INHIBITION OF HYPERACUTE TRANSPLANT REJECTION BY SOLUBLE PROTEINS WITH THE FUNCTIONAL DOMAINS OF CD46 AND Fc??RII1

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Abstract
Background. Recombinant soluble forms of complement regulatory molecules, including the human complement regulatory protein CD46 (rsCD46), have been shown to inhibit hyperacute transplant rejection (HAR) and protect against complement- mediated inflammatory tissue damage.Similarly, recombinant soluble forms of the immunoglobulin receptor FcγRII (rsFcγRII) can attenuate antibody-mediated inflammatory responses. We have produced and tested the function of novel recombinant chimeric proteins that incorporate the functional domains of both CD46 (membrane cofactor protein, MCP) and the low affinity human IgG receptor FcγRII (CD32). Methods. Two recombinant soluble chimeric proteins (CD46:FcR and FcR:CD46) were designed and produced using a human cell expression system. Their ability to protect cells against complement-mediated lysis (through the CD46 domain) and bind human IgG (through the Fc receptor domain) was assessed in vitro. They were also tested in vivo in the rat reverse passive Arthus reaction and a murine model of hyperacute cardiac transplant rejection. Results. In vitro, the functional domains of the chimeric proteins each retained their activity. In vivo, the serum half-life of the recombinant chimeric proteins in mice was more than either rsCD46 or rsFcγRII. In the rat reverse passive Arthus reaction, intradermal injection of each recombinant protein substantially reduced inflammatory skin edema (>50%) and polymorphonuclear neutrophil infiltration (>90%). In the hyperacute rejection model, i.v. treatment with FcR:CD46 prevented complement- mediated rejection, macroscopic bruising, edema, and thrombosis more effectively than rsCD46. Conclusions. CD46/FcγRII bifunctional proteins have an improved ability to control complement- mediated hyperacute graft rejection and have therapeutic potential in other conditions involving antibody-mediated inflammation.