LFA-1-specific therapy prolongs allograft survival in rhesus macaques
LFA-1-specific therapy prolongs allograft survival in rhesus macaques
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DOI：
10.1172/jci43895
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发表时间：
2010-12-01
影响因子：
15.9
通讯作者：
Larsen, Christian P.
中科院分区：
文献类型：
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作者：
Badell, Idelberto R.;Russell, Maria C.;Larsen, Christian P.
移植的结果受到与当前免疫抑制方法相关的次优长期移植物存活率和毒性的限制。T细胞共刺激阻断已显示出作为避免常规免疫抑制疗法的副作用的替代策略的前景，但单独靶向CD 28介导的共刺激已被证明不足以预防灵长类动物的移植物排斥。供体特异性记忆性T（TM）细胞由于其增强的效应器功能和降低的对共刺激信号的依赖性而与共刺激阻断抗性移植排斥有关。因此，我们测试了一种潜在的策略，通过靶向优先在这些细胞上表达的分子（例如粘附分子淋巴细胞功能相关抗原1（LFA-1））来克服TM细胞驱动的排斥反应。在这里，我们表明，短期治疗（即，诱导治疗）与巴利昔单抗（IL-2 R α特异性mAb）和西罗莫司（雷帕霉素的哺乳动物靶抑制剂）或贝拉西普（CD 28共刺激阻断剂CTLA 4 Ig的高亲和力变体）的组合相对于对照治疗延长了非人灵长类动物中胰岛同种异体移植物的存活。此外，TS-1/22在体内掩蔽TM细胞上的LFA-1，并在体外抑制表达高水平LFA-1的同种异体增殖和产生精氨酸的效应T细胞的产生。这些结果支持使用LFA-1特异性诱导疗法来中和抗共刺激阻断的T细胞群体，并进一步评估LFA-1特异性疗法用于移植。
Outcomes in transplantation have been limited by suboptimal long-term graft survival and toxicities associated with current immunosuppressive approaches. T cell costimulation blockade has shown promise as an alternative strategy to avoid the side effects of conventional immunosuppressive therapies, but targeting CD28-mediated costimulation alone has proven insufficient to prevent graft rejection in primates. Donor-specific memory T (TM) cells have been implicated in costimulation blockade-resistant transplant rejection, due to their enhanced effector function and decreased reliance on costimulatory signaling. Thus, we have tested a potential strategy to overcome TM cell-driven rejection by targeting molecules preferentially expressed on these cells, such as the adhesion molecule lymphocyte function-associated antigen 1 (LFA-1). Here, we show that short-term treatment (i.e., induction therapy) with the LFA-1-specific antibody TS-1/22 in combination with either basiliximab (an IL-2R alpha-specific mAb) and sirolimus (a mammalian target of rapamycin inhibitor) or belatacept (a high-affinity variant of the CD28 costimulation-blocker CTLA4Ig) prolonged islet allograft survival in nonhuman primates relative to control treatments. Moreover, TS-1/22 masked LFA-1 on TM cells in vivo and inhibited the generation of alloproliferative and cytokine-producing effector T cells that expressed high levels of LFA-1 in vitro. These results support the use of LFA-1-specific induction therapy to neutralize costimulation blockade-resistant populations of T cells and further evaluation of LFA-1-specific therapeutics for use in transplantation.