Horvath-Arcidiacono J A, Mostowski H S, Bloom E T
Laboratory of Cellular Immunology (HFM-518), Center for Biologics Evaluation Research, Food and Drug Administration, Bethesda, MD 20892, USA.
Int Immunol. 1996 May;8(5):661-73. doi: 10.1093/intimm/8.5.661.
Because IL-12 restores allogeneic cytotoxic T lymphocyte (CTL) activity by T cells of aged mice in vitro, we initially assessed whether IL-12 could overcome age-related deficits when given to aged mice in vivo. Growth of P815(H-2(d)) was enhanced in aged compared with young BALB/c (H-2(d)) mice and tumor growth was curtailed by IL-12 in both age groups. Unexpectedly, secondary CTL stimulated ex vivo with P815 were reduced in IL-12-treated mice compared with controls. Primary CTL generated ex vivo across MHC differences in IL-12 treated BALB/c and C57BL/6 young mice were reduced by 90-99%, were dose- and time-dependent, and were associated with reduced allo-stimulated NK-like activity and [3H]thymidine incorporation. IFN-gamma was elevated in sera and in supernatants from allo-stimulated cultures from IL-12-treated mice, while IL-4 was reduced in such supernatants, suggesting that, despite reduced CTL, IL-12 was associated with increased Th1- and reduced Th2-type cytokine production. IL-12 also induced splenomegaly, primarily due to increased numbers of cells lacking markers of mature T, B and NK cells, or macrophages, or polymorphonuclear leukocyte morphology. IFN-gamma mutant mice exhibited reduced splenic enlargement in response to IL-12, suggesting that the splenomegaly was due, in part, to IFN-gamma production. However, reduced CTL generation was not due entirely to dilution of CTL precursor cells because spleen cellularity and size increased 3-fold while CTL activity decreased 10- to 100-fold, and CTL generation normalized to CD8(+) T effector cells was still significantly reduced in IL-12-treated mice. Interestingly, purified CD4(+) and CD8(+) T cells from IL-12-treated normal mice exhibited greater proliferative and cytolytic activities respectively compared with controls. Thus, effector T cells in IL-12-treated mice were not impaired, but exhibited augmented responsiveness, suggesting that IL-12 induced complex interactions among spleen cell populations and that these effects, in part, are mediated by IFN-gamma.
由于白细胞介素-12（IL-12）在体外可恢复老年小鼠T细胞的同种异体细胞毒性T淋巴细胞（CTL）活性，我们最初评估了在体内给予老年小鼠IL-12是否能克服与年龄相关的缺陷。与年轻的BALB/c（H-2(d)）小鼠相比，老年小鼠中P815（H-2(d)）的生长增强，且在两个年龄组中IL-12均抑制了肿瘤生长。出乎意料的是，与对照组相比，经IL-12处理的小鼠中用P815体外刺激产生的继发性CTL减少。在经IL-12处理的BALB/c和C57BL/6年轻小鼠中，体外跨越主要组织相容性复合体（MHC）差异产生的原发性CTL减少了90%-99%，呈剂量和时间依赖性，且与同种异体刺激的自然杀伤样活性降低及[3H]胸腺嘧啶核苷掺入减少有关。在经IL-12处理的小鼠的血清及同种异体刺激培养物的上清液中，γ干扰素（IFN-γ）升高，而在此类上清液中白细胞介素-4（IL-4）减少，这表明尽管CTL减少，但IL-12与Th1型细胞因子产生增加及Th2型细胞因子产生减少有关。IL-12还诱导了脾肿大，主要是由于缺乏成熟T、B和NK细胞标志物或巨噬细胞或多形核白细胞形态的细胞数量增加。IFN-γ突变小鼠对IL-12的反应中脾肿大减轻，这表明脾肿大部分归因于IFN-γ的产生。然而，CTL生成减少并不完全归因于CTL前体细胞的稀释，因为脾细胞数量和大小增加了3倍，而CTL活性降低了10至100倍，且经IL-12处理的小鼠中以CD8(+)T效应细胞标准化的CTL生成仍显著减少。有趣的是，与对照组相比，从经IL-12处理的正常小鼠中纯化的CD4(+)和CD8(+)T细胞分别表现出更大的增殖和细胞溶解活性。因此，经IL-1
