gms | German Medical Science

Background: Recent progress in the understanding of pathogenic pathways in psoriasis and psoriatic arthritis (PsA) has led to the identification of the IL-23/TH17 axis as a critical component and enabled the development of effective new cytokine blocking therapeutic strategies. Among the effector cytokines of this pathway GM-CSF has been demonstrated as a promising therapeutic target in clinical studies of rheumatoid arthritis. To elucidate the therapeutic potential of GM-CSF-neutralization for psoriatic arthritis (PsA), we investigated its efficacy to ameliorate skin inflammation in a model of psoriasis in the absence of a valid murine model for PsA.

Methods: For investigations on the potential of an anti-GM-CSF antibody (MOR12507) to treat psoriasis we have chosen the murine model of imiquimod (IMQ)-induced psoriasis since it exhibits an extend of similarity with regard to the involved immunological pathways with the human disease. In parallel, a comparative study of IMQ-induced psoriasis was performed in C57/Bl6J mice with a disrupted GM CSF-gene and wild type mice.

Results: GM CSF neutralization resulted in significant amelioration of IMQ-induced psoriasis in mice that received MOR12507 i.p. compared to IgG-isotype control. Clinical improvement was associated with reduction of keratinocyte proliferation and neutrophil migration into the skin. Furthermore, Tnfa mRNA expression was significantly reduced in the MOR12507-treated group. Surprisingly, GM CSF-deficient and GM CSF-sufficient mice did not exhibit any differences in clinical psoriasis manifestations, keratinocyte proliferation and neutrophil infiltration by contrast to the results of antibody-mediated GM-CSF blockade in wild type mice. To elucidate whether GM CSF-deficient mice might have developed a mechanism to compensate for the inborn lack of GM-CSF we studied the pathogenesis of IMQ-induced psoriasis in these mice in detail and uncovered an alternative pathway in which different cell populations and cytokines are involved.

Conclusion: The disease ameliorating effect of GM CSF neutralization associated with a reduction of Tnfa mRNA expression supports the potential value of GM-CSF as a therapeutic target in psoriasis/PsA. The identification of an alternative pathogenic pathway of IMQ-induced psoriasis in a state of continuous lack of GM-CSF in knock-out mice might gain future relevance for monitoring long term GM-CSF blockade, when entering clinical application to treat chronic immune-mediated inflammatory diseases.