The involvement of Th17-cells in the development of the autoimmune response in relapsing remitting multiple sclerosis (RRMS) is well documented. However, there is still no consensus regarding the cytokines required for the differentiation of human Th17-cells. Our preliminary studies have identified IL- 11 as a new Th17-promoting cytokine. Furthermore, we found that IL-11 is the most significantly increased cytokine in the serum and cerebrospinal fluid (CSF) of patients with clinically isolated syndrome (CIS) suggestive of MS. Although we have also demonstrated an increase in the IL-11 serum and CSF levels in patients with clinically definitive RRMS in comparison to healthy controls (HCs), and significantly higher serum IL-11 levels during the clinical exacerbations in comparison to the remissions, those results still do not confirm a causative role of this cytokine in the development of the inflammatory CNS disease. The rationale for our proposed research is that the in-vivo animal model of the disease will allow us to directly characterize the role of IL-11 in the development of the autoimmune response. Based on preliminary results, our central hypothesis is that IL-11 may play a critical role in the regulation of Th17-cells, which represent a pathogeni cell subset driving the autoimmune response in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Our long-term goal is to characterize the molecular mechanisms through which IL-11 initiates, augments and perpetuates the autoimmune response in RRMS. We will pursue the following specific aims: 1. Characterize the role of IL-11 in the development of the Th17-mediated autoimmune response in EAE. The study will: 1.A. Identify to what extent IL-11 induces the development of RR EAE. 1.B. Determine the effectiveness of anti-IL-11 mAb in the prevention and suppression of the clinical and histopathological parameters of RR EAE. 2. Determine the effect of IL-11-mediated Th17-cell differentiation and expansion on the development of encephalitogenic Th17-cells. More specifically, we will: 2.A. Determine the effect of IL-11-mediated na?ve CD4+ T-cell differentiation in the Th17-cell passive transfer EAE. 2.B. Identify the effect of IL-11-mediated Th17 memory cell expansion in adoptive transfer EAE. The proposed in-vivo animal studies are expected to characterize the role of IL-11 in the development of the Th17-cell- mediated CNS inflammatory disease, and to provide results that will justify selective targeting of IL-11 in the treatment for RRMS.
Our preliminary results have identified an increased IL-11 serum and cerebrospinal fluid levels in patients with the earliest clinical presentation of MS, and the IL-11-mediated differentiation of Th17-cells. While our human results suggest the role of IL-11 in the development of the inflammatory response in MS, the in-vivo animal model of the disease will allow us to directly characterize a causal role of IL-11 in the initiation and the expansion of the autoimmune response in EAE. The results are expected to identify novel therapeutic targets for this disabling neurological disease.
