635 Mary Ellen Jones, CB #7290
The work ongoing in the laboratory focuses on two general areas. The first entails investigation of mechanisms regulating autoimmune recognition and responses to self-proteins. For this purpose we employ a murine model of Type 1 diabetes (T1D) that is characterized by the T cell mediated destruction of the insulin producing beta cells found in pancreatic islets. A broad range of aspects regarding the disease process are being studied, including the development and immunoregulation of beta cell-specific CD4+ and CD8+ T cells, biochemical interactions between T cell receptors and MHC molecules, and the regulation of dendritic cell and macrophage activation and effector function.
A second key area of focus of the group is the development of “vaccines” to prevent and/or treat T1D, in addition to establishing tolerance for islet transplants. Approaches include the use of genetic-based vaccines such as adeno-associated virus vectors expressing various immunoregulatory cytokines, and antibodies to selectively target beta cell-specific T cells. In addition, efforts are ongoing to develop strategies to promote beta cell replication and reverse longstanding diabetes. Our translational studies include the use of humanized mouse models to directly assess the effects of various immunotherapies on human pathogenic and regulatory immune effector cells, and human beta cells.
In summary, the work ongoing in the laboratory encompasses both fundamental and translational aspects of immune recognition of self-proteins in the context of autoimmunity.
He Q, Morillon YM, Kroger, CJ, Wang B, Tisch R. 2013. Thymic development of autoreactive T cells in NOD mice is regulated in an age-dependent manner. J. Immunol. 191:5858-5866.
Johnson MC, Garland AL, Nicolson SC, Li C, Samulski RJ, Wang B, Tisch R. 2013. b cell-specific IL-2 therapy increases islet Foxp3+Treg and suppresses type 1 diabetes in NOD mice. Diabetes 62:3775-3784.
Martin A, Tisch RM, Getts DR. 2013. Manipulating T cell-mediated pathology: targets and functions of monoclonal antibody immunotherapy. Clin. Immunol. 148:136-147.
Diz R, Garland A, Vincent BG, Johnson MC, Spidale N, Wang B, Tisch R. 2012. Autoreactive effector/memory CD4+ and CD8+ T cells infiltrating grafted and endogenous islets in diabetic NOD mice exhibit similar T cell receptor usage. PlosOne 7(12):e52054.
Yi Z, Diz R, Martin AJ, Morillon YM, Kline DE, Wang B, Tisch R. 2012. Long-term remission of diabetes in NOD mice is induced by nondepleting anti-CD4 and anti-CD8 antibodies. Diabetes 61:2871-2880.
Yi Z, Li L, Garland A, He Q, Wang H, Katz JD, Tisch R, Wang B. 2012. IFNg receptor deficiency prevents diabetes induction by diabetogenic CD4+ T cells but not CD8+ T cells. Eur. J. Immunol. 42:2010-2018.
Liblau R, Wekerle H, Tisch R. 2011. Cumulative autoimmunity: T cell clones recognizing several self-epitopes exhibit enhanced pathogenicity. Front. Immun. 2:47 doi:10.3389/fimmu.2011.00047
Goudy KS, Johnson MC, Garland A, Li C, Samulski RJ, Wang B, Tisch R (2011). Reduced IL-2 expression in NOD mice leads to a temporal increase in CD62Llo FoxP3+ CD4+ T cells with limited suppressor activity. Eur J Immunol. 41(5):1480-90. doi: 10.1002/eji.201040890.
Goudy KS, Johnson MC, Garland A, Li C, Samulski RJ, Wang B, Tisch R (2011). Inducible adeno-associated virus-mediated IL-2 gene therapy prevents autoimmune diabetes. J Immunol. 186(6):3779-86.
Johnson MC, Wang B, Tisch R (2011). Genetic vaccination for re-establishing T-cell tolerance in type 1 diabetes. Hum Vaccin. 7(1):27-36.
Kroger CJ, Flores RR, Morillon M, Wang B, Tisch R (2010). Dysregulation of thymic clonal deletion and the escape of autoreactive T cells. Arch Immunol Ther Exp (Warsz). 58(6):449-57.
Tisch R (2010). Immunogenic versus tolerogenic dendritic cells: a matter of maturation. Int Rev Immunol. 29(2):111-8. Review.
Wallet, M.A., R.R. Flores, Y. Wang, Z. Yi, C.J. Kroger, C.E. Mathews, H.S. Earp, G. Matsushima, B. Wang, and R. Tisch. 2009. MerTK regulates thymic selection of autoreactive T cells. Proc. Natl. Acad. Sci. USA 106:4810-4815.
Yi, Z., L. Li, H.S. Earp, G.K. Matsushima, B. Wang, and R. Tisch. 2009. A novel role for c-Src and STAT3 in apoptotic cell-mediated MerTK-dependent immunoregulation of dendritic cells. Blood 114:3191-3198.
Li, L., Z. Yi, B. Wang, and R. Tisch. 2009. Suppression of T cell-mediated autoimmunity by peptide-MHC class II dimer vaccination. J. Immunol. 183:4809-4816.
Wallet, M.A., P. Sen, R.R. Flores, Y. Wang, Z. Yi, Y. Huang, C.E. Mathews, H.S. Earp, G. Matsushima, B. Wang, and R. Tisch. 2008. MerTK is required for apoptotic cell-induced T cell-tolerance. J. Exp. Med. 205:219-232.
Xiu, Y.+, C.P. Wong+, Y. Hamaguchi, Y. Wang, S.M. Pop, R.M. Tisch*, and T.F. Tedder*. 2008. B cell depletion by anti-CD20 monoclonal antibody prevents diabetes in NOD mice despite isotype-specific differences in FcgR effector functions. J. Immunol. 180:2863.
Li, L., B. Wang, J.A. Frelinger, and R. Tisch. 2008. T cell promiscuity in autoimmune diabetes. Diabetes 57:2099-2106.
Goudy, K.S., B. Wang, and R. Tisch. 2008. Gen gun-mediated DNA vaccination enhances antigen-specific immunotherapy at a late preclinical stage of type 1 diabetes in nonobese diabetic mice. Clin. Immunol. 129:49-57.
Sen, P., M.A. Wallet, Z. Yi, Y. Huang, M. Henderson, C.E. Mathews, H.S. Earp, G. Matsushima, A. S. Baldwin, and R. M. Tisch. 2007. Apoptotic cells induce MerTK-dependent blockade of NF-kB activation in dendritic cells. Blood 109:653-660.
Wong, C.P., R. Stevens, B. Long, L. Li, Y. Wang, M.A. Wallet, K.S. Goudy, J.A. Frelinger, and R. Tisch. 2007. Identical beta cell-specific CD8+ T cell clonotypes typically reside in PBL and the pancreatic islets. J. Immunol. 178:1388-1395.
Pop, S.M., C.P. Wong, Q. He, Y. Wang, M.A. Wallet, K.S. Goudy, and R. Tisch. 2007. The type and frequency of immunoregulatory CD4+ T cells govern the efficacy of anitgen-specific immunotherapy in diabetic NOD mice. Diabetes 56:1395-1402.
Wong, C.P., L. Li, J.A. Frelinger, and R. Tisch. 2006. Early autoimmune destruction of islet grafts is associated with a restricted repertoire of IGRP-specific CD8+ T cells in diabetic NOD mice. J. Immunol. 176:1637-1644.
Long, B., C.P. Wong, Y. Wang, and R. Tisch. 2006. Lymphopenia-driven CD8+ cells are resistant to antigen-induced tolerance in NOD.scid mice. Eur. J. Immunol. 36:2003-2012.
Wallet, M.A., and R. Tisch. 2006. Type 1 diabetes, inflammation and dendritic cells. Drug Discovery Today: Disease Mechanisms 3:373-379.
Pop, S.M., C.P. Wong, D.A Coulton, S.H. Clarke, and R. Tisch. 2005. Single cell analysis shows decreasing FoxP3 and TGFbeta1 co-expressing CD4+CD25+ regulatory T cells during autoimmune diabetes. J. Exp. Med. 201:1333-1346.
Wallet, M.A., P. Sen, and R. Tisch. 2005. Immunoregulation of dendritic cells. Clin. Med. Res. 3:166-175.
Goudy, K.S., and R. Tisch. 2005. Immunotherapy for the prevention and treatment of type 1 diabetes. Int. Rev. Immunol. 24:307-326.