Figure 1. Schematic of potential approaches to harnessing negative regulatory pathways for the prevention or cure of autoimmune diseases.

(A) Potential strategies operating within the lymphoid organs include the following: biologicals delivering a negative signal through the inhibitory receptors (IRs) on activated T cells (i); antibodies targeting other molecules (ii), which in turn enhance expression and function of negative costimulatory receptors on activated T cells; bispecific antibodies (iii) targeting TCR and inhibitory receptors simultaneously, thereby delivering a negative signal; gene therapy (iv) or “coating” (v) of APCs using ligands or antibodies targeting inhibitory receptors. (B) Potential strategies operating within the parenchyma of target organs include the following: gene therapy of target tissue (e.g., islets) and passenger APCs, with ligands or antibodies targeting inhibitory receptors (i); coating or “decoration” of target tissue (e.g., islets) and passenger APCs with ligands of inhibitory receptors (ii).