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.
| 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: |
| 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 |
| 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 |
| 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 |
| Preusser, Matthias; Lim, Michael; Hafler, David A et al. (2015) Prospects of immune checkpoint modulators in the treatment of glioblastoma. Nat Rev Neurol 11:504-14 |
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