While many effective immunosuppressive drugs exist and are in wide use, most target ubiquitously expressed molecules. Examples include steroids, ciclosporin A, tacrolimus, mycophenolate mofetil, and sirolimus. Consequently, these drugs have adverse effects unrelated to their immunosuppressive actions, and much effort has been directed towards identifying molecular targets with expression restricted to immune and inflammatory cells. In principle, such drugs could provide immunosuppression yet lack the toxicity associated with current therapies.

It is now well established that cytokines have critical roles in regulating immunity and inflammation; indeed targeting cytokines themselves has been an effective new strategy for immunosuppression.¹ However, targeting intracellular cytokine signalling also now appears to be a viable new approach. Janus kinases (Jaks) and signal transducers and activators of transcription (STATs) have been demonstrated to be critical elements in signalling by certain families of cytokines. Importantly, the generation of a selective inhibitor of Jak3 appears to be feasible and effective. This report discusses the approach of targeting Jaks and STATs, with emphasis on Jak3 and a newly identified Jak3 antagonist.

CYTOKINES AND IMMUNOREGULATION

Cytokines comprise more than 50 secreted factors that regulate processes ranging from body growth, lactation, and adiposity to haematopoiesis but are especially important for regulating inflammatory and immune responses.² That is, cytokines control both innate and adaptive immunity and are critical for lymphoid development and homoeostasis, as well as the ultimate differentiation of helper and memory T cells.

Interleukin (IL)-2, 4, 7, 9, 15, and 21 comprise one family of cytokines that uses a common receptor subunit termed the common γ chain, or γc (table 1).^3–5 These cytokines are particularly important with respect to lymphoid development and function. For instance, IL-7 is critical for lymphocyte development and function and mice lacking IL-7R expression have arrested thymocyte development at the double negative (CD4–CD8–) stage.^6–11 …