Regulation of Type I IFNs in Tolerance and Autoimmunity

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PROJECT SUMMARY/ABSTRACT: Interferon alpha (IFN-a) is a pivotal player in the regulation of the innate and the adaptive immune responses, primarily through the activation of dendritic cells (DCs). Abnormal activation of DCs may shift the presentation of self-Ags from tolerance to autoimmunity and, indeed, excessive responses to IFN-a have been proposed to be pathogenic in autoimmune diseases such as lupus. Our long-term goal is to discover biologic factors able to inhibit the response to IFN-a in DCs and determine their effects on the development of autoimmune diseases. Our recent studies indicate that IL-4 suppresses the response of DCs to IFN-a in vitro and in vivo. We propose to investigate the molecular mechanisms by which IL-4 inhibits the innate response to IFN-a and the consequences on the adaptive immune responses. Furthermore, we have found that bone marrow-derived DCs from lupus-prone mice have an intrinsic hyperactivation of the Type I IFN response that is inhibited by IL-4 and we intend to determine the potential of IL-4 as therapy in lupus. In Aim I, we will determine the molecular mechanisms underlying IL-4 suppressive effects on IFN responses. We hypothesize that IL-4 acts on molecules that affect both the first response to paracrine IFN-a/b and the positive feedback loop induced by autocrine IFNab. On the basis of our Preliminary Studies and available literature on IL-4, we hypothesize that a newly IL-4-induced protein inhibits either 1) the phosphorylation of STAT1-2 or 2) the transcription of IFN stimulated genes (ISG) such as IFN-a/b. We will address which signaling pathway, downstream of IL-4R, is mediating IL-4 suppression of IFN response, which mechanism is blocking the STAT1-2 phosphorylation and which mechanism is blocking IFN-b transcription during IL-4 suppression of IFN response. In Aim II, we will test the effects of IL-4 on the stimulation of two adaptive immune responses stimulated by IFN-a, cross-priming and isotype antibody switching in vivo. In Aim III, we will determine the effects of IL-4 targeted to DCs on the development of lupus autoimmunity. We will use two protocols: a) injection of DCs transduced with a lentivirus carrying IL-4, and b) transplantation of bone marrow progenitors transduced with the same lentivirus, and will compare them with systemic administration of IL-4, in terms of therapeutic efficacy and development of side effects. This project will shed light on the regulation of the innate and adaptive responses by cytokines and their potential as novel therapeutic strategy to cure systemic lupus erythematosous. In addition, we will test two novel protocols of gene transfer targeting DCs that may be useful to deliver candidate genes for immune-modulation and induction of tolerance in autoimmunity and transplantation.