Department of Immunology, Rush University Medical Center, Chicago, Illinois 60612, USA.
J Biomed Mater Res A. 2010 Jun 15;93(4):1312-21. doi: 10.1002/jbm.a.32627.
Aseptic osteolysis has been associated with excessive immune reactivity to particulate implant debris; however, innate and adaptive immune mechanisms that underlie implant debris reactivity remain incompletely understood. Although particulate debris has been implicated as the major type of implant debris mediating macrophage-induced osteolysis, the degree to which metal ions affect a proinflammatory response (if at all) remains unknown. We hypothesized that both soluble and particulate metal implant debris will induce proinflammatory responses in human monocytes resulting in cytokine production and elevated expression of T cell costimulatory molecules, facilitating adaptive immune responses. We tested this hypothesis by characterizing the response of a human monocyte cell line (THP-1), isolated primary human monocytes and PBMCs challenged with Co-Cr-Mo alloy particles and soluble cobalt, chromium, molybdenum, and nickel ions. Our results indicate that soluble cobalt, nickel, and molybdenum can induce monocyte up-regulation of T cell costimulatory molecules (CD80, CD86, ICAM-1) in human monocytes/macrophages. Furthermore, cobalt, molybdenum ions, and Co-Cr-Mo alloy particles similarly induce elevated secretion of IL-1beta, TNFalpha, and IL-6. Antibody blockade of CD80 and CD86, crucial secondary molecules for adaptive responses, abrogated lymphocyte reactivity to metal challenge in metal reactive subjects. Also the addition of IL-1 receptor antagonist (IL-1ra), (which indirectly blocks pro-IL-1beta and thus IL-1beta release), significantly reduced lymphocyte reactivity in metal-reactive subjects. Thus, both soluble and particulate metal implant debris induce monocyte/macrophage proinflammatory responses that are metal and individual specific. This suggests metal-induced up-regulation of costimulatory molecules and proinflammatory cytokine production is necessary to induce lymphocyte activation/proliferation to metal implant debris.
无菌性骨溶解与对颗粒状植入物碎片的过度免疫反应有关；然而，介导植入物碎片反应的固有和适应性免疫机制仍不完全清楚。虽然颗粒状碎片已被认为是介导巨噬细胞诱导骨溶解的主要类型的植入物碎片，但金属离子影响促炎反应的程度（如果有的话）仍然未知。我们假设，可溶性和颗粒状金属植入物碎片都会在人单核细胞中诱导促炎反应，导致细胞因子产生和 T 细胞共刺激分子的上调，从而促进适应性免疫反应。我们通过表征人单核细胞系（THP-1）、分离的原代人单核细胞和 PBMC 对 Co-Cr-Mo 合金颗粒和可溶性钴、铬、钼和镍离子的反应来验证这一假设。我们的结果表明，可溶性钴、镍和钼可以诱导人单核细胞/巨噬细胞上调 T 细胞共刺激分子（CD80、CD86、ICAM-1）。此外，钴、钼离子和 Co-Cr-Mo 合金颗粒同样诱导 IL-1beta、TNFalpha 和 IL-6 的分泌升高。阻断 CD80 和 CD86 的抗体，这是适应性反应的关键二级分子，消除了对金属反应性个体中金属挑战的淋巴细胞反应性。此外，添加 IL-1 受体拮抗剂（IL-1ra）（间接阻断 pro-IL-1beta，从而减少 IL-1beta 的释放），可显著降低金属反应性个体中的淋巴细胞反应性。因此，可溶性和颗粒状金属植入物碎片均可诱导单核细胞/巨噬细胞的促炎反应，且具有金属和个体特异性。这表明金属诱导的共刺激分子和促炎细胞因子的上调是诱导对金属植入物碎片的淋巴细胞激活/增殖所必需的。
