Antibody responses protect us from a plethora of pathogens, but can also be pathogenic in allergic and autoimmune diseases. New approaches for selectively disarming these deleterious antibody responses would provide a breakthrough over broadly immunosuppressive therapies that can leave patients immunocompromised. Exploiting the natural function of inhibitory receptors on immune cells to drive immunological tolerance toward specific antigens is a promising strategy. One class of inhibitory receptors on immune cells is the sialic acid-binding immunoglobulin-type lectin (Siglec) family. This family couples recognition of their sialic acid-containing glycan ligands to regulation of immune cell function under the appropriate physiological conditions. As B-cells are the ultimate source of antibodies, we have been investigating the natural function of Siglecs on these B-cells, most notably CD22 (Siglec-2). Through developing a multivalent platform to engage CD22, we have shown that it is possible to delete the ‘disease-causing’ B-cells while preserving the function of all other B-cells. This platform – called Siglec-engaging tolerances-inducing antigenic liposomes (STALs) – consists of liposomal nanoparticles that display both antigen and a high affinity, selective glycan ligand of CD22. STALs induce cross-linking of CD22 and the BCR and drive an apoptotic signal only in the antigenic B-cells. This modulator platform has allowed us to test different antigens, target both murine and human CD22 with different glycan ligands, as well as encapsulate an immunosuppressant drug to enhance tolerance. Progress towards using STALs for inducing tolerance to antigens in allergies (e.g. peanut allergies) and autoimmunity (e.g. rheumatoid arthritis) will be presented. (NIH grants AI050143, AI099141; DOD grant W81XWH-16-1-0303)

Exploiting the inhibitory function of CD22 on B-cells to prevent antibody responses

255th National Meeting (2018)

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