New strategies for immunosuppression: interfering with cytokines by targeting the Jak/Stat pathway.
OBJECTIVE
Numerous immunosuppressants are available, but their adverse effects related to actions on nonlymphoid cells is problematic. Cytokines are key regulators of immune and inflammatory responses, and blocking their actions has become an important modality in treating autoimmune disorders. This review will discuss strategies to develop novel immunosuppressants that arise from advances in the understanding of cytokine signaling.


RESULTS
It is now recognized that large number of cytokines exert their effect by binding to receptors that activate the Janus kinase/signal transducer and activator of transcription pathway, so targeting intracellular signaling pathways is a logical strategy. A selective inhibitor of Janus kinase 3 has now been generated and is effective for transplant rejection in nonhuman primates and other models. Advances have also been made in understanding the functions of Stat family transcription factors, and approaches to interfering with the action of these DNA binding proteins are being devised. In addition, the identification of negative regulators of cytokine signaling offers additional therapeutic opportunities.


CONCLUSIONS
A selective inhibitor of Janus kinase 3 has now been generated and likely represents a new class of effective immunosuppressants. Strategies for targeting signal transducers and activators of transcription pathway are being intensively studied at present and hold potential promise. Multiple endogenous mechanisms exist for negatively regulating cytokine signaling; whether novel therapies can be devised that exploit these mechanisms remains to be determined.
O'Shea
John J
JJ
Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892-1820, USA. osheaj@arb.niams.nih.gov
Park
Heiyoung
H
Pesu
Marko
M
Borie
Dominic
D
Changelian
Paul
P
D000818:Animals; D016207:Cytokines / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000187:drug effects* / Q000378:metabolism; D015195:Drug Design; D017408:Guidelines as Topic; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D053613:Janus Kinase 1; D011505:Protein-Tyrosine Kinases / Q000187:drug effects* / Q000378:metabolism; D050794:STAT1 Transcription Factor; D016511:Severe Combined Immunodeficiency / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015534:Trans-Activators / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
D016207:Cytokines; D004268:DNA-Binding Proteins; D007166:Immunosuppressive Agents; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1