Type 1 diabetes mellitus (T1DM) is an autoimmune disease resulting from the T cell mediated destruction of insulin-producing beta cells located in the pancreas. Current treatment, which includes insulin replacement by injection, frequent blood glucose monitoring, and dietary/exercise discipline, can prevent death from hormonal insufficiency, but is not curative and does not completely prevent the long-term complications including nerve damage, and vascular damage to both large and small blood vessels. The blood vessel damage in turn results in injury to various organs, including the heart, brain, kidneys, and eyes. Life expectancy is shortened by an estimated one-third compared to individuals without T1DM. This work, initiated in the mid 1990's at the Naval Medical Research Institute and further developed at the University of Ulm in Germany and subsequently for the past 2 years at the NIH has characterized a unique murine model of autoimmune diabetes using rat-insulin promoter (RIP)-CD80 transgenic mice (RIP-CD80 mice). These animals are predisposed to immune mediated beta cell destruction based on their beta cell-specific expression of the costimulatory molecule CD80. While RIP-CD80 mice rarely develop spontaneous diabetes (incidence 6.7%, compared to none of wild type mice), we've observed and have initially characterized the profound susceptibility these mice display to develop progressive islet infiltration and eventually insulin dependent diabetes mellitus (IDDM) following immunization with beta cell autoantigens (i.e. protein molecules that are expressed specifically by the pancreatic beta cells of these mice). For instance, these animals, unlike non-transgenic littermates, uniformly develop islet cell destruction and insulin dependent diabetes mellitus (IDDM) upon immunization with an insulin precursor, a beta cell autoantigen strongly suspected to be involved in the pathogenesis of human T1DM. We have shown that at least one relevant autoantigenic CTL epitope (H-2b) must be present in the mature insulin molecule, which contrasts with current algorhythm-based epitope prediction models. Moreover, our model has so far been more predictive of immune responses to therapeutic agents than the non-obese diabetic (NOD) mouse, a model most widely used to study autoimmune diabetes. Our objectives using the RIP-CD80 mouse model can be summarized as follows: (1) Identify important self-antigens (Ag) and CTL-epitopes serving as the initial targets for the developing autoimmune response. We will explore several routes to immunize with candidate auto-antigens, including peptide immunizations, DNA-vaccines, and retrovirally transduced dendritic cells (DC), for their ability to elicit MHC class I restricted T cell responses, insulitis, and diabetes. (2) Study beta cell specific T cell responses in an adoptive transfer model where the primary autoreactive T cell sensitization will take place either in vitro, or by immunizing in vivo, as proposed above in (1). These studies will focus on the mechanisms of the developing beta cell destructive immune responses, and will attempt to identify novel therapeutic approaches to interfere with the ongoing immune responses. (3) Continue to explore our preliminary data suggesting that non-professional antigen-presenting cells (APC), such pancreatic beta cells or fibroblastoid cells, can prime naive precursor CTL in vivo, and stimulate a chronic autoimmune response. The immune response induced by the non-professional APCs contrasts with that produced by professional APC (i.e. those derived from the hematopoetic lineage, such as dendritic cells) in that professional APCs induce a uniform and fulminant islet destruction and diabetes. It is important to recognized that the islet destruction observed in human T1DM is typically not fulminant but is more consistent with the chronic process we've observed. (4) Test potential immunotherapeutic agents being considered for trials in patients with new onset T1DM for their ability to prevent disease in the mouse model. Diabetes induction in the RIP-CD80 model can be biased toward one dependent almost exclusively on CD8+ T cells (antigen pulsed fibroblast immunization) or using different immunization strategies (e.g. DNA vaccination) toward one dependent upon both CD4+ and CD8+ T cells. (5) We have adapted the RIP-CD80 model as an in vivo system capable of testing cells felt to represent progenitors for beta cells for their capacity to generate functional insulin producing cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Intramural Research (Z01)
Project #
1Z01DK062002-04
Application #
6821154
Study Section
(TAB)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2003
Total Cost
Indirect Cost
Name
U.S. National Inst Diabetes/Digst/Kidney
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Lin, Huei-Min; Lee, Ji-Hyeon; Yadav, Hariom et al. (2009) Transforming growth factor-beta/Smad3 signaling regulates insulin gene transcription and pancreatic islet beta-cell function. J Biol Chem 284:12246-57
Craig, Anthony T; Gavrilova, Oksana; Dwyer, Nancy K et al. (2009) Transduction of rat pancreatic islets with pseudotyped adeno-associated virus vectors. Virol J 6:61
Pechhold, Klaus; Koczwara, Kerstin; Zhu, Xiaolong et al. (2009) Blood glucose levels regulate pancreatic beta-cell proliferation during experimentally-induced and spontaneous autoimmune diabetes in mice. PLoS One 4:e4827
Pechhold, Klaus; Zhu, Xiaolong; Harrison, Victor S et al. (2009) Dynamic changes in pancreatic endocrine cell abundance, distribution, and function in antigen-induced and spontaneous autoimmune diabetes. Diabetes 58:1175-84
Cortes, Lizette M; Mattapallil, Mary J; Silver, Phyllis B et al. (2008) Repertoire analysis and new pathogenic epitopes of IRBP in C57BL/6 (H-2b) and B10.RIII (H-2r) mice. Invest Ophthalmol Vis Sci 49:1946-56
Pechhold, Klaus; Chakrabarty, Sagarika; Harlan, David M (2007) Cytotoxic T cell-mediated diabetes in RIP-CD80 transgenic mice: autoantigen peptide sensitivity and fine specificity. Ann N Y Acad Sci 1103:132-42
Liu, Eric H; Siegel, Richard M; Harlan, David M et al. (2007) T cell-directed therapies: lessons learned and future prospects. Nat Immunol 8:25-30
Zhang, Ning; Yang, De; Dong, Huifang et al. (2006) Adenosine A2a receptors induce heterologous desensitization of chemokine receptors. Blood 108:38-44
Taylor-Fishwick, David A; Bowman, Angela; Hamblet, Natasha et al. (2006) Islet neogenesis associated protein transgenic mice are resistant to hyperglycemia induced by streptozotocin. J Endocrinol 190:729-37
Kang, Elizabeth M; Zickler, Philipp P; Burns, Sean et al. (2005) Hematopoietic stem cell transplantation prevents diabetes in NOD mice but does not contribute to significant islet cell regeneration once disease is established. Exp Hematol 33:699-705

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