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Review
. 2018 Oct 8;9:2306.
doi: 10.3389/fimmu.2018.02306. eCollection 2018.

Immune Checkpoints as Therapeutic Targets in Autoimmunity

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Free PMC article
Review

Immune Checkpoints as Therapeutic Targets in Autoimmunity

Christopher Paluch et al. Front Immunol. .
Free PMC article

Abstract

Antibodies that block the immune checkpoint receptors PD1 and CTLA4 have revolutionized the treatment of melanoma and several other cancers, but in the process, a new class of drug side effect has emerged-immune related adverse events. The observation that therapeutic blockade of these inhibitory receptors is sufficient to break self-tolerance, highlights their crucial role in the physiological modulation of immune responses. Here, we discuss the rationale for targeting immune checkpoint receptors with agonistic agents in autoimmunity, to restore tolerance when it is lost. We review progress that has been made to date, using Fc-fusion proteins, monoclonal antibodies or other novel constructs to induce immunosuppressive signaling through these pathways. Finally, we explore potential mechanisms by which these receptors trigger and modulate immune cell function, and how understanding these processes might shape the design of more effective therapeutic agents in future.

Keywords: agonist; antibody; autoimmunity; immune checkpoint; immunosuppression; inhibitory receptor.

Figures

Figure 1
Figure 1
Possible mechanisms of action of agonist agents, based on the kinetic-segregation model of receptor signaling. (A) The kinetic-segregation model. (Left) Checkpoint receptors contain intracellular motifs such as the ITIM which are phosphorylated by small membrane associated kinases (e.g., Lck) but rapidly dephosphorylated by abundant bulky phosphatases (e.g., CD45), with no net signaling. (Right) When the receptor encounters its ligand on an apposing cell the balance of kinase and phosphatase activity is tipped in favor of kinases, for example by steric exclusion of phosphatases from the contact zone, resulting in net phosphorylation of the ITIM and subsequent recruitment of signaling machinery which inhibits cellular activation. (B) Triggering by aggregation. An agonist compound may cause receptor triggering by densely clustering kinase-associated receptors so that bulky phosphatases are again sterically excluded. (C) Triggering by an Fc receptor immobilized compound. An agonist that binds to Fc receptors on an apposing cell could lead to triggering by holding the receptor in a close contact zone that phosphatases cannot enter.

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