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

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.