Cytokine pathways in the pathogenesis of idiopathic Multicentric Castleman Disease
UHLFELDER D. 1, SCHÄFER H. 1, BLANFELD M. 1, ANDRUSZEWSKI D. 1, SCHELMBAUER C. 1, GAIDA M. 2, WAISMAN A. 1,3, MUFAZALOV I. 1,3
1 Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany; 2 Institute of Pathology, University Medical Center Mainz, Mainz, Germany; 3 Research Center for Immunotherapy (FZI), Mainz, Mainz, Germany
Multicentric Castleman Disease (MCD) is a group of lymphoproliferative disorders which affect multiple lymph node stations. A severe subtype with unknown etiology is termed idiopathic MCD (iMCD). In this disease, the cytokine interleukin-6 (IL-6) is considered a major pathogenic factor causing systemic inflammation, plasmacytosis and life-threatening organ dysfunction. Siltuximab, an anti-IL-6 monoclonal antibody, is the only FDA-approved drug for iMCD patients which provides significant symptom relief. However, the response rates to anti-IL-6 treatment remain rather low. To facilitate the progress in improving treatment protocols, there is an unmet need to develop suitable preclinical iMCD models.
In this study we aimed to develop a mouse strain with the cell-type-specific IL-6 overexpression, to serve as a model for iMCD.
We generated transgenic mice which can overexpress IL-6 upon Cre-mediated excision of a STOP cassette. We achieved irreversible IL-6 overexpression (IL-6OE) by crossing conditional transgenic mice to mice carrying Foxp3-cre-recombinase. These mice were immunophenotyped using flow cytometry and immunohistochemistry to evaluate iMCD-like symptoms. ELISA was used to measure immunoglobulin and cytokine levels in IL-6OE mice.
IL-6OE mice displayed increased levels of IL-6 in the serum and tissue. This resulted in developing symptoms which were similar to the latest iMCD diagnostic criteria established by the Castleman Disease Collaborative Network. IL-6OE mice developed multifocal lymphadenopathy and pathohistological characteristics including plasmacytosis, anemia, thrombocytopenia, hypergammaglobulinemia, renal dysfunction, and splenomegaly. Among different immunoglobulins, the most pronounced increase was noted for IgG1. To test predictive validity of our model we genetically blocked IL-6 signaling by deleting IL-6 receptor and this way rescued the phenotype of IL-6OE mice. When the IL-1 signaling was blocked the survival of IL-6OE mice was improved.
We established a novel IL-6-based murine model of idiopathic Multicentric Castleman Disease with full penetrance. We demonstrated a pathogenic role of IL-1 signaling in iMCD-like disease in mice.