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IL-17A controls IL-17F production and maintains blood neutrophil counts in mice.

ABSTRACT: G-CSF, its receptor, and IL-17 receptor A (IL-17RA) are all required to maintain baseline neutrophil counts in mice. In this study, we tested whether IL-17F could compensate and maintain baseline neutrophil counts in the absence of IL-17A. Unlike the reduced neutrophil counts found in IL-17RA-deficient mice, neutrophil counts were mildly increased in IL-17A-deficient (Il17a(-/-)) animals. There was no evidence for infection or altered neutrophil function. Plasma G-CSF and IL-17F levels were elevated in Il17a(-/-) compared with wild-type mice. IL-17F was mainly produced in the spleen and mesenteric lymph nodes, but IL-23 was unaltered in Il17a(-/-) mice. Instead, Il17a(-/-) splenocytes differentiated with IL-6, TGF-beta, and IL-23 ex vivo produced significantly more IL-17F in response to IL-23 than wild-type cells. Adding rIL-17A to Il17a(-/-) splenocyte cultures reduced IL-17F mRNA and protein secretion. These effects were also observed in wild-type but not IL-17RA-deficient cells. We conclude that IL-17A mediated suppression of IL-17F production and secretion requires IL-17RA and is relevant to maintain the normal set point of blood neutrophil counts in vivo.

SUBMITTER: von Vietinghoff S

PROVIDER: S-EPMC2759196 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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IL-17A controls IL-17F production and maintains blood neutrophil counts in mice.

von Vietinghoff Sibylle S Ley Klaus K

Journal of immunology (Baltimore, Md. : 1950) 20090619 2

G-CSF, its receptor, and IL-17 receptor A (IL-17RA) are all required to maintain baseline neutrophil counts in mice. In this study, we tested whether IL-17F could compensate and maintain baseline neutrophil counts in the absence of IL-17A. Unlike the reduced neutrophil counts found in IL-17RA-deficient mice, neutrophil counts were mildly increased in IL-17A-deficient (Il17a(-/-)) animals. There was no evidence for infection or altered neutrophil function. Plasma G-CSF and IL-17F levels were elev ...[more]

PMID: 19542376

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Project description:Interleukin (IL)-17A is a key driver of inflammation and the principal target of anti-IL-17 therapeutic monoclonal antibodies. IL-17A, and its structurally similar family member IL-17F, have been shown to be functionally dysregulated in certain human immune-mediated inflammatory diseases such as psoriasis, psoriatic arthritis, and axial spondyloarthritis. Given the overlapping biology of these two cytokines, we postulated that dual neutralization of IL-17A and IL-17F may provide a greater depth of clinical response in IL-17-mediated diseases than IL-17A inhibition alone. We identified 496.g1, a humanized antibody with strong affinity for IL-17A but poor affinity for IL-17F. Affinity maturation of 496.g1 to 496.g3 greatly enhanced the affinity of the Fab fragment for IL-17F while retaining strong binding to IL-17A. As an IgG1, the affinity for IL-17A and IL-17F was 3.2 pM and 23 pM, respectively. Comparison of 496.g3 IgG1 with the commercially available anti-IL-17A monoclonal antibodies ixekizumab and secukinumab, by surface plasmon resonance and in a human in vitro IL-17A functional assay, showed that 496.g3 and ixekizumab display equivalent affinity for IL-17A, and that both antibodies are markedly more potent than secukinumab. In contrast to ixekizumab and secukinumab, 496.g3 exhibited the unique feature of also being able to neutralize the biological activity of IL-17F. Therefore, antibody 496.g3 was selected for clinical development for its ability to neutralize the biologic function of both IL-17A and IL-17F and was renamed bimekizumab (formerly UCB4940). Early clinical data in patients with psoriasis, in those with psoriatic arthritis, and from the Phase 2 studies in psoriasis, psoriatic arthritis, and ankylosing spondylitis, are encouraging and support the targeted approach of dual neutralization of IL-17A and IL-17F. Taken together, these findings provide the rationale for the continued clinical evaluation of bimekizumab in patients with immune-mediated inflammatory diseases.

Dataset Information

IL-17A controls IL-17F production and maintains blood neutrophil counts in mice.

Publications

IL-17A controls IL-17F production and maintains blood neutrophil counts in mice.

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