Targeting lymphocyte co-stimulation: From bench to bedside

T and B lymphocytes are central regulators and effectors of immune responses and are believed to have a key role in many autoimmune diseases. Targeting the activation or effector function of lymphocytes is a potentially effective approach to treat autoimmunity. Typically, T-cell activation occurs after engagement of the T-cell receptor with its cognate peptide-major histocompatibility complex (signal 1) and subsequent engagement of co-stimulatory molecules (signal 2). This “second signal” contributes to T-cell activation by promoting proliferation, survival, and effector function. In general, activation in the absence of co-stimulation leads to a reduced immune response, anergy, or even tolerance. B-cell activation similarly requires co-stimulation for the development of complete effector function. The most potent co-stimulatory molecules identified to date are CD28 for T-cells and CD40 for B-cells. Both molecules are recognized for their potential as immune modulators; however, thus far neither molecule ...