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  • Review Article
  • Published:

A new modality for immunosuppression: targeting the JAK/STAT pathway

Nature Reviews Drug Discovery volume 3, pages 555–564 (2004)Cite this article

Key Points

  • Although immunosuppressive therapy is effective at present, toxicity remains an important problem.

  • Many of the existing immunosuppressive agents are directed against ubiquitous targets and therefore have side effects that are unrelated to immunosuppression. Consequently, generating drugs against molecules with restricted expression and/or function might be advantageous.

  • The Janus kinase JAK3 is crucial for signalling by key immunoregulatory cytokines, but has restricted expression and function. This is best illustrated by patients with mutations of the gene encoding this kinase: such children have severe combined immunodeficiency but do not have abnormalities outside of the immune system. This phenotype suggests that JAK3 might be an ideal target.

  • A selective JAK3 inhibitor, CP-690,550, has now been generated to effectively block immune responses both in vitro and in vivo. Other JAK3 inhibitors have been previously described, but none are as potent or selective as CP-690,550. This drug is effective in models of transplant rejection and is not associated with the toxicities that are seen with other immunosuppressive agents. A JAK3 inhibitor is likely to have uses in many settings beyond transplantation, including autoimmune disease and possibly haematopoietic malignancy.

  • Targeting other JAKS and other elements in the JAK/STAT pathway is also conceptually appealing. On the basis of the phenotype that is associated with TYK2 deficiency, a TYK2 antagonist might be useful in inhibiting diseases that are characterized by the activation of TH1 cells. Given their importance in malignant transformation and immunoregulation, STAT proteins have received considerable attention as therapeutic targets and STAT inhibitors are being studied at present. SOCs proteins are cytokine-induced feedback inhibitors of signalling, which can also be considered as potential targets.

Abstract

Thousands of organs are transplanted each year and millions of people suffer from autoimmune diseases, which creates a need for an armamentarium of immunosuppressive drugs. Unfortunately, immunosuppressants have unwanted side effects owing, in part, to the fact that they have ubiquitous molecular targets. Cytokines have emerged as important controllers of the immune response, and work during the past decade has identified Janus kinases (JAKs) and signal transducers, and activators of transcription (STATs), as crucial intracellular elements in cytokine signalling. Here, we discuss the potential of the JAK/STAT pathway as a target for new immunosuppressants. In particular, the inhibition of JAK3 seems to be an excellent strategy, because of the selective expression and precise functions of this kinase.

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Figure 1: Schematic of JAK3 structure.
Figure 2: Overview of cytokine signalling and the molecular basis of severe combined immunodeficiency.
Figure 3: A selective JAK3 antagonist inhibits JAK activity, blocking early cytokine signalling and resultant STAT activation.
Figure 4

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Authors and Affiliations

  1. Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    John J. O'Shea & Marko Pesu

  2. Transplantation Immunology Laboratory, Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, 94305, California, USA

    Dominic C. Borie

  3. Department of Antibacterials, Immunology and Cancer, Pfizer Global Research and Development, Groton, 06340, Connecticut, USA

    Paul S. Changelian

Authors
  1. John J. O'Shea
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  2. Marko Pesu
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Correspondence to John J. O'Shea, Dominic C. Borie or Paul S. Changelian.

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Competing interests

Dr O'Shea's and Borie's laboratory have received support from Pfizer. Dr Borie also has personal financial interests. Dr Changelian is employed by Pfizer and has personal financial interests.

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DATABASES

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IL-2

IL-2RG

IL-4

IL-7

IL-7R

IL-9

IL-15

IL-21

IL-23

JAK1

JAK2

JAK3

SOCS1

SOCS2

SOCS3

STAT3

STAT4

STAT5

STAT6

TYK2

Online Mendelian Inheritance in Man

asthma

autosomal recessive SCID

chronic myelogenous leukaemia

hyperimmunoglobulin E syndrome

multiple sclerosis

rheumatoid arthritis

systemic lupus erythematosus

X-SCID

FURTHER INFORMATION

John O'Shea's homepage

Transplant Immunology in the Department of Cardiothoracic Surgery, Stanford University

Glossary

IMMUNOSUPPRESSANT

A compound that inhibits immune responses and is used to treat a wide range of diseases, from allergies and asthma to severe autoimmune disease and transplant rejection.

PROTEIN TYROSINE KINASE

An enzyme with phosphotransferase activity, which specifically catalyses the transfer of phosphate from ATP to tyrosine residues on proteins.

CYTOKINES

A large diverse group of small secreted glycoproteins, which regulate the function of a wide range of cells.

HOMEOSTASIS

A generic term describing the status of physiological normality. With respect to the immune system, the concept refers to the maintenance of normal numbers and composition of peripheral lymphocytes.

HELPER T CELLS

(TH). A subset of CD4+ T cells. Following antigen-mediated activation, these cells coordinate the immune response by the secretion of cytokines and cell–cell interactions.

MEMORY T CELL

A long-lived T lymphocyte that has encountered its antigen. During subsequent encounters with the antigen, memory cells are more readily activated than naive cells.

INTERLEUKIN

(IL). This is a generic term for cytokines that are produced by leukocytes, which have important roles in immunoregulation, host defence and inflammation.

SELF TOLERANCE

The lack of response to self antigens; the concept refers to mechanisms that prevent the generation of immune and inflammatory responses to normal cells and tissues. Cytokines, such as interleukin-12, are one mechanism that controls tolerance.

REGULATORY T CELL

(TReg). A lymphoid cell that suppresses humoral and cell-mediated immunity.

DENDRITIC CELLS

(DCs). These professional antigen-presenting cells are increasingly recognized as having crucial immunoregulatory functions. They are found in various tissues where they take up antigens, process them, migrate to the lymph nodes and present the antigens to T cells.

MAST CELL

A bone marrow-derived cell that is present in various tissues; they are important contributors to allergic disease and recent data have also pointed towards a role in arthritis.

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O'Shea, J., Pesu, M., Borie, D. et al. A new modality for immunosuppression: targeting the JAK/STAT pathway. Nat Rev Drug Discov 3, 555–564 (2004). https://doi.org/10.1038/nrd1441

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