CELLULAR BASIS FOR SILICONE-INDUCED IMMUNE RESPONSES

硅诱导免疫反应的细胞基础

• 批准号: 2069785
• 负责人: FREDIKA A ROBERTSON
• 金额: $ 12.9万
• 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/2069785
• 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 在植入物周围形成纤维囊， 据报告，在接受硅胶治疗的患者中， 植入物. 纤维囊的形成和随后的 植入物的挛缩可导致广泛的症状， 相对轻微的反应，例如疼痛、不适和植入 位移等严重的反应，如发展连接 组织疾病，包括硬皮病、类风湿性关节炎和狼疮 红斑 尽管有许多研究记录了 硅胶植入后纤维包裹的发展 弹性体生物聚合物，宿主对这些反应的潜在机制 外来物质仍不清楚。 我们的假设是可溶性的 组织固定细胞产生的介质和细胞表面分子. 植入和浸润白细胞的局部部位， 淋巴细胞调节宿主对硅酮生物聚合物的反应。 先前 我们实验室的研究使用了一种新的体内气囊模型， 表征宿主对植入生物材料的反应 重建或重建的目的。 在这个模型中， 通过在背部皮肤下皮下注射空气而形成， 然后将兔子或大鼠和生物材料放入袋中。 这 模型提供了一种方法来检查组织变化引起的 生物聚合物的植入，并且还允许表征 以及渗透到袋中的细胞的活化状态， 硅弹性体的存在。 此外，该模型允许细胞 其粘附在待表征的生物聚合物本身上。 使用此 体内模型，无硅聚二甲基硅氧烷（PDMS）植入 发现刺激早期（1-2d），中性粒细胞的快速浸润 和巨噬细胞进入生物材料植入的局部区域， 在第7-14天，淋巴细胞浸润。 在2-7 d内， PDMS植入物被成纤维细胞样细胞覆盖。 液体隔离 发现从局部部位的细胞对单核细胞具有高度趋化性， 淋巴细胞，并含有显著水平的白细胞介素-1生物 活动 植入部位的非粘附细胞浸润 产生增强的氢过氧化物和超氧阴离子水平。 一 宿主对生物材料反应的标志是 白细胞粘附到植入部位，成纤维细胞粘附到 有机硅生物材料。 其中一个机制， 白细胞和成纤维细胞的滞留是通过苦参碱诱导的 细胞表面受体-配体对的表达/上调，例如 细胞间粘附分子（ICAM-1; CD 54）和整合素分子 淋巴细胞功能相关抗原（LFA-1，CD 11 a/CD 18）。 在 建议的研究，原位杂交和逆转录酶 将进行聚合酶链反应研究来评估 产生细胞因子如白细胞介素-1（IL-1）、肿瘤坏死因子 因子-α（TNF-α）和淋巴因子如干扰素-γ和 白细胞介素2由组织固定细胞和浸润白细胞产生。 其他生长因子产生的时间顺序，如 碱性成纤维细胞生长因子（bFGF），其诱导成纤维细胞 扩散，也将受到审查。 我们实验室最近的研究 表明体内注射针对IL-1抗体 抑制细胞如成纤维细胞的增殖，而抗体 针对整联蛋白/粘附分子抑制白细胞迁移 局部炎症部位 这些方法，以及使用 蛋白激酶C抑制剂星形孢菌素的使用和IL-1的使用 受体拮抗剂，将用于提供深入了解的途径， 可用于减少或消除宿主对硅酮的反应 生物聚合物植入