Guinan E C, Boussiotis V A, Neuberg D, Brennan L L, Hirano N, Nadler L M, Gribben J G
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
N Engl J Med. 1999 Jun 3;340(22):1704-14. doi: 10.1056/NEJM199906033402202.
Successful allogeneic bone marrow transplantation relies on global immunosuppression or elimination of T cells. In contrast, the induction of anergy can inactivate specific sets of alloreactive T cells in the donor marrow. Previous work has shown that anergy can be induced by blocking the interaction of the B7 molecule on the surface of antigen-presenting cells with the CD28 molecule on the surface of T cells, thus preventing key signaling events essential for the activation of T cells. To investigate the feasibility of this approach with respect to transplantation of histoincompatible bone marrow, we undertook a clinical trial of ex vivo induction of anergy in T cells present in donor marrow to recipient alloantigens.
Outcomes in 12 transplant recipients were evaluated. The recipients' peripheral-blood lymphocytes were collected before myeloablation and served as alloantigen-presenting cells. To induce alloantigen-specific anergy, bone marrow from a donor mismatched with the recipient for one HLA haplotype was cocultured with irradiated cells from the recipient for 36 hours in the presence of CTLA-4-Ig, an agent that inhibits B7:CD28-mediated costimulation. After conventional myeloablation and immunoprophylaxis, the treated donor cells were transfused into the recipient.
After the induction of anergy, the frequency of T cells capable of recognizing alloantigens of the recipient in donor marrow was sharply reduced (P<0.001), whereas the responsiveness to alloantigens from persons unrelated to the recipient or the donor was unaffected (P=0.51). In the 11 patients who could be evaluated, the haploidentical bone marrow cells engrafted. Of these 11 patients, 3 had acute graft-versus-host disease (GVHD) confined to the gastrointestinal tract. No deaths were attributable to GVHD. Five of the 12 patients were alive and in remission 4.5 to 29 months after transplantation.
Donor bone marrow treated ex vivo to induce anergy to alloantigens from the recipient can reconstitute hematopoiesis in vivo with a relatively low risk of GVHD.
成功的异基因骨髓移植依赖于全面的免疫抑制或T细胞的清除。相比之下，无反应性的诱导可使供体骨髓中特定的同种异体反应性T细胞失活。先前的研究表明，通过阻断抗原呈递细胞表面的B7分子与T细胞表面的CD28分子之间的相互作用，可诱导无反应性，从而阻止T细胞激活所必需的关键信号事件。为了研究这种方法在组织不相容骨髓移植方面的可行性，我们进行了一项临床试验，对供体骨髓中存在的针对受体同种异体抗原的T细胞进行体外无反应性诱导。
评估了12例移植受者的结果。在进行清髓性预处理之前收集受者的外周血淋巴细胞，并将其用作同种异体抗原呈递细胞。为了诱导同种异体抗原特异性无反应性，将与受者一个HLA单倍型不匹配的供体骨髓与受者的经辐照细胞在CTLA-4-Ig（一种抑制B7:CD28介导的共刺激的药物）存在的情况下共培养36小时。在进行常规清髓性预处理和免疫预防后，将经处理的供体细胞输注到受者体内。
诱导无反应性后，供体骨髓中能够识别受者同种异体抗原的T细胞频率急剧降低（P<0.001），而对与受者或供体无关的人的同种异体抗原的反应性未受影响（P=0.51）。在11例可评估的患者中，单倍型相合的骨髓细胞实现了植入。在这11例患者中，3例发生了局限于胃肠道的急性移植物抗宿主病（GVHD）。没有死亡归因于GVHD。12例患者中有5例在移植后4.5至29个月存活且处于缓解状态。
经体外处理以诱导对来自受者的同种异体抗原产生无反应性的供体骨髓能够在体内重建造血功能，且发生GVHD的风险相对较低。
Zotero 插件