CELLULAR BASIS FOR SILICONE-INDUCED IMMUNE RESPONSES

硅诱导免疫反应的细胞基础

• 批准号: 3149511
• 负责人: FREDIKA A ROBERTSON
• 金额: $ 13.88万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-01 至 1996-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3149511
• 关键词: biological models; biomaterial compatibility; cell adhesion molecules; cellular immunity; cytokine receptors; enzyme inhibitors; fibroblast growth factor; histology; in situ hybridization; inflammation; inhibitor /antagonist; interferon gamma; interleukin 1; interleukin 2; laboratory mouse; laboratory rabbit; leukocyte oxidative burst; polymerase chain reaction; protein kinase C; silicone rubber; tumor necrosis factor alpha

Implantation of silicon elastomer biopolymers is associated with the formation of a fibrous capsule surrounding the implant, which has been reported to occur in as high as 74% of patients receiving silicone implants. The formation of fibrous capsule and the subsequent contracture of the implant can result in a wide range of symptoms ranging from relatively mild reactions such as pain, discomfort and implant displacement to such severe reactions as the development of connective tissue diseases including scleroderma, rheumatoid arthritis and lupus erythematosus. Although there have been numerous studies documenting the development of fibrous encapsulation following implantation of silicone elastomer biopolymers, the mechanisms underlying host responses to these foreign materials remain unclear. It is our Hypothesis that soluble mediators and cell surface molecules produced by tissue fixed cells at the local site of implantation and infiltrating leukocytes and lymphocytes regulate the host response to silicone biopolymers. Previous studies in our laboratory used a novel in vivo air pouch model to characterize the host response to biomaterials which are implanted for replacement or reconstructive purposes. In this model, an air pouch is formed by subcutaneous injection of air beneath the dorsal skin of rabbits or rats and biomaterials are then placed in the pouch. This model provides a means to examine tissue alterations induced by implantation of biopolymers and also allows characterization of the types and states of activation of cells which infiltrate into the pouch in the presence of silicon elastomer. Furthermore, this model allows the cells which adhere to the biopolymer itself to be characterized. Using this in vivo model, implantation of silica free polydimethylsiloxane (PDMS) was found to stimulate an early (1-2d), rapid infiltration of neutrophils and macrophages into the local area of biomaterial implantation, which was followed at d 7-14 by infiltration of lymphocytes. Within 2-7 d, the PDMS implant became covered by fibroblastic-like cells. Fluid isolated from the local site was found to be highly chemotactic for monocytes and lymphocytes and contained significant levels of Interleukin-1 biological activity. Infiltrating nonadherent cells within the site of implantation produced enhanced levels of both hydroperoxide and superoxide anion. A hallmark of the host response to biomaterials is the localization of leukocytes to the site of implantation and adherence of fibroblasts to silicone biomaterials. One of the mechanisms by which localization and retention of leukocytes and fibroblasts occurs is via cytokine-induced expression/upregulation of cell surface receptor-ligand pairs, such as intercellular adhesion molecule (ICAM-1; CD54) and the integrin molecule lymphocyte function associated antigen (LFA-1, CD11a/CD18). In the proposed studies, in situ hybridization and reverse transcriptase polymerase chain reaction studies will be performed to evaluate the production of cytokines such as Interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), and lymphokines such as interferon-gamma and Interleukin-2 produced by tissue fixed cells and infiltrating leukocytes. The temporal sequence of production of other growth factors, such as basic fibroblast growth factor (bFGF), which induces fibroblast proliferation, will also be examined. Recent studies in our laboratory indicate that in vivo injection of antibodies directed against IL-1 inhibit proliferation of cells such as fibroblasts, while antibodies directed against integrin/adhesion molecules inhibit leukocyte migration to a local site of inflammation. These approaches, as well as the use of a protein kinase C inhibitor, staurosporine, and the use of IL-1 receptor antagonist, will be used to provide insight into pathways which can be used to diminish or abrogate the host response to silicone biopolymer implantation.

硅弹性体生物聚合物的植入与 种植体周围形成纤维性囊膜，已被 据报道，在接受硅胶治疗的患者中，高达74%的患者会发生这种情况 植入物。纤维包膜的形成及其后遗症 植入物的收缩会导致一系列的症状 从相对轻微的反应，如疼痛，不适和植入 置换到像连接词的发展这样的严重反应 组织疾病，包括硬皮病、类风湿性关节炎和狼疮 红斑狼疮。尽管已经有许多研究记录了 硅胶植入术后纤维包膜的研究进展 弹性体生物聚合物，宿主对这些生物聚合物的反应机制 外国材料仍不清楚。我们的假设是，可溶于 组织固定细胞产生的介体和细胞表面分子 植入和渗入白细胞的局部部位和 淋巴细胞调节宿主对硅胶生物聚合物的反应。上一首 我们实验室的研究使用了一种新的活体气囊模型来 描述宿主对植入人体的生物材料的反应 用于替换或重建目的。在这个模型中，气囊是 由背部皮肤下面的皮下注射空气形成 然后把兔子或大鼠和生物材料放进袋子里。这 模型提供了一种检查由 生物聚合物的植入，也允许表征类型 以及渗透到眼袋中的细胞的激活状态 硅橡胶的存在。此外，该模型允许细胞 它们附着在生物聚合物本身上进行表征。使用这个 无硅聚二甲基硅氧烷(PDMS)体内植入实验研究 被发现可以刺激早期(1-2d)的中性粒细胞快速渗透 和巨噬细胞进入生物材料植入的局部区域，这 7~14d出现淋巴细胞渗出。在2-7天内， PDMS种植体被成纤维细胞样细胞覆盖。流体隔离 对单核细胞有高度趋化作用， 淋巴细胞和含有显著水平的白介素1生物 活动。种植部位内非贴壁细胞的渗入 产生更高水平的过氧化氢和超氧阴离子。一个 宿主对生物材料反应的特点是本地化 白细胞到植入部位和成纤维细胞与 有机硅生物材料。本地化和地方化的机制之一 白细胞和成纤维细胞的滞留是通过细胞因子诱导的 细胞表面受体-配体对的表达/上调，如 细胞间黏附分子(ICAM-1；CD54)与整合素分子 淋巴细胞功能相关抗原(LFA-1，CD11a/CD18)。在 建议的研究、原位杂交和逆转录酶 将进行聚合酶链式反应研究以评估 产生白介素1(IL-1)等细胞因子，肿瘤坏死 因子-α(TNF-α)和淋巴因子，如干扰素-γ和 由组织固定细胞和渗入的白细胞产生的白介素2。 其他生长因子的生产的时间序列，如 碱性成纤维细胞生长因子，诱导成纤维细胞 扩散，也将被检查。我们实验室的最新研究 提示体内注射针对IL-1的抗体 抑制成纤维细胞等细胞的增殖，而抗体 针对整合素/黏附分子抑制白细胞迁移 转移到一个局部发炎的地方。这些方法，以及使用 蛋白激酶C抑制剂星形孢菌素的应用和IL-1的使用 受体拮抗剂，将被用来洞察 可用于减少或消除宿主对硅胶的反应 生物聚合物植入。