Design of Antigen-Specific Immunotherapies Through Modulation of Peripheral Tolerance Pathways

Abstract

Current therapies for autoimmune diseases lack specificity for the offending immune cell population resulting in a wide range of side effects and weakening of the immune system. This presents a clear need for antigen-specific immunotherapies (ASITs) capable of selectively modulating autoreactive immune cells while maintaining the patient’s ability to respond to foreign pathogens. Lymphocyte activation is dependent on receiving two signals in tandem: interaction with the antigen of interest and co-stimulatory signals. Disruption of this two-signal model for lymphocyte activation in the context of the autoantigen is key to developing successful ASITs. Antigen-drug conjugates represent a novel class of therapeutics for the induction of immune tolerance designed to direct the effects of small molecule immunosuppressants through conjugation to the autoantigen of interest (Chapter 2). This strategy has proven successful in ameliorating paralytic symptoms in a murine model of multiple sclerosis (MS) known as experimental autoimmune encephalomyelitis (EAE). This was achieved through conjugation of the corticosteroid dexamethasone (DEX) to the peptide autoantigen proteolipid protein (PLP139-151). Further studies into the disruption of co-stimulatory signals in EAE revealed a protective role for the programmed cell death 1 (PD-1) pathway, and antagonism of natural receptor engagement resulted in cellular exhaustion, alleviating inflammatory markers (Chapter 3). Ultimately, antigen-only ASITs represent possibly the safest form of immune modulation in autoimmune diseases and may be achieved through multivalent displays of autoantigen. For example, a tetravalent display of PLP139-151 (4-arm PLP139-151) completely ameliorated EAE symptoms through depletion of PLP-responsive B cells and induction of a tolerogenic shift in co-stimulatory markers (Chapter 4). These results support the advancement of multiple avenues of approach in the development of ASIT for treating autoimmunity.