This project will investigate the potential of our recent discovery that antigen specific B cell tolerance can be induced in an animal by administering an antigen coupled to siglec ligand decorated nanoparticles [Duong et al. (2010) J. Exp. Med. 184, 4183]. The motivation for this application stems from the recognition that many autoimmune diseases and allergies result from a B cell response to self and non-self antigens, respectively. If tolerance can be induced to the offending antigen, significant therapeutic benefit might be achieved. Our goal is to develop a modular platform, siglec ligand toleragenic liposomes (STL), for facile conjugation of various medically relevant antigens, and demonstrate that it can be used to induce robust antigen specific B cell tolerance in vivo. Preliminary data show that administration to mice of STL simultaneously displaying a glycan ligand of CD22 and an antigen, induces robust antigen specific tolerance to subsequent challenge with antigen only. CD22 is a B cell specific member of the siglec family of immunoglobulin (Ig) receptors that recognize sialic acid containing glycans as self-ligands and participates as a co-receptor in regulation of cell signaling. Evidence to date suggests that tolerance is induced by STL, resulting in ligation of CD22 to the B cell receptor (BCR), producing an apoptotic signal and selective depletion of the B cells that recognize the antigen, amplifying a natural function of CD22 for maintenance of peripheral B cell tolerance. The major objectives of the project are 1) to optimize the modular STL platform for display of antigen and siglec ligands for inducing tolerance, 2) to assess the relative ability of specific ligands of CD22 and Siglec-G, the other major B cell siglec, to induce tolerance, 3) to assess the ability of STL to tolerize antigen speciic memory B cells, and 4) to demonstrate the utility of STL for inducing tolerance to a panel of diverse medically important antigens, and reduce the pathology mediated by antigen reactive B cells in models of EAE and allergic asthma. If successful, the STL platform could provide an alternative for B cell depletion therapies for treatment of autoimmune other antigen mediated diseases, representing a 'surgical'strike by ablating antigen specific B cells while leaving the rest of the B cell population and immunological memory intact.
This project is aimed at developing a novel approach to selectively deplete the white blood cells (B cells) that cause autoimmune diseases and allergic asthma. If successful, it will be an alternative to current drugs that deplete all B cells, leavinga patient without an important segment of the immune system.
|Macauley, Matthew S; Paulson, James C (2014) Siglecs induce tolerance to cell surface antigens by BIM-dependent deletion of the antigen-reactive B cells. J Immunol 193:4312-21|
|Macauley, Matthew S; Crocker, Paul R; Paulson, James C (2014) Siglec-mediated regulation of immune cell function in disease. Nat Rev Immunol 14:653-66|
|Macauley, Matthew S; Paulson, James C (2014) Immunology: glyco-engineering 'super-self'. Nat Chem Biol 10:7-8|
|Macauley, Matthew S; Pfrengle, Fabian; Rademacher, Christoph et al. (2013) Antigenic liposomes displaying CD22 ligands induce antigen-specific B cell apoptosis. J Clin Invest 123:3074-83|
|Pfrengle, Fabian; Macauley, Matthew S; Kawasaki, Norihito et al. (2013) Copresentation of antigen and ligands of Siglec-G induces B cell tolerance independent of CD22. J Immunol 191:1724-31|