Protection of nonself surfaces from complement attack by factor H-binding peptides: implications for therapeutic medicine

J Immunol. 2011 Apr 1;186(7):4269-77. doi: 10.4049/jimmunol.1003802. Epub 2011 Feb 21.

Abstract

Exposure of nonself surfaces such as those of biomaterials or transplanted cells and organs to host blood frequently triggers innate immune responses, thereby affecting both their functionality and tolerability. Activation of the alternative pathway of complement plays a decisive role in this unfavorable reaction. Whereas previous studies demonstrated that immobilization of physiological regulators of complement activation (RCA) can attenuate this foreign body-induced activation, simple and efficient approaches for coating artificial surfaces with intact RCA are still missing. The conjugation of small molecular entities that capture RCA with high affinity is an intriguing alternative, as this creates a surface with autoregulatory activity upon exposure to blood. We therefore screened two variable cysteine-constrained phage-displayed peptide libraries for factor H-binding peptides. We discovered three peptide classes that differed with respect to their main target binding areas. Peptides binding to the broad middle region of factor H (domains 5-18) were of particular interest, as they do not interfere with either regulatory or binding activities. One peptide in this group (5C6) was further characterized and showed high factor H-capturing activity while retaining its functional integrity. Most importantly, when 5C6 was coated to a model polystyrene surface and exposed to human lepirudin-anticoagulated plasma, the bound peptide captured factor H and substantially inhibited complement activation by the alternative pathway. Our study therefore provides a promising and novel approach to produce therapeutic materials with enhanced biocompatibility.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biocompatible Materials / metabolism
  • Cloning, Molecular
  • Complement C3b / antagonists & inhibitors
  • Complement C3b / metabolism
  • Complement Factor H / metabolism
  • Complement Factor H / therapeutic use
  • Complement Factor I / antagonists & inhibitors
  • Complement Factor I / metabolism
  • Complement Inactivator Proteins / metabolism
  • Complement Pathway, Alternative / immunology*
  • Hemolysis
  • Humans
  • Peptide Fragments / metabolism*
  • Peptide Fragments / therapeutic use*
  • Peptide Library
  • Protein Binding / immunology
  • Surface Properties

Substances

  • Biocompatible Materials
  • Complement Inactivator Proteins
  • Peptide Fragments
  • Peptide Library
  • complement factor H, human
  • Complement C3b
  • Complement Factor H
  • Complement Factor I