CD4-dependent generation of dominant transplantation tolerance induced by simultaneous perturbation of CD154 and LFA-1 pathways
CD4-dependent generation of dominant transplantation tolerance induced by simultaneous perturbation of CD154 and LFA-1 pathways
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DOI：
10.4049/jimmunol.169.9.4831
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发表时间：
2002-11-01
影响因子：
4.4
通讯作者：
Gill, RG
中科院分区：
文献类型：
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作者：
Nicolls, MR;Coulombe, M;Gill, RG
CD 154和LFA-1（CD 11 a）代表了受体/配体相互作用（分别为共刺激和粘附/归巢）的概念上不同的途径，这些途径已被有效靶向诱导长期同种异体移植物接受和耐受。在目前的研究中，我们确定了这些途径特异性mAb诱导的耐受性的相对功效和性质。体外分析表明，同时靶向CD 154和LFA-1导致对同种异体反应性的显著抑制，表明联合抗CD 154/抗LFA-1治疗在体内可能非常有效。因此，我们评估了联合靶向CD 154和LFA-1的mAb疗法用于诱导对胰岛同种异体移植物的移植耐受。抗CD 154或抗LFA-1单药治疗对诱导长期同种异体移植物存活部分有效，而联合治疗导致高反应C57 BL/6受者的同种异体移植物接受一致。这种联合治疗不消耗淋巴细胞，也不需要长期删除供者反应性T淋巴细胞来维持同种异体移植物存活。重要的是，联合抗CD 154/抗LFA治疗独特地导致“显性”移植耐受。因此，CD 154和LFA-1分子的同时扰动可导致通过单独单一疗法方法无法实现的深刻耐受诱导。此外，结果表明，这种调节耐受性可以与强抗供体反应性的存在共存，表明主动耐受性不需要供体反应性T细胞的相应缺失。有趣的是，尽管这种调节状态的诱导是高度依赖于CD 4的，但体内耐受性的过继转移较少依赖于CD 4。
CD154 and LFA-1 (CD11a) represent conceptually distinct pathways of receptor/ligand interactions (costimulation and adhesion/homing, respectively) that have been effectively targeted to induce long-term allograft acceptance and tolerance. In the current study, we determined the relative efficacy and nature of tolerance induced by mAbs specific for these pathways. In vitro analysis indicated that simultaneous targeting of CD154 and LFA-1 resulted in profound inhibition of alloreactivity, suggesting that combined anti-CD154/anti-LFA-1 therapy could be highly effective in vivo. Thus, we evaluated combining mAb therapies targeting CD154 and LFA-1 for inducing transplantation tolerance to pancreatic islet allografts. Monotherapy with either anti-CD154 or anti-LFA-1 was partially effective for inducing long-term allograft survival, whereas the combination resulted in uniform allograft acceptance in high-responder C57BL/6 recipients. This combined therapy was not lymphocyte depleting and did not require the long-term deletion of donor-reactive T lymphocytes to maintain allograft survival. Importantly, combined anti-CD154/anti-LFA therapy uniquely resulted in "dominant" transplantation tolerance. Therefore, simultaneous perturbation of CD154 and LFA-1 molecules can result in profound tolerance induction not accomplished through individual monotherapy approaches. Furthermore, results show that such regulatory tolerance can coexist with the presence of robust anti-donor reactivity, suggesting that active tolerance does not require a corresponding deletion of donor-reactive T cells. Interestingly, although the induction of this regulatory state was highly CD4 dependent, the adoptive transfer of tolerance was less CD4 dependent in vivo.