Objective
In this project, we aim to achieve two aims. First, using a pharmacological approach, we will test if our Hdac7-selective inhibitor could inhibit Th17 cell differentiation, plasticity, and their production of pathogenic cytokines, thereby inhibiting autoimmune diseases using animal models. Second, using a genetic approach, we will test if Hdac7 expression in Th17 cells promotes disease pathogenesis of MS, SLE, and T1D and whether Hdac7 controls the gene transcription of Th17 cells similary or differently in different disease conditions. Our overarching goal will be to establish Th17 plasticity as a targetable avenue for autoimmune diseases, and provide proof-of-concept data of Hdac7-selective inhibitor for the wide application of MS, SLE, and T1D.
Background Rationale
Th17 pathway is central to autoimmune diseases, including multiple sclerosis (MS), systemic lupus erythematosus (SLE) and Type 1 diabetes (T1D). However, antibodies neutralizing IL-17A have yielded unsatisfactory results in human MS, SLE and T1D, as have been shown in other autoimmune diseases such as inflammatory bowel diseases. A reconciliation of these findings has now been achieved through the discovery of Th17 plasticity, a process that allows Th17 cells to produce other inflammatory cytokines in addition to IL-17A. For example, Th17 cell production of IFN-γ has been shown to cause tissue-specific damage in different autoimmune diseases, and antibodies neutralizing IFN-γ or upstream cytokine IL-23/IL-21 that promote Th17 plasticity are more effective than IL-17A neutralization alone in ameliorating human MS, SLE, and T1D. These studies collectively suggest that Th17 cell plasticity is a common disease-modifying mechanism for MS, SLE, and T1D. However, the molecular driver of Th17 plasticity remains unclear, hindering the development of effective small-molecule inhibitors that would allow for effective and simple administration routes for autoimmune patients. We have previously demonstrated that epigenetic protein Hdac7 is required for Th17 cell differentiation and intestinal inflammation. Using Th17-cell specific gene deletion and animal models of MS, we have recently discovered that Hdac7 promotes Th17 cell plasticity, their development to IL17A+IFNγ+ cells, and production of inflammatory cytokines, in central nervous system inflammation. We further developed an Hdac7-selective inhibitor that disrupts the interaction of Hdac7 with Th17-specific transcriptional factors, which may be therapeutically effective in different animal models of autoimmune diseases. These exciting genetic and chemical tools are excellent for their wider testing of animal models of different autoimmune diseases.
Description of Project
Th17 pathway is central to autoimmune diseases, including multiple sclerosis (MS), systemic lupus erythematosus (SLE) and Type 1 diabetes (T1D). However, antibodies neutralizing IL-17A have yielded unsatisfactory results in human MS, SLE and T1D, as have been shown in other autoimmune diseases such as inflammatory bowel diseases. A reconciliation of these findings has now been achieved through the discovery of Th17 plasticity, a process that allows Th17 cells to produce other inflammatory cytokines in addition to IL-17A. For example, Th17 cell production of IFN-γ has been shown to cause tissue-specific damage in different autoimmune diseases, and antibodies neutralizing IFN-γ or upstream cytokine IL-23/IL-21 that promote Th17 plasticity are more effective than IL-17A neutralization alone in ameliorating human MS, SLE, and T1D. These studies collectively suggest that Th17 cell plasticity is a common disease-modifying mechanism for MS, SLE, and T1D. However, the molecular driver of Th17 plasticity remains unclear, hindering the development of effective small-molecule inhibitors that would allow for effective and simple administration routes for autoimmune patients. We have previously demonstrated that epigenetic protein Hdac7 is required for Th17 cell differentiation and intestinal inflammation. Using Th17-cell specific gene deletion and animal models of MS, we have recently discovered that Hdac7 promotes Th17 cell plasticity, their development to IL17A+IFNγ+ cells, and production of inflammatory cytokines, in central nervous system inflammation. We further developed an Hdac7-selective inhibitor that disrupts the interaction of Hdac7 with Th17-specific transcriptional factors, which may be therapeutically effective in different animal models of autoimmune diseases. In this project, we aim to achieve two aims. First, using a pharmacological approach, we will test whether our Hdac7-selective inhibitor could inhibit Th17 cell differentiation, plasticity, and their production of pathogenic cytokines, thereby inhibiting autoimmune diseases using animal models. Second, using a genetic approach, we will test if Hdac7 expression in Th17 cells promotes disease pathogenesis of MS, SLE, and T1D, and whether Hdac7 controls the gene transcription of Th17 cells similarly or differently in different disease conditions. Our overarching goal is to establish Th17 cell plasticity as a targetable avenue for autoimmune diseases, and provide proof-of-concept data of Hdac7-selective inhibitor for the wide application of MS, SLE and T1D.
Anticipated Outcome
First, we expect that our Hdac7-selective inhibitor will inhibit Th17 cell differentiation, plasticity, and their production of pathogenic cytokines, associated with the amelioration of different animal models of autoimmune diseases. Second, using I17a-Cre mice, we expect that Hdac7 deletion in Th17 cells will reduce disease pathogenesis of MS, SLE, and T1D, and the production of pathogenic cytokines in diseased tissues in different animal models. We also expect to compare the similarities and differences of Hdac7-mediated gene transcription of Th17 cells in different disease conditions. Our overarching goal is to establish the central mechanism of Th17 plasticity as a targetable avenue for autoimmune diseases, and provide proof-of-concept data of Hdac7-selective inhibitor for the wide application of MS, SLE, and T1D.
Relevance to T1D
Th17 plasticity and pathogenicity have now been characterized as over-production of pro-inflammatory cytokines IFN-γ and/or GM-CSF, and downregulation of regulatory IL-10, in cells that are originally Th17 cells (exTh17). The strong evidence of Th17 cells to adopt a Th1 cell-like profile, either IFN-γ+exTh17 or IFN-γ+Th17 cells, indicates that Th17 plasticity is the main driver of inflammation in different autoimmune diseases, including IBD, MS, SLE, and T1D. Notably, although approaches to inhibit pathogenic Th17 cells are currently being developed, our understanding of how Class IIa Hdacs function in pathogenic Th17-mediated autoimmune diseases has remained elusive, and thus seriously hampers their potential as viable epigenetic drugs for MS, SLE, and T1D. We showed that Hdac4/7 are required for intestinal inflammation and development of a pathogenic Th17 cell subset (IL17A+IFN-γ+) in animal models of intestinal inflammation. Using cellular models of Th17 cell culture, we also showed that Hdac4 directly activates pathogenic genes while Hdac7 represses Il10 expression in pathogenic Th17 cells. Using the MS model EAE mice, we have recently discovered that epigenetic protein Hdac7 promotes central nervous system inflammation. Further, using Th17-fate-mapping EAE mice, IL17A+IFN-γ+ cells and production of inflammatory cytokines are reduced in Th17 cells when Hdac7 is deleted. These data demonstrated that Hdac7 is both required for differentiation and plasticity of Th17 cells. We further developed an Hdac7-selective inhibitor that disrupts the interaction of Hdac7 with Th17-specific transcriptional factors, which may be therapeutically effective in different animal models of autoimmune diseases. Therefore, we believe that Hdac7 likely regulates the conversion of mature Th17 cells to different pathogenic (IFNγ+, GM-CSF+) or regulatory subsets (IL-10+), and we seek to establish the therapeutic efficacies of Hdac7-selective inhibitors in MS, SLE, and T1D.