Immune Checkpoints, a Novel Class of Therapeutic Targets for Autoimmune Diseases

Abstract

Autoimmune diseases, such as multiple sclerosis and type-1 diabetes, are the outcomes of a failure of immune tolerance. Immune tolerance is sustained through interplays between two inter-dependent clusters of immune activities: immune stimulation and immune regulation. The mechanisms of immune regulation are exploited as therapeutic targets for the treatment of autoimmune diseases. One of these mechanisms is immune checkpoints (ICPs). The roles of ICPs in maintaining immune tolerance and hence suppressing autoimmunity were revealed in animal models and validated by the clinical successes of ICP-targeted therapeutics for autoimmune diseases. Recently, these roles were highlighted by the clinical discovery that the blockade of ICPs causes autoimmune disorders. Given the crucial roles of ICPs in immune tolerance, it is plausible to leverage ICPs as a group of therapeutic targets to restore immune tolerance and treat autoimmune diseases. In this review, we first summarize working mechanisms of ICPs, particularly those that have been utilized for therapeutic development. Then, we recount the agents and approaches that were developed to target ICPs and treat autoimmune disorders. These agents take forms of fusion proteins, antibodies, nucleic acids, and cells. We also review and discuss safety information for these therapeutics. We wrap up this review by providing prospects for the development of ICP-targeting therapeutics. In summary, the ever-increasing studies and results of ICP-targeting of therapeutics underscore their tremendous potential to become a powerful class of medicine for autoimmune diseases.

Keywords: autoimmune diseases; cell; fusion protein; immune checkpoints; nucleic acid; therapeutics; viral protein.

Figure 1

Schematics of eight immune checkpoints (ICPs). For each ICP, one type of cells is used as the representatives that host ICP receptors or ligands. The main immune activation and inhibition implications of ICPs are illustrated with the representative cell types. It is noteworthy that the receptors and ligands may be expressed by additional cell types. The functional implications of ICPs are not limited to what are illustrated here.

Figure 2

Schematics for the different forms of ICP-targeting therapeutics. One representative for each form of therapeutics was shown. (A) Viral proteins. UL144 is used to engage with BTLA and activate the corresponding ICP, which enhances immune inhibitory signals. (B) Soluble ligand and receptors. A fusion of CTLA-4 and Fc is used to engage with CD86/CD86 and activate the CTLA-4 ICP, which enhance immune inhibitory signals. (C) Nucleic acids. A coding gene of PD-L1 is used to increase the expression of PD-L1 in host cells. The increased expression strengthens the PD-1 ICP and immune inhibitory signals. (D) Antibodies. An anti-BTLA antibody is used as an agonist to enhance the BTLA ICP, which amplifies immune inhibitory signals. (E) Cells. DCs are collected and transfected with the coding genes of PD-L1 and MOG peptide. These engineered DCs have the enhanced expression of PD-L1 and MOG peptides. After these DCs are transferred back into mice, they promote immune inhibitory signals in vivo through the PD-1 ICP and the presentation of the MOG peptide to T cells.