Immune checkpoint receptors in regulating immune reactivity in rheumatic disease.

Sabrina Ceeraz,Christopher M Burns,Randolph J Noelle,Elizabeth C Nowak

doi:10.1186/s13075-014-0469-1

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.

Highlights

Rheumatic diseases include inflammatory disorders that cause pain, inflammation, or damage in joints and other organs, resulting in significant morbidity, mortality, and societal costs
Examples that are felt to be the result of autoimmunity include rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), psoriasis, systemic sclerosis (SSc), and Sjogren’s syndrome (SS)
A wealth of both mouse and human data indicate that co-stimulatory and co-inhibitory molecules are critical in a number of autoimmune rheumatic diseases (Figure 1)

Summary

Introduction

Rheumatic diseases include inflammatory disorders that cause pain, inflammation, or damage in joints and other organs, resulting in significant morbidity, mortality, and societal costs. One study showed that αCD279 Ab treatment is associated with increases in CD8+ and CD4+ regulatory T cells and protection from disease in NZBWF-1 mice [41,42] Because of these contradictory results, how the CD279 pathway signals in SLE remains unknown. 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). The remaining authors declare that they have no competing interests

Conclusions

Findings

Jenkins MK