/j.1600-6143.2010.03317.x. Epub 2010 Nov 10.
Costimulation blockade (CoB), specifically CD28/B7 inhibition with belatacept, is an emerging clinical replacement for calcineurin inhibitor-based immunosuppression in allotransplantation. However, there is accumulating evidence that belatacept incompletely controls alloreactive T cells that lose CD28 expression during terminal differentiation. We have recently shown that the CD2-specific fusion protein alefacept controls costimulation blockade-resistant allograft rejection in nonhuman primates. Here, we have investigated the relationship between human alloreactive T cells, costimulation blockade sensitivity and CD2 expression to determine whether these findings warrant potential clinical translation. Using polychromatic flow cytometry, we found that CD8(+) effector memory T cells are distinctly high CD2 and low CD28 expressors. Alloresponsive CD8(+) CD2(hi) CD28(-) T cells contained the highest proportion of cells with polyfunctional cytokine (IFNγ, TNF and IL-2) and cytotoxic effector molecule (CD107a and granzyme B) expression capability. Treatment with belatacept in vitro incompletely attenuated allospecific proliferation, but alefacept inhibited belatacept-resistant proliferation. These results suggest that highly alloreactive effector T cells exert their late stage functions without reliance on ongoing CD28/B7 costimulation. Their high CD2 expression increases their susceptibility to alefacept. These studies combined with in vivo nonhuman primate data provide a rationale for translation of an immunosuppression regimen pairing alefacept and belatacept to human renal transplantation.
共刺激阻断（CoB），特别是使用贝利尤单抗抑制 CD28/B7，是同种异体移植中替代钙调神经磷酸酶抑制剂为基础的免疫抑制的新兴临床方法。然而，越来越多的证据表明，贝利尤单抗不能完全控制在终末分化过程中丧失 CD28 表达的同种反应性 T 细胞。我们最近表明，CD2 特异性融合蛋白阿利珠单抗控制了非人灵长类动物中对共刺激阻断耐药的同种异体移植物排斥反应。在这里，我们研究了人同种反应性 T 细胞、共刺激阻断敏感性和 CD2 表达之间的关系，以确定这些发现是否需要潜在的临床转化。使用多色流式细胞术，我们发现 CD8(+)效应记忆 T 细胞明显高表达 CD2 和低表达 CD28。同种反应性 CD8(+) CD2(hi) CD28(-) T 细胞含有具有多功能细胞因子（IFNγ、TNF 和 IL-2）和细胞毒性效应分子（CD107a 和 granzyme B）表达能力的细胞比例最高。体外用贝利尤单抗治疗不能完全减弱同种特异性增殖，但阿利珠单抗抑制了贝利尤单抗耐药的增殖。这些结果表明，高度同种反应性效应 T 细胞在不依赖持续 CD28/B7 共刺激的情况下发挥其晚期功能。它们高表达的 CD2 增加了对阿利珠单抗的敏感性。这些研究与体内非人类灵长类动物数据相结合，为将阿利珠单抗和贝利尤单抗联合应用于人类肾移植的免疫抑制方案提供了依据。
