JAK3 inhibition as a new concept for immune suppression

Although current immunosuppressive drugs are effective, they have numerous severe side effects that mandate the search for new agents. Mutations in the gene for janus kinase (JAK)3 result in severe combined immune deficiency with severely impaired humoral and cellular immunity, an observation that has prompted the development of JAK3 inhibitors. Due to its central role in lymphocyte activation, proliferation and homeostasis, targeting the JAK/signal transducer and activator of transcription (STAT) pathway may provide the required efficacy, without the toxicities associated with current therapies. Several studies conducted in rodents have validated the proof-of-concept, with a variety of JAK3 inhibitors demonstrating efficacy for immune suppression. In addition, the selective JAK3 inhibitor CP-690550 (Pfizer Inc) significantly improved allograft survival in a stringent preclinical model in primates and exhibited a good safety profile in non-human primates. This, along with studies of protein kinase inhibitors for cancer treatment, could demonstrate that development of effective, safe and selective kinase inhibitors for immunosuppression is possible.