Immune checkpoint receptors in regulating immune reactivity in rheumatic disease

Abstract

Immune checkpoint regulators are critical modulators of the immune system, allowing the initiation of a productive immune response and preventing the onset of autoimmunity. Co-inhibitory and co-stimulatory immune checkpoint receptors are required for full T-cell activation and effector functions such as the production of cytokines. In autoimmune rheumatic diseases, impaired tolerance leads to the development of diseases such as rheumatoid arthritis, systemic lupus erythematosus, and Sjogren's syndrome. Targeting the pathways of the inhibitory immune checkpoint molecules CD152 (cytotoxic T lymphocyte antigen-4) and CD279 (programmed death-1) in cancer shows robust anti-tumor responses and tumor regression. This observation suggests that, in autoimmune diseases, the converse strategy of engaging these molecules may alleviate inflammation owing to the success of abatacept (CD152-Ig) in rheumatoid arthritis patients. We review the preclinical and clinical developments in targeting immune checkpoint regulators in rheumatic disease.

Figure 1

Current in vivo immune checkpoint receptor therapies in rheumatic diseases. T-cell activation requires two signals. The first is via the T-cell receptor (TCR), where peptide is presented by the major histocompatibility complex (MHC) on responder cells. The second involves a network of co-inhibitory and co-stimulatory molecules pathways such as CD80/CD86–CD28/cytotoxic T lymphocyte antigen-4 (CTLA-4), inducible co-stimulator (ICOS)–ICOS ligand (ICOSL), programmed death-1 (PD-1), programme death ligand-1/2 (PD-L1/PD-L2), 4-1BB–4-1BB ligand (4-1BBL), CD40–CD154 ligand, OX40–OX40 ligand and CD27–CD70. This diagram summarizes current therapies for manipulating these pathways to suppress disease in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjogren’s syndrome (SS), psoriasis (Ps), and systemic sclerosis (SSc). Ab, antibody; CTX, cyclophosphamide; JIA, juvenile idiopathic arthritis.