Single domain antibody-antigen adducts that target Class II MHC induce antigen-specific tolerance

Abstract The association of autoimmune diseases with particular allelic variants of Class II MHC (MHCII) products implicates presentation of the offending self-antigen(s) to T cells. Antigen presenting cells are tolerogenic when they encounter antigen under non-inflammatory conditions. Manipulation of antigen presentation would therefore be a possible intervention to induce antigen-specific tolerance. We show that, under non-inflammatory conditions, systemic administration of a single dose of a nanobody that recognizes MHCII (VHH MHCII) conjugated to the relevant self-antigen affords long-lasting protection against induction of experimental autoimmune encephalitis (EAE), type 1 diabetes (T1D), and rheumatoid arthritis (RA). Co-administration of the VHH MHCII-antigen adduct together with dexamethasone, conjugated to VHH MHCII via a cleavable linker, not only halted progression of established EAE in symptomatic mice but even reverted the severity of EAE, establishing this approach as a potential means of treating autoimmune conditions.