Jak3 and the pathogenesis of severe combined immunodeficiency

The discovery that Jak3 mutations area significant cause of severe combined immunodeficiency (SCID), a rare inherited defect characterized by lymphopenia, has provided valuable insights into the functions of Jak3 in lymphoid development and function. The current therapy for patients suffering from Jak3 SCID is hematopoetic stem cell transplantation, although gene therapy trials have also been performed. In lieu of crystal Structure data, these patient-derived mutations have aided in the elucidation of the functions and structure of Jak3. By virtue of its requirement for lymphoid functions, Jak3 makes a tantalizing target for immunosuppression and anti-cancer therapy. Herein, we discuss the normal actions of the gamma(c) cytokines, the pathogenesis and treatment of SCID, and finally, the production of a new, selective Jak3 inhibitor capable of preventing transplant rejection in two animal models. Further study of Jak3 will hopefully provide insights into the clinical treatment of patients suffering front immune-mediated diseases. (C) 2004 Published by Elsevier Ltd.