Costimulation couture: a designer approach to regulating autoimmunity

Abstract

Negative or inhibitory costimulatory pathways regulate T cell activation and play a role in peripheral tolerance. Targeting these pathways harnesses the physiologic mechanisms of regulating autoimmunity and could prove beneficial for the therapy of autoimmune diseases. However, attempts at targeting these pathways have been fraught with difficulties. In this issue of the JCI, Fife et al. describe a creative approach for targeting CTL-associated antigen 4 (CTLA-4) on activated T cells via genetically engineered B cells to prevent autoimmune diabetes in the NOD mouse (see the related article beginning on page 2252). Novel "designer" strategies targeting negative costimulatory pathways provide reasons for optimism in the search for a cure for devastating autoimmune diseases.

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).