Autoimmune hemolytic anemia (AIHA) is caused by the destruction of autoantibody-coated RBCs by phagocytes. Many studies have shown that the Fc?Rs expressed on phagocytes play a vital role in binding and phagocytosis of antibody-coated RBCs. The current therapies used to treat AIHA, such as steroids, have been shown to act by non-specifically suppressing the function of Fc?Rs or phagocytes and result in many unwanted side effects. This warrants a need to develop targeted therapies based on known immune mechanisms that cause AIHA. Recent studies strongly suggest that blocking Fc?R- mediated phagocytosis of antibody-coated RBCs may be a viable approach for treating AIHA. Although blocking receptor functions using decoy receptor-based therapies have been proven clinically successful, the presence of high levels of circulating IgG pose a unique challenge to the use of recombinant Fc?Rs as therapeutic molecule. The circulating IgG will immediately neutralize if high affinity Fc?Rs are administered whereas low affinity Fc?Rs are ineffective at therapeutically achievable concentrations. We have developed a novel Fc?R dimer of low affinity Fc?R, CD16AIg, which can bind IC with high avidity while showing no binding to monomeric IgG. Further, our preliminary studies show that the CD16AIg dimer can block the phagocytosis of antibody-coated erythrocytes by mouse macrophages in vitro and block neutrophil extravasations and inflammation induced by ICs in vivo. In this grant application we propose to explore the possibility of using Fc?R dimers as a therapeutic modality to block the clearance of antibody-coated RBCs by phagocytes in AIHA. We hypothesize that Fc?RIg dimers can bind to antibody-coated RBC and competitively block phagocytosis by Fc?R-bearing phagocytic cells in vivo and will restore RBC counts to the normal level.
The specific aims are: 1) Determine whether competitive blocking of macrophage binding to antibody-coated RBCs by recombinant Fc?RIg dimers could prevent clearance of antibody-coated erythrocytes from circulation. 2) Determine whether competitive blocking of macrophage binding to antibody-coated RBCs using recombinant Fc?RIg dimers prevent experimental AIHA induced by autoantibodies of different isotypes. 3) Determine whether administration of recombinant low affinity Fc?Rs dimers can delay or cure spontaneous AIHA in young and old NZB mice. The results obtained from the proposed studies will demonstrate whether competitively blocking antibody-coated RBCs to phagocytes by using decoy Fc?Rs dimers will attenuate immune hemolytic anemia induced by IgG antibodies. These studies will also form a solid foundation for the development of novel decoy Fc?R-based therapies for treatment of AIHA and other antibody-mediated autoimmune disorders in humans. ? ? ?
|Shashidharamurthy, R; Machiah, D; Bozeman, E N et al. (2012) Hydrodynamic delivery of plasmid DNA encoding human Fc?R-Ig dimers blocks immune-complex mediated inflammation in mice. Gene Ther 19:877-85|
|Shashidharamurthy, Rangaiah; Zhang, Fang; Amano, Aaron et al. (2009) Dynamics of the interaction of human IgG subtype immune complexes with cells expressing R and H allelic forms of a low-affinity Fc gamma receptor CD32A. J Immunol 183:8216-24|