HARNESSING SIGLECS TO INDUCE IMMUNE TOLERANCE

JamesC. Paulson ⁰; Britni Arlian ⁰; Shiteng Duan ⁰; Matthew Macauley ⁰; CorwinM. Nycholat ⁰; Lijuan Pang ⁰; Amrita Srivastava ⁰

The sialic acid-binding immunoglobulin-type lectin family of cell adhesion receptors called Ssiglecs comprise 14 members in humans and 9 members in mice that are predominately expressed on white blood cells of the immune system. Most siglecs carry regulatory motifs that can regulate receptors involved in mediating immune responses, and help the immune system distinguish between self and non-self. Antigens induce an immune response by binding to activitory receptors that then activate the cell. To pursue ourWe have developed a liposomal nanoparticle platform that exploits the inhibitory functions of siglecs for suppression of antigen induced immune cell activation. The tolerogenic nanoparticles display an antigen and ligand of an inhibitory Siglec expressed on the cells that recognize the antigen. When an immune cell receptor recognizes the antigen, the Siglecs are recruited to the immunological synapse, suppressing the immune response and effectively inducing tolerance to the antigen.  interest to elucidate and exploit the functions of siglecs in immune cells, we develop glycan ligands of high affinity and selectivity for each siglec, which can then be used as reliable probes to target and study cells expressing that siglec both in vitro and in vivo. Ligands suitable for in vivo targeting of various white blood cells have been identified for eleven different human and murine siglecs. These have been used to develop siglec-targeting nanoparticles specific for each siglec. To date we have demonstrated the utility of siglec ligand-decorated nanoparticles to deliver antigens and chemotherapeutic agents to immune cells, and to suppress antigen-mediated immune responses of B cells and mast cells. (NIH grants AI050143, AI099141, HL107151, CA013889).