Journal Article

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

Borie, Dominic C., O'Shea, John J., Pesu, Marko, Changelian, Paul S.

2004

Overview

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 T H 1 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. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Animals / Biomedical and Life Sciences / Biomedicine / Biotechnology / Cancer Research / Complications and side effects / Cytokine receptors / Enzyme Inhibitors - chemistry / Enzyme Inhibitors - pharmacology / Health aspects / Humans / Immunosuppression - methods / Immunosuppressive agents / Immunosuppressive Agents - chemistry / Immunosuppressive Agents - pharmacology / Interleukin Receptor Common gamma Subunit / Janus Kinase 3 / Medicinal Chemistry / Molecular Medicine / Molecular Structure / Mutation / Pharmacology/Toxicology / Physiological aspects / Protein-Tyrosine Kinases - antagonists & inhibitors / Protein-Tyrosine Kinases - genetics / Receptors, Interleukin-7 - genetics / Receptors, Interleukin-7 - immunology / review-article / Severe Combined Immunodeficiency - drug therapy / Severe Combined Immunodeficiency - enzymology / Signal Transduction - drug effects / Signal Transduction - immunology / Trans-Activators - antagonists & inhibitors