Targeting the Jak/STAT pathway for immunosuppression

Abstract

Studies in humans with mutations of Jak3 and its associated receptor subunits have predicted that selective Jak3 antagonists could represent a new class of immunosuppressants. In contrast to existing drugs, Jak3 has limited tissue expression and discrete functions. A highly selective inhibitor would therefore not be expected to result in toxicities seen with existing immunosuppressants. A selective Jak3 antagonist, CP-690 550, has now been developed and is effective in models of transplant rejection including studies in non-human primates. Importantly, it is also not associated with unacceptable adverse effects indicative of substantial Jak2 inhibition. As the drug moves towards clinical trials in humans, it will be important to determine other clinical settings ranging from autoimmunity and allergy to cancer in which this new agent might be useful. Given the importance of cytokines in regulating all phases of the immune response, the successful generation of a selective Jak inhibitor demonstrates the feasibility of targeting Jaks and raises the question as to whether targeting other Jaks might also be useful. In principle, targeting STATs and the negative regulators of cytokine signalling could be effective and these molecules will surely continue to receive considerable attention as therapeutic targets.