Multiples Sclerosis (MS) is an important clinical problem, but molecular targets for antigen-specific therapeutic immune intervention remain elusive. The immune phenotype of MS is best mimicked in the experimental autoimmune encephalomyelitis (EAE) model in mice. Antigen presenting cells such as dendritic cells (DCs) play a pivotal role in mediating peripheral tolerance and suppressing inflammation. In EAE, these cells lose their tolerogenic properties resulting in uncontrolled neuronal inflammation. Current therapies involve non-specific immune suppression with long-term side effect and not just antigen specific suppression. We have shown recently that Wnt-?-catenin pathway in dendritic cells and macrophages play critical role in modulating inflammatory responses in the intestine. Given that EAE is a chronic inflammatory disease, we sought to determine the function of Wnt-?-catenin pathway in dendritic cells and macrophages in autoimmune brain inflammation. Now, we show that, functionally, the ?-catenin/TCF signaling pathway plays a critical biological role in programming DCs and Macrophages to induce tolerogenic response and prevents brain inflammation. However, downstream mechanisms by which ?-catenin/TCF pathway in DCs acts to create tolerance and prevents EAE are completely unknown. Our central hypothesis is that ?-catenin/TCF transcription factors constitute a key molecular pathway in promoting regulatory phenotype in DCs that drives their ability to induce T regulatory cells (Tregs) differentiation and suppress Th1/Th17 cell differentiation. Together these are critical for promoting tolerance and suppressing EAE. We will test our hypothesis in the following specific aims (i) Test the hypothesis that ?-catenin induced activation of the TCF transcription factor pathway is critical for the induction of two key immune regulatory genes - IL-10 and TGF-?1 in response to adjuvant-induced EAE (Aim 1);(ii) Test the hypothesis that the ?-catenin/TCF-4 pathway in DCs is critical for inducing MBP-specific T regulatory cells differentiation and suppressing pathological Th1/Th17 cell differentiation (Aim 2);(iii) Test the hypothesis that, functionally, the ?-catenin/TCF pathway plays a critical biological role in inducing tolerogenic response and suppressing pathologic inflammatory response in the brain and spinal cord (Aim 3). The successful completion of the proposed studies will provide new mechanistic insights into how the ?- catenin/TCF pathway in DCs and macrophages regulate a balance between tolerance and inflammatory responses, and will provide a mechanistic rationale for targeting this pathway in MS. Pharmacological activators of ?-catenin pathway already exist, and more are in development. The proposed studies will provide a rationale for the development of an entirely new class of agents that may have significant therapeutic impact in treating MS.
A fundamental puzzle in immunology is how the immune system decides between tolerogenic response versus inflammatory response against commensals, pathogens and self-antigens. Antigen presenting cells such as dendritic cells (DCs) and macrophages (Mbeta2) play a central role in this complex decision making process, but the molecular pathways that program these cells are not known. We have identified a novel molecular pathway that programs dendritic cells and macrophages to a regulatory phenotype to induce tolerogenic response and limit autoimmune brain inflammation. The information gained from these studies will provide will provide a rationale for the development of an entirely new class of agents that may have significant therapeutic impact in treating chronic inflammatory disease like multiple sclerosis.
