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.
Borie
Dominic C
DC
Transplantation Immunology Laboratory, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5407, USA. dborie@stanford.edu
Si
Ming-Sing
MS
Morris
Randall E
RE
Reitz
Bruce A
BA
Changelian
Paul S
PS
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D053616:Janus Kinase 3; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D016511:Severe Combined Immunodeficiency / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology
D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; D053616:Janus Kinase 3