Comoli P, Locatelli F, Moretta A, Montagna D, Calcaterra V, Cometa A, Basso S, Zecca M, Maccario R
Department of Pediatric Sciences, University of Pavia, IRCCS Policlinic S Matteo, Italy.
Bone Marrow Transplant. 2001 Jun;27(12):1263-73. doi: 10.1038/sj.bmt.1703063.
The success of allogeneic hematopoietic stem cell transplantation from HLA-disparate donors depends on the development of new strategies for graft-versus-host disease prevention able to target specifically donor antihost alloreactivity, while preserving GVL and antiviral immune surveillance. Recent experimental and clinical work has shown the feasibility of an approach based on induction of anergy to host alloantigens through blockade of B7/CD28 costimulatory signal in donor T cells, but data on the impact of this strategy on the recovery of the immune system are still lacking. We devised an ex vivo method for induction of host alloantigen-specific unresponsiveness based on treatment with the B7/CD28 blocking agent CTLA4-Ig associated with CsA. We then proceeded to assess the maintenance of an effective immune response towards viral pathogens and tumor cells after CTLA4-Ig/CsA treatment, by measuring the frequency of CTL precursors directed against CMV- and EBV-infected targets, and against autologous leukemic blasts. We demonstrated that (1) CTLA4-Ig and CsA can act synergistically in inducing a state of unresponsiveness to alloantigens; (2) the number of leukemia-reactive, EBV-specific and CMV-specific CTLp is not impaired by CTLA4-Ig/CsA treatment. Our data provide the first direct in vitro evidence that it is possible to preserve antiviral and antileukemia effector cells after blockade of CD28/B7 interaction during MLR.
来自HLA不相合供者的异基因造血干细胞移植的成功取决于开发新的移植物抗宿主病预防策略，该策略能够特异性地靶向供者抗宿主同种异体反应性，同时保留移植物抗白血病效应和抗病毒免疫监视功能。最近的实验和临床研究表明，通过阻断供者T细胞中的B7/CD28共刺激信号来诱导对宿主同种异体抗原的无反应性这一方法具有可行性，但关于该策略对免疫系统恢复影响的数据仍然缺乏。我们设计了一种基于用与环孢素A（CsA）联合使用的B7/CD28阻断剂CTLA4-Ig进行处理来诱导宿主同种异体抗原特异性无反应性的体外方法。然后，我们通过测量针对巨细胞病毒（CMV）和EB病毒感染靶标以及自体白血病原始细胞的细胞毒性T淋巴细胞（CTL）前体的频率，来评估CTLA4-Ig/CsA处理后对病毒病原体和肿瘤细胞的有效免疫反应的维持情况。我们证明：（1）CTLA4-Ig和CsA在诱导对同种异体抗原的无反应状态方面可协同作用；（2）CTLA4-Ig/CsA处理不会损害白血病反应性、EB病毒特异性和CMV特异性CTL前体的数量。我们的数据提供了首个直接的体外证据，即在混合淋巴细胞反应（MLR）期间阻断CD28/B7相互作用后，有可能保留抗病毒和抗白血病效应细胞。
