Direct killing of xenograft cells by CD8+ T cells of discordant xenograft recipients.
Direct killing of xenograft cells by CD8+ T cells of discordant xenograft recipients.
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不一致的异种移植受体的 CD8 T 细胞直接杀死异种移植细胞。
DOI：
10.1097/00007890-200212150-00017
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发表时间：
2002
期刊：
影响因子：
6.2
通讯作者：
Galili,Uri
中科院分区：
文献类型：
--
作者：
Tanemura,Masahiro;Chong,AnitaS;DiSesa,VerdiJ;Galili,Uri
背景。长期在猴子体内的猪异种移植显示CD8+ T细胞浸润到移植到猴子体内的猪软骨异种移植物中。方法采用α 1,3半乳糖基转移酶敲除小鼠，反复腹腔注射猪肾膜，观察CD8+ T细胞对猪移植肾细胞的杀伤作用。猪肾细胞系PK15与猪肾膜具有许多相同的抗原，可作为异种移植靶细胞的细胞毒性实验模型。结果：用猪肾膜免疫小鼠脾脏获得的新鲜淋巴细胞对猪细胞没有明显的细胞毒活性。然而，将这些淋巴细胞与辐照的PK15细胞孵育并添加重组白细胞介素(IL)-2 (100 U/mL)，在孵育的第三天，导致CD8+细胞毒性T淋巴细胞（CTL）广泛增殖和扩增。这些CTL经过12天的孵育，非特异性地杀死猪、人和小鼠的正常和恶性细胞。在没有刺激性猪细胞或没有IL-2的情况下，这些CTL不能在培养中产生。这些CTL不能在PK15细胞和il -2共同培养的幼年小鼠淋巴细胞中产生。所获得的数据表明，来自异种移植受体的CD8+ T细胞可以在体外受到异种抗原和IL-2的刺激，分化成高活性的非特异性CTL，能够杀死多种异种和同基因细胞。异种移植物体内类似的微环境条件可能诱导浸润的CD8+ T细胞局部分化为CTL， CTL可以破坏非特异性相邻的异种移植物细胞。由于缺乏足够高浓度的IL-2，这些细胞在异种移植物外可能不活跃。
Background.Long-term pig xenografts in monkeys demonstrated the infiltration of CD8+ T cells into pig cartilage xenografts, transplanted into monkeys. The objective of the present study was to determine in an experimental animal model whether CD8+ T cells in pig xenograft recipients exert any direct cytotoxic effect on pig cells.Methods.The killing of xenograft cells by CD8+ T cells, obtained from xenograft recipients, was studied in α1, 3galactosyltransferase knockout mice that were repeatedly injected intraperitoneally with pig kidney membranes. The pig kidney cell line PK15, which shares many antigens with pig kidney membranes, served as a model for xenograft target cells in cytotoxicity assays. Cell lines from other species were also studied as target cells.Results.Lymphocytes obtained freshly from spleens of mice immunized with pig kidney membranes failed to display significant cytotoxic activity against pig cells. However, incubation of these lymphocytes with irradiated PK15 cells and addition of recombinant interleukin (IL)-2 (100 U/mL), on the third day of incubation, resulted in extensive proliferation and expansion of CD8+ cytotoxic T lymphocytes (CTL). These CTL, obtained after 12 days of incubation, killed nonspecifically pig, human, and mouse normal and malignant cells. These CTL were not generated in cultures in the absence of stimulatory pig cells or in the absence of IL-2. These CTL could not be generated in cultures of lymphocytes from naive mice that were incubated with PK15 cells and IL-2.Conclusions.The data obtained imply that CD8+ T cells from xenograft recipients can be stimulated in vitro by xenoantigens and IL-2 to differentiate into highly reactive nonspecific CTL that are capable of killing a large variety of xenogeneic and syngeneic cells. Similar in vivo microenvironmental conditions within the xenograft may induce the local differentiation of infiltrating CD8+ T cells into CTL that can destroy nonspecifically adjacent xenograft cells. Such cells may not be active outside the xenograft because of the absence of IL-2 in sufficiently high concentrations.