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Immune checkpoint receptors in regulating immune reactivity in rheumatic disease.

Ceeraz S, Nowak EC, Burns CM, Noelle RJ - Arthritis Res. Ther. (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, 1 Medical Center Drive, Lebanon, NH 03756, USA. sabrina.c.delong@dartmouth.edu

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.

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Currentin vivoimmune 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.
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Fig1: Currentin vivoimmune 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.

Mentions: In summary, checkpoint regulators represent viable immunotherapeutic targets for the treatment of both autoimmunity and cancer. 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). In addition, interventions in multiple murine models utilizing several of these pathways, either by blocking co-stimulatory receptors or by engaging inhibitory receptors, have profound therapeutic effects. However, abatacept is the only agent to achieve FDA approval in the autoimmune human diseases RA and JIA. To date, these findings have not translated into safe and effective therapy for other diseases. In light of the veritable explosion of effective treatments for RA and the approval of more agents for the treatment of psoriatic arthritis, a particular disappointment is the limited progress on this front in SLE. Expectations are still high that this will be achieved within the next few years. The current leading contenders for a successful agent in SLE from a checkpoint regulator perspective are αCD275, abatacept, or a modified αCD154 Ab. Perhaps SS and certainly SSc remain even more daunting disease targets. The intense ongoing investigation in this already fruitful area will undoubtedly produce more candidates for clinical trials in SLE and other rheumatic diseases in the near future.Figure 1


Immune checkpoint receptors in regulating immune reactivity in rheumatic disease.

Ceeraz S, Nowak EC, Burns CM, Noelle RJ - Arthritis Res. Ther. (2014)

Currentin vivoimmune 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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4289356&req=5

Fig1: Currentin vivoimmune 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.
Mentions: In summary, checkpoint regulators represent viable immunotherapeutic targets for the treatment of both autoimmunity and cancer. 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). In addition, interventions in multiple murine models utilizing several of these pathways, either by blocking co-stimulatory receptors or by engaging inhibitory receptors, have profound therapeutic effects. However, abatacept is the only agent to achieve FDA approval in the autoimmune human diseases RA and JIA. To date, these findings have not translated into safe and effective therapy for other diseases. In light of the veritable explosion of effective treatments for RA and the approval of more agents for the treatment of psoriatic arthritis, a particular disappointment is the limited progress on this front in SLE. Expectations are still high that this will be achieved within the next few years. The current leading contenders for a successful agent in SLE from a checkpoint regulator perspective are αCD275, abatacept, or a modified αCD154 Ab. Perhaps SS and certainly SSc remain even more daunting disease targets. The intense ongoing investigation in this already fruitful area will undoubtedly produce more candidates for clinical trials in SLE and other rheumatic diseases in the near future.Figure 1

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, 1 Medical Center Drive, Lebanon, NH 03756, USA. sabrina.c.delong@dartmouth.edu

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.

Show MeSH
Related in: MedlinePlus