TUNABLE COMPLEMENT ACTIVATION BY PARTICLES WITH VARIABLE SIZE AND Fc DENSITY

Author:

PACHECO PATRICIA M.1,LE BENJAMIN2,WHITE DAVID3,SULCHEK TODD4

Affiliation:

1. George W. Woodruff School of Mechanical Engineering, Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, USA

2. Coulter School of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, USA

3. United States Department of Agriculture, National Centers for Animal Health, Ames, Iowa 50010, USA

4. George W. Woodruff School of Mechanical Engineering, Coulter School of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, USA

Abstract

The complement system is an integral innate immune component that is made up of a cascade of enzymatic proteins that, once activated, results in lysis of invading pathogens, opsonization or recruitment of other innate and/or acquired immune responders, or some combination of the three. Due to the importance of the signal amplification and control points present in the cascade, complement is highly sensitive to subtle variations in initiation conditions, including nanoscale changes to molecular spacing. Using Fc-functionalized microparticles and nanoparticles, we find that activation requires a minimum threshold surface concentration of Fc of at least 20% surface coverage. This result indicates that a high surface density Fc is necessary for micro/nanoparticle complement activation through the classical pathway. In addition, the magnitude of the response was dependent on the size of the particle, with larger particles causing decreased activation. We hypothesize that a high density of Fc is needed to efficiently bind and closely appose molecular initiators of the complement cascade, from initiation to terminal complement complex formation. These fundamental studies of the interaction of microparticles and nanoparticles with the immune system suggest design rules for particle size and molecular density that impact immunostimulation through the complement system. Providing a therapeutic agent to modulate the complement response could aid a variety of treatment strategies. Engineered nanoparticles with controlled gaps between molecular activators could lead to new types of immunomodulatory agents.

Publisher

World Scientific Pub Co Pte Lt

Subject

General Medicine

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