In vivo regulation of interleukin 1beta in patients with cryopyrin-associated periodic syndromes.
The investigation of interleukin 1beta (IL-1beta) in human inflammatory diseases is hampered by the fact that it is virtually undetectable in human plasma. We demonstrate that by administering the anti-human IL-1beta antibody canakinumab (ACZ885) to humans, the resulting formation of IL-1beta-antibody complexes allowed the detection of in vivo-produced IL-1beta. A two-compartment mathematical model was generated that predicted a constitutive production rate of 6 ng/d IL-1beta in healthy subjects. In contrast, patients with cryopyrin-associated periodic syndromes (CAPS), a rare monogenetic disease driven by uncontrolled caspase-1 activity and IL-1 production, produced a mean of 31 ng/d. Treatment with canakinumab not only induced long-lasting complete clinical response but also reduced the production rate of IL-1beta to normal levels within 8 wk of treatment, suggesting that IL-1beta production in these patients was mainly IL-1beta driven. The model further indicated that IL-1beta is the only cytokine driving disease severity and duration of response to canakinumab. A correction for natural IL-1 antagonists was not required to fit the data. Together, the study allowed new insights into the production and regulation of IL-1beta in man. It also indicated that CAPS is entirely mediated by IL-1beta and that canakinumab treatment restores physiological IL-1beta production.
National Amyloidosis Centre, Royal Free and University College Medical School, London NW3 2PF, England, UK.
Helen J
HJ
Lachmann
Philip
P
Lowe
Sandra Daniela
SD
Felix
Christiane
C
Rordorf
Kieron
K
Leslie
Sheril
S
Madhoo
Helmut
H
Wittkowski
Stephan
S
Bek
Nicole
N
Hartmann
Sophie
S
Bosset
Philip N
PN
Hawkins
Thomas
T
Jung
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D002097:C-Reactive Protein / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D010505:Familial Mediterranean Fever / Q000097:blood / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D006706:Homeostasis; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use; D053583:Interleukin-1beta / Q000276:immunology*; D015850:Interleukin-6 / Q000097:blood; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017472:Receptors, Interleukin-1 / Q000097:blood; D000685:Serum Amyloid A Protein / Q000378:metabolism; D014581:Urticaria / Q000097:blood / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology
D000911:Antibodies, Monoclonal; D002352:Carrier Proteins; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D015850:Interleukin-6; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D017472:Receptors, Interleukin-1; D000685:Serum Amyloid A Protein; D002097:C-Reactive Protein