Recently, several islet antigens have been implicated in IDDM, but the factors that control their presentation by MHC class II molecules is unknown. The main objective of this proposal is to identify the components involved in generation of the epitopes recognized by the circulating autoreactive T cells, and the role that cells of distinct lineages play in disease progression, using the NOD model of IDDM.
In specific aim 1, the roles that invariant chain and DM play in generation of class II: peptide complexes from the islet antigens will be examined. We will create APC that differ only in the expression of these cofactors and then evaluate presentation of the islet autoantigens. In addition, biochemical analyses will be performed to evaluate whether the NOD class II molecule displays unique intracellular trafficking patterns or atypical interactions with Ii and/or DM to evaluate whether some of the unique disease association with this class II allele relate to generalized characteristics of intracellular events involved in class II restricted presentation.
In specific aim 2, the capacity of cells of different lineages to generate the epitopes recognized by circulating autoimmune T cells will be examined and will focus on macrophages, dendritic cells, endothelial cells and pancreatic beta cells. We will evaluate whether these cells generate the activating T cell epitope, or alternatively if they generate antagonist peptide;MHC class II complexes. In this aim we will also evaluate the potential of the islet antigens recognized by circulating T cells during IDDM 9GAD, carboxypeptidase H, HSP 60) to be presented by an endogenous class II presentation pathway. None of these are expressed at appreciable levels at the cell surface, and each has a distinctive subcellular localization that might lead to generation of unique peptides. Finally, in aim 3, it will be tested whether expression of MHC class II molecules on cells that lack accessory function, specifically pancreatic beta cells, antagonizes the autoimmune process. Transgenic NOD mice will be derived that constitutively express their own syngeneic class II molecules on their pancreatic beta cells. In addition to monitoring transgenic mice for disease incidence, we will also use several adoptive transfer strategies to precipitate autoimmune attach. If the pancreatic beta cells that constitutively express class II molecules are able to display class II islet antigen specific epitopes, and if their accessory function remains insufficient for differentiation of the TjhI subset of T cells, they may be capable of antagonizing the initiation or progression of the disease. The phenotypic characteristics of autoimmune CD4 T cells will be evaluated both in vivo and in vitro. Finally., to directly demonstrate that the mechanism involved in disease antagonism caused by constitutive expression NOD class II on the pancreatic beta cells is related specifically to their lack of accessory function, we will cross the RIP-I- Ag7 mouse to the RIP-B7-1 mouse, which will endow the pancreatic beta cell with potent accessory activity for T cell activation.
|Szot, Gregory L; Yadav, Mahesh; Lang, Jiena et al. (2015) Tolerance induction and reversal of diabetes in mice transplanted with human embryonic stem cell-derived pancreatic endoderm. Cell Stem Cell 16:148-57|
|Bluestone, Jeffrey A; Buckner, Jane H; Fitch, Mark et al. (2015) Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med 7:315ra189|
|Bour-Jordan, Hélène; Bluestone, Jeffrey A (2009) Regulating the regulators: costimulatory signals control the homeostasis and function of regulatory T cells. Immunol Rev 229:41-66|
|Bluestone, Jeffrey A; Kuchroo, Vijay (2009) Autoimmunity. Curr Opin Immunol 21:579-81|
|Meagher, Craig; Tang, Qizhi; Fife, Brian T et al. (2008) Spontaneous development of a pancreatic exocrine disease in CD28-deficient NOD mice. J Immunol 180:7793-803|
|Kabak, Shara; Clark, Marcus R (2004) Membrane-targeted peptides derived from Igalpha attenuate B-cell antigen receptor function. Biochem Biophys Res Commun 324:1249-55|
|McFarland, B J; Katz, J F; Beeson, C et al. (2001) Energetic asymmetry among hydrogen bonds in MHC class II*peptide complexes. Proc Natl Acad Sci U S A 98:9231-6|
|Salomon, B; Rhee, L; Bour-Jordan, H et al. (2001) Development of spontaneous autoimmune peripheral polyneuropathy in B7-2-deficient NOD mice. J Exp Med 194:677-84|
|Chatenoud, L; Salomon, B; Bluestone, J A (2001) Suppressor T cells--they're back and critical for regulation of autoimmunity! Immunol Rev 182:149-63|
|O'Herrin, S M; Slansky, J E; Tang, Q et al. (2001) Antigen-specific blockade of T cells in vivo using dimeric MHC peptide. J Immunol 167:2555-60|
Showing the most recent 10 out of 38 publications