Inhibition of IL-6 trans-signaling in SLE

IL-6 is a major inflammatory cytokine of relevance to SLE. It is involved in the humoral immune response as well as in target organ damage. IL-6 binds directly to IL6 receptor (IL-6R) that is expressed on the membrane of a limited number of cell types, and then associates with the co-receptor gp130 to transduce an intracellular signal. This is known as classic IL-6 signaling. IL-6 can also bind to a soluble form of IL-6R to form a complex that engages membrane gp130, inducing the same set of signaling cascades. This is known as IL-6 trans-signaling. Since gp130 is ubiquitously expressed, trans-signaling allows IL-6 to target a much broader range of cells than just those that express IL-6R. Furthermore, during inflammation increases in levels of IL-6 and increased shedding of soluble IL-6 receptor allow trans-signaling to become active and contribute to inflammatory cascades. We hypothesize that an inhibitor of IL-6 trans-signaling, gp130-Fc, will be an effective treatment for ongoing SLE activity and will be safer than current therapies that target both classic and trans-signaling. We will test this hypothesis in several murine SLE models. Our goals are to determine the effects of gp130-Fc on B cell responses to a model antigen and to autoantigen, to determine the effects of gp130-Fc on systemic autoimmunity and target organ injury in mouse models of SLE and to to analyze the role of IL-6 trans-signaling as a mediator of the various components of the renal inflammatory response. Since a human gp130-Fc is in development for the treatment of other autoimmune diseases, success of the proof-of-principle studies proposed here should allow rapid translation to human cli nical trials for active SLE.