Autoimmune Encephalomyelitis and c-Rel

University Of Pennsylvania, Philadelphia PA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): The Rel/NF-KB family of transcription factors play pivotal roles in inflammation and immunity. The long-term goal of our research is to elucidate the mechanisms of Rel/NF-kB action in autoimmune diseases. This proposal is based on our recent discovery that c-Rel-deficient mice are resistant to experimental autoimmune encephalomyelitis (EAE), and are unable to develop a strong TH1 type response to self-myelin antigens. The goal of this proposal is to elucidate the mechanisms of c-Rel action in animal models of multiple sclerosis. A major challenge to study the roles of transcription factors in autoimmune diseases is that they are often expressed by a variety of cell types. In the case of c-Rel, it is expressed not only by cells of the immune system, but also by cells of target organs such as brain and spinal cord. The roles of c-Rel in different cell types must be established before a comprehensive understanding of c-Rel action in autoimmunity can be achieved. We hypothesize that c-Rel expressed by immune cells and neural cells may play different roles in EAE: c-Rel expressed by immune cells orchestrates the activation and effector function of inflammatory cells leading to tissue injury, whereas c-Rel expressed by neural cells protects them from inflammation-induced cell death, presumably by activating anti-apoptotic genes. To test these hypotheses, we will study the roles of c-Rel in 1) activation of myelin-specific T cells, 2) formation of inflammatory lesions, and 3) death of inflammatory and neural cells in EAE. The roles of c-Rel expressed by different cell types will be dissected using transgenic adoptive transfer models and bone-marrow chimeric models. Information generated from these studies may not only help elucidate the mechanisms of c-Rel action in EAE but also aid in developing a general strategy to study the roles of transcription factors in autoimmune diseases. Novel strategies targeting Rel/NF-kB may then be developed to treat or prevent the autoimmune diseases.