Autoimmune diseases afflict millions of people worldwide and are the fourth leading cause of disability in women in the US (USDHHS, 2000). Thousands more seek treatment to prevent rejection of tissue and organ transplants. Unfortunately, current immunosuppressive treatments are often inadequate and associated with many undesirable side effects. Immunoregulatory T cells (Tregs) potently suppress immune responses and offer a promising therapeutic alternative. The discovery of a novel approach to induce Tregs is important and timely. The Ah receptor (AhR) is a ligand-activated transcription factor that induces the differentiation of CD4+Tregs. Our laboratory made the original discovery in studies to define the mechanism underlying the potent immunosuppressive effects of the prototypic AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Since then, several laboratories have validated and extended the scope of Treg induction by TCDD. Studies have also shown that treatment of mice with TCDD suppresses the development of a variety of autoimmune diseases, including our own studies using the non-obese diabetic (NOD) mouse model of Type 1 diabetes, in association with increased frequency of Tregs. Together these findings support a strong case for the AhR as a therapeutic target for treatment of immune-mediated diseases via the induction of Tregs. The goal of our current grant is the discovery of alternative AhR ligands that are capable of inducing AhR-dependent Tregs. We have successfully screened small molecule compound libraries and identified a lead compound (AHRL1) that is structurally distinct from TCDD but activates AhR at nanomolar concentrations. AHRL1 induces AhR-dependent Tregs in vivo that are phenotypically identical to Tregs induced by TCDD and is immunosuppressive in a graft-vs-host response. The hypothesis to be tested in this renewal application is that activation of the transcription factor AhR in CD4+ T cells by certain AhR ligands regulates the expression of specific genes that induce their differentiation into AHR-Tregs, resulting in effective suppression of autoimmune disease. The ultimate goal of our studies is to understand the mechanisms by which AHR activation induces Tregs and identify promising compound(s) that function via AHR for treatment of immune-mediated diseases.
In Specific Aim 1, we hypothesize that AHR ligands other than TCDD are effective in suppressing chronic autoimmune disease via the induction of AHR-dependent Tregs. We will determine the influence of treatment with AHRL1 on the development of diabetes in NOD mice and the association between disease-free survival and increased numbers of Foxp3+CD25+CD4+ Tregs. We will also track the AHR-Treg population over time in mice treated with AHR ligands (AHRL1 and TCDD) to identify changes in gene expression that correlate with disease outcome.
In Specific Aim 2, we hypothesize that activation of AHR in T cells alters signaling pathways leading to their differentiation into Tregs. We will determine the functions of AHR required to induce Tregs by utilizing T cells derived from two distinct mouse lines that express (i) DNA-binding or (ii) nuclear localization-defective AHR. We will also determine the functional significance of specific genes that we identified to be upregulated by TCDD and AHRL1 in AHR-Tregs. The results of these studies will significantly expand our current understanding of the molecular pathways of AHR activation in T cells that lead to Treg induction and will provide an unprecedented foundation for pursuing AHR ligands as more effective, less toxic drugs for the treatment of autoimmune diseases.
The results of these studies will greatly expand our current understanding of the molecular pathways of Aryl Hydrocarbon Receptor (AHR) activation in T cells leading to Treg induction and will provide a stronger foundation for pursuing AHR ligands as novel drugs in the treatment of autoimmune diseases.)The discovery of a novel ligand-activated pathway to induce Tregs is a timely achievement given that millions of people suffer from a vast array of immune-mediated diseases that are often progressive and associated with increased morbidity and mortality.)
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