IL-11 Induces Th17-Cell Responses in Relapsing Remitting Multiple Sclerosis (RRMS) (P5.338)

Objective: To characterize the role of IL-11 in the development of the autoimmune response in RRMS.Background: IL-11 is the most upregulated cytokine in the serum and CSF of patients with clinically isolated syndrome (CIS) suggestive of MS and, which in the in-vitro studies induces Th17-cell differentiation.Methods: Intracellular cytokine staining was performed in PBMC and CSF samples from 6 untreated RRMS patients. Brain biopsy tissue obtained from 5 MS patients during diagnostic workup was used for immunohistochemistry studies.44 SJL mice with PLP139-151-induced RREAE received one dose of IL-11 (25 ug/kg) i.p. or saline during the first or second clinical flare-up. 16 h later mice were sacrificed, and blood, spleen, lymph nodes, spinal cord and brain tissue was used for the intracellular cytokine staining, gene expression studies and ELISA cytokine measurements.Results: The percentage of IL-11 and IL-17A-expressing CD4+ T-cells was significantly increased in CSF (47.2[percnt]) from the RRMS patients in comparison to the corresponding blood sample (6.6[percnt]). The percentage of IL-11+CD4+ T-cells positively correlated with the percentage of IL-17A+CD4+ cells in blood samples. Immunohistochemistry studies of the active MS lesions revealed that 62.8[percnt] of CD4+ cells expressed IL-11, and 65.9[percnt] CD4+ cells expressed IL-17A.In EAE studies, IL-11 administration significantly increased the clinical disease activity, as well as the amount of the inflammatory infiltrates in the spinal cord. IL-11 administration during the first relapse increased the percentage of IL-17A+CD4+ cells in PBMCs and the spinal cord inflammatory infiltrates, while the IL-11 administration during the second relapse increased the percentage of IL-17A+CD4+ cells in PBMCs, spleen and spinal cord cell infiltrates.Conclusions: Our study has demonstrated that IL-11+CD4+ T cells accumulate in the CSF and active brain MS lesions. Studies of mice with RREAE confirmed the causal role of IL-11 in the induction of Th17 responses. Disclosure: Dr. Markovic Plese has received personal compensation for activities with Genzyme Inc. Dr. Zhang has received personal compensation for activities with EMD Serono. Dr. Khan has nothing to disclose. Dr. Zelasky has nothing to disclose. Dr. Kurtoglu has nothing to disclose. Dr. Cohen has nothing to disclose. Dr. Miller has nothing to disclose. Dr Sobel has received research support from the National Institutes of Health.