PDF(Pubmed)
Abstract：
γδ T cells and natural killer (NK) cells have attracted much attention as promising effector cell subsets for adoptive transfer for use in the treatment of malignant and infectious diseases, because they exhibit potent cytotoxic activity against a variety of malignant tumors, as well as virus-infected cells, in a major histocompatibility complex (MHC)-unrestricted manner. In addition, γδ T cells and NK cells express a high level of CD16, a receptor required for antibody-dependent cellular cytotoxicity. Adult T-cell leukemia-lymphoma (ATL) is caused by human T-lymphotropic virus type I (HTLV-1) and is characterized by the proliferation of malignant peripheral CD4+ T cells. Although several treatments, such as chemotherapy, monoclonal antibodies, and allogeneic hematopoietic stem cell transplantation, are currently available, their efficacy is limited. In order to develop alternative therapeutic modalities, we considered the possibility of infusion therapy harnessing γδ T cells and NK cells expanded using a novel nitrogen-containing bisphosphonate prodrug (PTA) and interleukin (IL)-2/IL-18, and we examined the efficacy of the cell-based therapy for ATL in vitro. Peripheral blood samples were collected from 55 patients with ATL and peripheral blood mononuclear cells (PBMCs) were stimulated with PTA and IL-2/IL-18 for 11 days to expand γδ T cells and NK cells. To expand NK cells alone, CD3+ T-cell-depleted PBMCs were cultured with IL-2/IL-18 for 10 days. Subsequently, the expanded cells were examined for cytotoxicity against ATL cell lines in vitro. The proportion of γδ T cells in PBMCs was markedly low in elderly ATL patients. The median expansion rate of the γδ T cells was 1998-fold, and it was 12-fold for the NK cells, indicating that γδ T cells derived from ATL patients were efficiently expanded ex vivo, irrespective of aging and HTLV-1 infection status. Anti-CCR4 antibodies enhanced the cytotoxic activity of the γδ T cells and NK cells against HTLV-1-infected CCR4-expressing CD4+ T cells in an antibody concentration-dependent manner. Taken together, the adoptive transfer of γδ T cells and NK cells expanded with PTA/IL-2/IL-18 is a promising alternative therapy for ATL.
摘要：
γδT细胞和自然杀伤（NK）细胞作为有希望的效应细胞亚群用于过继转移，用于治疗恶性和感染性疾病，引起了广泛的关注。因为它们对各种恶性肿瘤表现出有效的细胞毒活性，以及病毒感染的细胞，以主要组织相容性复合体（MHC）不受限制的方式。此外,γδT细胞和NK细胞表达高水平的CD16，这是抗体依赖性细胞毒性所需的受体。成人T细胞白血病淋巴瘤（ATL）是由人类I型T淋巴细胞病毒（HTLV-1）引起的，其特征是恶性外周CD4T细胞的增殖。虽然有几种治疗方法，比如化疗，单克隆抗体，异基因造血干细胞移植，目前可用,其功效是有限的。为了开发替代治疗方式，我们考虑了利用新型含氮双膦酸盐前药(PTA)和白细胞介素(IL)-2/IL-18扩增γδT细胞和NK细胞进行输注治疗的可能性,并且我们在体外检查了基于细胞的治疗对ATL的疗效.收集55例ATL患者的外周血样本，用PTA和IL-2/IL-18刺激外周血单核细胞（PBMC）11天以扩增γδT细胞和NK细胞。单独扩增NK细胞，用IL-2/IL-18培养CD3+T细胞耗尽的PBMC10天。随后，在体外检查扩增的细胞对ATL细胞系的细胞毒性。老年ATL患者PBMC中γδT细胞的比例明显较低。γδT细胞的中位扩增速率为1998倍，它是NK细胞的12倍，表明来自ATL患者的γδT细胞在体外有效扩增，与衰老和HTLV-1感染状态无关。抗CCR4抗体以抗体浓度依赖性方式增强了γδT细胞和NK细胞对HTLV-1感染的表达CCR4的CD4+T细胞的细胞毒活性。一起来看,用PTA/IL-2/IL-18扩增的γδT细胞和NK细胞的过继转移是ATL的有希望的替代疗法。
