Holt Brandon Alexander, Bellavia Michael C, Potter Daniel, White David, Stowell Sean R, Sulchek Todd
Wallace H. Coulter Department of Biomedical Engineering at the Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
The Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA and The G. W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
Biomater Sci. 2017 Feb 28;5(3):463-474. doi: 10.1039/c6bm00608f.
The complement system is an integral component of the humoral immune system, and describes a cascade of interacting proteins responsible for the opsonization and lysis of foreign pathogens, in addition to the recruitment of immune cells. However, complement activation is also implicated in the progression and complication of immune dysfunctions such as sepsis. Microparticle (MP) biomaterials capable of tuning the local magnitude of serum complement activation could improve complement-mediated cytotoxicity to serum-resistant bacteria or calm an overactive immune response during sepsis. We demonstrate that model Fc-functionalized microparticles can be designed to either enhance or diminish the local cytotoxic effect of complement activation in human serum. The particles were formed with either the antibody Fc domains oriented outward from the particle surface or randomly adsorbed in a non-oriented fashion. In the oriented Fc form, complement products were directly sequestered to the particle surface, including C5a, a potent anaphylatoxin that, when elevated, is associated with poor sepsis prognosis. The oriented particle also lowered the cytotoxicity of serum and thus decreased the antibiotic effect when compared to serum alone. Conversely, the non-oriented microparticles were found to sequester similar levels of C5a, but much lower levels of iC3b and TCC on the microparticle surface, thereby increasing the amount of the soluble terminal complement complex. In addition, the non-oriented microparticles extend the distance over which TCC forms and enhance serum cytotoxicity to bacteria. Together, these two types of complement-modulating particles provide the first biomaterial that can functionally modify the range of complement activation at sites distant from the particle surface. Thus, biomaterials that exploit Fc presentation provide new possibilities to functionally modulate complement activation to achieve a desired clinical result.
补体系统是体液免疫系统的一个组成部分，它描述了一系列相互作用的蛋白质，这些蛋白质除了负责募集免疫细胞外，还负责对外来病原体进行调理作用和裂解。然而，补体激活也与免疫功能障碍（如脓毒症）的进展和并发症有关。能够调节血清补体激活局部强度的微粒（MP）生物材料可以改善补体介导的对血清耐药细菌的细胞毒性，或在脓毒症期间平息过度活跃的免疫反应。我们证明，模型Fc功能化微粒可以设计成增强或减弱人血清中补体激活的局部细胞毒性作用。这些微粒的形成方式是，抗体Fc结构域要么从微粒表面向外定向排列，要么以非定向方式随机吸附。在定向Fc形式中，补体产物直接被隔离到微粒表面，包括C5a，一种强效过敏毒素，当它升高时，与脓毒症预后不良有关。与单独的血清相比，定向微粒还降低了血清的细胞毒性，从而降低了抗生素效应。相反，发现非定向微粒隔离的C5a水平相似，但微粒表面的iC3b和TCC水平要低得多，从而增加了可溶性末端补体复合物的量。此外，非定向微粒延长了TCC形成的距离，并增强了血清对细菌的细胞毒性。总之，这两种补体调节微粒提供了第一种能够在远离微粒表面的部位功能性改变补体激活范围的生物材料。因此，利用Fc呈递的生物材料为功能性调节补体激活以实现理想的临床结果提供了新的可能性。
