Selective Targeting of High-Affinity LFA-1 Does Not Augment Costimulation Blockade in a Nonhuman Primate Renal Transplantation Model.
Selective Targeting of High-Affinity LFA-1 Does Not Augment Costimulation Blockade in a Nonhuman Primate Renal Transplantation Model.
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DOI：
10.1111/ajt.14141
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发表时间：
2017-05
期刊：
影响因子：
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通讯作者：
Kirk AD
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文献类型：
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作者：
Samy KP;Anderson DJ;Lo DJ;Mulvihill MS;Song M;Farris AB;Parker BS;MacDonald AL;Lu C;Springer TA;Kachlany SC;Reimann KA;How T;Leopardi FV;Franke KS;Williams KD;Collins BH;Kirk AD
与基于钙调磷酸酶抑制剂（CNI）的免疫抑制相比，通过belatacept进行共刺激阻断（CoB）是一种发病率较低的选择。然而，它有较高的早期急性排斥率。这些早期排斥反应部分是由记忆T细胞介导的，记忆T细胞减少了对belatacept靶向途径的依赖，并增加了粘附分子的表达。其中一个分子是白细胞功能相关抗原(LFA)-1。LFA-1以两种形式存在，一种是通常表达的低亲和力形式，另一种是仅在激活期间表达的瞬时高亲和力形式。我们已经证明，与LFA-1反应的抗体，无论其结构如何，都能有效地消除记忆T细胞，但代价是损害保护性免疫。在这里，我们测试了两种新型药物，Leukotoxin A和AL-579，它们都靶向LFA-1的高亲和力形式，以确定这种更精确的靶向是否可以防止耐药排斥反应。尽管有体外和体内配体特异性活性的证据，但两种药物与belatacept联合使用时都没有优于belatacept单药治疗。白毒素A在产生疗效之前接近毒性上限，而AL-579未能显著改变外周免疫反应。这些数据和先前的研究表明，LFA-1阻断剂可能不是CoB耐药排斥反应的合适佐剂。
Costimulation blockade (CoB) via belatacept is a lower morbidity alternative to calcineurin inhibitor (CNI)-based immunosuppression. However, it has higher rates of early acute rejection. These early rejections are mediated in part by memory T cells, which have reduced dependence on the pathway targeted by belatacept, and increased adhesion molecule expression. One such molecule is Leukocyte Function Associated Antigen (LFA)-1. LFA-1 exists in two forms, a commonly expressed, low-affinity form, and a transient, high-affinity form, expressed only during activation. We have shown that antibodies reactive with LFA-1 irrespective of its configuration are effective in eliminating memory T cells, but at the cost of impaired protective immunity. Here we test two novel agents, Leukotoxin A and AL-579, each of which targets the high affinity form of LFA-1, to determine whether this more precise targeting prevents belatacept-resistant rejection. Despite evidence of ex vivo and in vivo ligand-specific activity, neither agent when combined with belatacept proved superior to belatacept monotherapy. Leukotoxin A approached a ceiling of toxicity prior to efficacy, while AL-579 failed to significantly alter the peripheral immune response. These data, and prior studies, suggest that LFA-1 blockade may not be a suitable adjuvant agent for CoB resistant rejection.