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Characterization of complement receptor 1 domains for prevention of complement‐mediated red cell destruction
Author(s) -
Mqadmi Amina,
Abdullah Yazan,
Yazdanbakhsh Karina
Publication year - 2005
Publication title -
transfusion
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.045
H-Index - 132
eISSN - 1537-2995
pISSN - 0041-1132
DOI - 10.1111/j.1537-2995.2004.04163.x
Subject(s) - complement system , hemolysis , in vivo , in vitro , complement receptor 1 , receptor , red blood cell , extracellular , recombinant dna , amino acid , alternative complement pathway , biochemistry , chemistry , biology , microbiology and biotechnology , immunology , immune system , gene , genetics
BACKGROUND: Complement activation resulting in intravascular hemolysis can cause transfusion‐associated mortality. We recently showed that a recombinant soluble form of complement receptor 1 (CR1) effectively reduces complement‐mediated red blood cell (RBC) destruction in vitro and more importantly prolongs the survival of transfused human RBCs in mice. To determine CR1‐active sites that prevent RBC destruction, structure‐function analysis of its extracellular 1930‐amino‐acid domain has been performed. STUDY DESIGN AND METHODS: Several CR1‐truncated soluble proteins were prepared and tested for their ability to prevent complement‐mediated RBC destruction in vitro and in mice. RESULTS: A 250‐amino‐acid region in CR1 that possesses antihemolytic activity and is effective in prolonging survival of transfused RBCs in vivo was identified. Mutation of two critical residues (D109N and E116K) in this 250‐amino‐acid domain, previously shown to improve complement‐inhibitory functions of CR1 derivatives, resulted in a more potent inhibition of complement activation in vitro. In vivo, however, the activity of mutant proteins was comparable to the wild‐type molecules. CONCLUSION: Our structure‐function studies have characterized smaller CR1‐based complement inhibitors for future development of structure‐derived transfusion therapeutics. Our studies underscore the importance of testing CR1 inhibitors in vivo.