Systemic lupus erythematosus (SLE or lupus) is a systemic autoimmune disease that affects multiple organs and has a high incidence in women and African Americans. Nearly 90% of the affected populations are women, and it occurs 3 times more frequently in African Americans. SLE is fatal in humans and leads to vital organ damage, disability, and death. In SLE, the immune complexes (IC) formed between autoantibodies and self-antigens bind to Fc gamma receptors (Fc3Rs) on inflammatory cells and trigger them, resulting in end organ damage. Genetic deletion of Fc3Rs in lupus-prone mice results in resistance to or attenuation of spontaneous lupus in mice, which suggest that it is possible to treat lupus-like diseases by blocking the interaction of IC with Fc3Rs. So far, Fc3R-based therapeutic approaches have been hampered by the low affinity of Fc3Rs, which necessitates the administration of physiologically unattainable levels of recombinant Fc receptors. Furthermore, the high level of circulating IgG immediately will neutralize the action of high affinity recombinant Fc receptors. Recent studies from our laboratory show that high avidity dimeric forms of low affinity Fc3Rs fusion proteins like CD16AIg, created by attaching a mutated Fc domain of IgG1 to the extracellular domain of Fc3Rs, compete with cell surface Fc3Rs and block IC binding and phagocytosis of antibody-coated cells by macrophages. CD16AIg dimers administered in vivo do not bind monomeric IgG but are still available to bind multivalent IC stably and block IC-induced tissue damage, neutrophil emigration, and mast cell degranulation in mice. Based on such evidence, we hypothesize that the administration of high avidity dimers of low affinity Fc3Rs will effectively attenuate or delay the end-organ damage in lupus. We propose to: 1) Determine whether administration of Fc3RIg dimers can prevent, delay, or attenuate antibody-induced glomerulonephritis in mice;2) Investigate the consequences of neutralizing IC by administering decoy Fc3RIg receptors on the progression of lupus nephritis using lupus-prone NZB/NZW F1 mice and CD32A transgenic mice models;3) Determine whether blocking IC binding to inflammatory cells by dimer administration leads to decreased production of inflammatory cytokines in lupus prone mice. The knowledge obtained from the proposed exploratory studies will provide important information about the design and use of low affinity recombinant Fc3RIg dimer-based therapeutics to treat lupus-nephritis in humans.
Systemic lupus erythematosus (SLE or lupus) is a chronic systemic autoimmune disease in humans that affects multiple organs with nearly 90% of the affected populations being women and occur 3 times more frequently in African Americans. The current proposal plans to develop and test novel recombinant Fc3R-based therapeutic strategy that will block the interaction of autoantibodies to Fc3R- expressed on inflammatory cells. The knowledge obtained from the proposed preclinical studies will have an impact on the development of recombinant Fc3R-based therapeutics to treat SLE 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|