Rationale and safety of anti-interleukin-23 and anti-interleukin-17A therapy.
OBJECTIVE
Interleukin-12 is a heterodimeric cytokine and an important mediator of the cellular immune response. The recent discovery of the novel cytokine interleukin-23 has led to a re-evaluation of interleukin-12 biology, as both cytokines use a common p40 subunit. This review discusses understanding of what distinguishes these related cytokines and the infection risks associated with targeting these cytokine pathways during treatment of inflammatory diseases.


RESULTS
Recent work has shown that interleukin-23 stimulates the development of a distinct subset of effector T cells that produce interleukin-17A. These interleukin-17A-producing cells are critical mediators of the inflammatory response in several mouse models of autoimmunity. Although it is well established that interleukin-12 is a critical mediator of host defense, the role of the interleukin-23/interleukin-17A axis during infections has only recently been evaluated.


CONCLUSIONS
Interleukin-12 and interleukin-23 have distinct roles in mediating host defense and autoimmune inflammation. Although targeting interleukin-12 and interleukin-23 simultaneously against the common p40 subunit is efficacious in clinical trials for human autoimmune diseases, targeting of interleukin-23 alone or the downstream effector cytokine interleukin-17A may be an effective treatment strategy for organ-specific autoimmune diseases. It is likely that targeting interleukin-23 or interleukin-17A alone, as opposed to targeting interleukin-12 and interleukin-23 together, will reduce the patients' risk of developing treatment-related infections.
Bowman
Edward P
EP
Discovery Research, Schering-Plough Biopharma, Palo Alto, California 94304, USA.
Chackerian
Alissa A
AA
Cua
Daniel J
DJ
D000818:Animals; D000906:Antibodies / Q000276:immunology* / Q000627:therapeutic use*; D015551:Autoimmunity / Q000276:immunology; D001424:Bacterial Infections / Q000276:immunology / Q000628:therapy*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology*; D020381:Interleukin-17 / Q000276:immunology*; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000276:immunology*; D051379:Mice; D009161:Mycobacterium; D009164:Mycobacterium Infections / Q000276:immunology / Q000628:therapy; D012475:Salmonella; D012480:Salmonella Infections / Q000276:immunology / Q000628:therapy
D000906:Antibodies; C508840:IL23A protein, human; C508841:Il23a protein, mouse; D020381:Interleukin-17; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D018664:Interleukin-12