Journal Article

Synthetically glycosylated antigens for the antigen-specific suppression of established immune responses

Antane, Jennifer T., Watkins, Elyse A., Wallace, Rachel P., Harrington, Jamie L., Reda, Joseph W., Budina, Erica, Slezak, Anna J., Nguyen, Mindy, Mishra, Rabinarayan, Hubbell, Jeffrey A., Wilson, D. Scott, Alpar, Aaron T., Bischoff, David J., Raczy, Michal R., LeGrand, Roger, Marlin, Romain, Kontos, Stephan, Lorentz, Kristen M., Gallouët, Anne-Sophie, Dereuddre-Bosquet, Nathalie, Tremain, Andrew C., Solanki, Ani, Maulloo, Chitavi D., Conley, Gregory P., Thornley, Thomas B.

2023

Overview

Inducing antigen-specific tolerance during an established immune response typically requires non-specific immunosuppressive signalling molecules. Hence, standard treatments for autoimmunity trigger global immunosuppression. Here we show that established antigen-specific responses in effector T cells and memory T cells can be suppressed by a polymer glycosylated with N-acetylgalactosamine (pGal) and conjugated to the antigen via a self-immolative linker that allows for the dissociation of the antigen on endocytosis and its presentation in the immunoregulatory environment. We show that pGal–antigen therapy induces antigen-specific tolerance in a mouse model of experimental autoimmune encephalomyelitis (with programmed cell-death-1 and the co-inhibitory ligand CD276 driving the tolerogenic responses), as well as the suppression of antigen-specific responses to vaccination against a DNA-based simian immunodeficiency virus in non-human primates. Our findings show that pGal–antigen therapy invokes mechanisms of immune tolerance to resolve antigen-specific inflammatory T-cell responses and suggest that the therapy may be applicable across autoimmune diseases. Established antigen-specific T-cell responses can be suppressed by conjugating the antigen to a glycosylated polymer, as shown in a mouse model of multiple sclerosis and with the suppression of responses to vaccination in non-human primates.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/31 / 45/91 / 631/250/21/569 / 631/61/24 / 64/60 / 82 / Antigen presentation / Antigens / Autoantigens / Autoimmune diseases / Autoimmunity / Biomedical and Life Sciences / Biomedical Engineering/Biotechnology / Biomedicine / Cell death / DNA vaccines / DNA viruses / Effector cells / Endocytosis / Experimental allergic encephalomyelitis / Immune system / Immunological memory / Immunological tolerance / Immunoregulation / Immunosuppression / Inflammation / Lymphocytes / Lymphocytes T / Memory cells / Multiple sclerosis / N-Acetylgalactosamine / Polymers / Primates / Therapy / Vaccination