Under funding for the original U19, we addressed several hypotheses that have provided new insights into the fundamental, mechanistic understanding of regulatory T cells and how these pathways are altered in animal models of autoimmune disease and in the human diseases type I diabetes and multiple sclerosis. In addition, we have developed novel immunotherapeutic approaches to induce regulatory T cells using oral anti-CD3. The grant will continue to focus on these fundamental aims, reflecting the discoveries we have made over the past five years. In this renewal, the overall goals of this Autoimmunity Prevention Center Project are: 1) To determine, in human autoimmune disease, which of the CD4+CD25+ subsets of DR+ and DR"""""""" regulatory T cells are defective; 2) The identification of a """"""""core set"""""""" of genes and proteins that are expressed on the """"""""innate"""""""", CD4+CD25+ regulatory T cells; 3) To determine which of the """"""""core sets"""""""" of genes and proteins are altered in the regulatory T cells found in blood and lymph nodes in patients with diabetes and MS; 4) To understand the mechanism of oral anti-CD3 and GRAIL transfection in T cells that allows the translation into human clinical trials by year five of the grant. The key goal is the development of specific drug targets and methods to induce the function of defective regulatory T cells in patients with autoimmune disease. Lay Summary: Diseases such as type I diabetes and multiple sclerosis are complex genetic diseases thought to be initiated by an autoimmune response directed against self-proteins in the inflamed tissue. Why autoreactive T cells attack the insulin producing islet cells in diabetes or the myelin in multiple sclerosis remains a major question. We recently demonstrated there is a loss of an important """"""""regulatory"""""""" immune cell in the circulation of patients with autoimmune disease. This grant assembles a group of investigators to understand why these regulatory cells are dysfunctional, and what can be done to restore their function. PROJECT 1: Mechanism of action of CD4+CD25+ T cells (FATHMAN, GARRISON C.) DESCRIPTION (provided by applicant): This is a competing renewal as a U19 for a previously funded U01 entitled, """"""""CD25+ Regulator CD4+ T Cells."""""""" Under funding for the original U01, several specific aims were addressed: initially (1) that expression of GRAIL (a recently identified anergy gene), following peptide administration iv, blocks IL-2 transcription and induces anergy, a form of tolerance, and (2) that GRAIL expression provides a novel and effective screen for the anergic phenotype in mice (and in man), and (3) that CD4+CD25+ suppressor T cells were involved in this form of tolerance induction, and a fourth (4) GVHD will be blocked by adoptive transfer of Tregs, was added in the second year of support. Ten articles were published on these four specific aims and this proposal will extend these studies as follows: Using microarray and RNAi technology for mRNA expression and gene silencing, the """"""""core genes"""""""" that define Treg core transcriptome will be identified. In this proposal, these """"""""core Treg"""""""" genes, identified by cDNA microarray studies, will be validated by functional genomics (RNAi) and tested in vitro in T cell proliferation assays and in vivo in a model of GVHD, and the """"""""peripheral Treg subset,"""""""" provisionally defined as CD4+ antigen specific T cells that contact antigen under anergy inducing conditions in the periphery, will be further characterized and studied as proposed in the following four specific aims: * Specific Aim 1: Identification of a """"""""core set"""""""" of CD4+CD25+ Treg genes, the Treg core transcriptome. * Specific Aim 2: Characterization of peripherally induced Tregs and core transcriptome identification. * Specific Aim 3: GRAIL transductants as Tregs for immunotherapy. * Specific Aim 4: To evaluate the role of specific genes on Treg function in an in vivo model of graft vs. host disease. The use of adoptive cellular therapy, in particular use of Tregs is rapidly gaining credibility as a useful potential therapy for immunoregulation, in particular in the setting of GVHD, a form of adoptively transferred autoimmune disease. Studies proposed in this project will attempt to identify the """"""""core"""""""" set of genes that define Tregs and then using RNA silencing techniques, attempt to identify functionally relevant genes through knock down and loss of function assays in vitro and using a model of GVHD in vivo. All of the techniques required for these studies are currently practiced in our labs.
| Ponath, Gerald; Lincoln, Matthew R; Levine-Ritterman, Maya et al. (2018) Enhanced astrocyte responses are driven by a genetic risk allele associated with multiple sclerosis. Nat Commun 9:5337 |
| Sumida, Tomokazu; Lincoln, Matthew R; Ukeje, Chinonso M et al. (2018) Activated ?-catenin in Foxp3+ regulatory T cells links inflammatory environments to autoimmunity. Nat Immunol 19:1391-1402 |
| Nylander, Alyssa N; Ponath, Gerald D; Axisa, Pierre-Paul et al. (2017) Podoplanin is a negative regulator of Th17 inflammation. JCI Insight 2: |
| Longbrake, Erin E; Hafler, David A (2016) Linking Genotype to Clinical Phenotype in Multiple Sclerosis: In Search of the Holy Grail. JAMA Neurol 73:777-8 |
| Chastre, Anne; Hafler, David A; O'Connor, Kevin C (2016) Evaluation of KIR4.1 as an Immune Target in Multiple Sclerosis. N Engl J Med 374:1495-6 |
| Cao, Yonghao; Nylander, Alyssa; Ramanan, Sriram et al. (2016) CNS demyelination and enhanced myelin-reactive responses after ipilimumab treatment. Neurology 86:1553-6 |
| Axisa, Pierre-Paul; Hafler, David A (2016) Multiple sclerosis: genetics, biomarkers, treatments. Curr Opin Neurol 29:345-53 |
| Farh, Kyle Kai-How; Marson, Alexander; Zhu, Jiang et al. (2015) Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature 518:337-43 |
| Hernandez, Amanda L; Kitz, Alexandra; Wu, Chuan et al. (2015) Sodium chloride inhibits the suppressive function of FOXP3+ regulatory T cells. J Clin Invest 125:4212-22 |
| Marson, Alexander; Housley, William J; Hafler, David A (2015) Genetic basis of autoimmunity. J Clin Invest 125:2234-41 |
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