Department of Medicine, Yale University School of Medicine Cancer Center, New Haven, CT 06520-8032, USA.
Blood. 2011 Nov 24;118(22):5965-76. doi: 10.1182/blood-2011-07-367011. Epub 2011 Sep 13.
Donor T cells contribute to the success of allogeneic hematopoietic stem cell transplantation (alloSCT). Alloreactive donor T cells attack leukemia cells, mediating the GVL effect. Donor T cells, including the memory T cells (T(M)) that are generated after infection, also promote immune reconstitution. Nonetheless, leukemia relapse and infection are major sources of treatment failure. Efforts to augment GVL and immune reconstitution have been limited by GVHD, the attack by donor T cells on host tissues. One approach to augmenting GVL has been to infuse ex vivo-generated T cells with defined specificities; however, this requires expertise that is not widely available. In the present study, we tested an alternative approach, adoptive immunotherapy with CD8+ T(M) from donors vaccinated against a single minor histocompatibility antigen (miHA) expressed by leukemia cells. Vaccination against the miHA H60 greatly augmented T(M)-mediated GVL against mouse chronic-phase (CP-CML) and blast crisis chronic myeloid leukemia (BC-CML). T(M)-mediated GVL was antigen specific and was optimal when H60 expression was hematopoietically restricted. Even when H60 was ubiquitous, donor H60 vaccination had a minimal impact on GVHD. T(M) from lymphocytic choriomeningitis virus (LCMV)-immune and H60-vaccinated donors augmented GVL and protected recipients from LCMV. These data establish a strategy for augmenting GVL and immune reconstitution without elaborate T-cell manipulation.
供者 T 细胞有助于异基因造血干细胞移植（alloSCT）的成功。同种反应性供者 T 细胞攻击白血病细胞，介导 GVL 效应。供者 T 细胞，包括感染后产生的记忆 T 细胞（T(M)），也促进免疫重建。然而，白血病复发和感染是治疗失败的主要原因。尽管努力增强 GVL 和免疫重建，但由于供者 T 细胞对宿主组织的攻击，GVHD 受到限制。增强 GVL 的一种方法是输注具有特定特异性的体外生成的 T 细胞；然而，这需要广泛可用的专业知识。在本研究中，我们测试了一种替代方法，即用针对白血病细胞表达的单一次要组织相容性抗原（miHA）进行疫苗接种的供者 CD8+T(M)进行过继免疫治疗。针对 miHA H60 的疫苗接种极大地增强了针对小鼠慢性期（CP-CML）和急变期慢性髓性白血病（BC-CML）的 T(M)介导的 GVL。T(M)介导的 GVL 具有抗原特异性，当 H60 表达具有造血限制性时最佳。即使 H60 普遍存在，供者 H60 疫苗接种对 GVHD 的影响也很小。来自淋巴细胞性脉络丛脑膜炎病毒（LCMV）免疫和 H60 疫苗接种供者的 T(M)增强了 GVL，并使受者免受 LCMV 的侵害。这些数据为增强 GVL 和免疫重建而无需精心的 T 细胞操作建立了一种策略。
