The goal of this project is to better understand mechanistically, how viral infections could be involved in the pathogenesis of type 1 diabetes (T1 D) using the NOD and RIP-LCMV mouse models. Our approach is based on the hypothesis (which also unifies this PPG) that viruses, even if they are incapable of causing autoimmune disease per se, will modulate an ongoing autoimmune process or, conversely, provide 'fertile field' for autoaggressive lymphocytes. Our preliminary data indicate that Coxsackie Virus B3 (CVB) as well as LCMV cross-reactive viruses can accelerate the diabetogenic process and result in clinical disease, when the infection occurs during a susceptible period in prediabetic mice. Based on these findings we wish to deepen our mechanistic insight and will address the following 3 aims:1. How does CVB accelerate T1 D? Evaluation of bystander effects (cytokines, in analogy to Dr.Fujinami's approach) that affect the aggressive response and antigen presenting cells(immunoproteasome activation in collaboration with Dr. Whitton).2. Do subdominant viral responses accelerate disease if they encounter a 'fertile field' in thepancreas/islets, and which qualities needs the viral infection provide to achieve this?3. Which type of viral infections will provide a diabetogenic environment for autoreactive CD8+clones and which factors are essential (collaboration with Dr. Whitton and Fujinami)?Mechanistic insight will help us to search for causative agents in human patients at risk to develop T1D.
| Schneider, Darius A; von Herrath, Matthias G (2013) Viruses and Type 1 diabetes: a dynamic labile equilibrium. Diabetes Manag (Lond) 3:217-223 |
| Van Belle, Tom L; Nierkens, Stefan; Arens, Ramon et al. (2012) Interleukin-21 receptor-mediated signals control autoreactive T cell infiltration in pancreatic islets. Immunity 36:1060-72 |
| Libbey, Jane E; Tsunoda, Ikuo; Fujinami, Robert S (2012) Possible role of interleukin-17 in a prime/challenge model of multiple sclerosis. J Neurovirol 18:471-8 |
| Boettler, Tobias; Cunha-Neto, Edecio; Kalil, Jorge et al. (2012) Can an immune-regulatory vaccine prevent HIV infection? Expert Rev Anti Infect Ther 10:299-305 |
| Filippi, Christophe M; Ehrhardt, Katrin; Estes, Elizabeth A et al. (2011) TLR2 signaling improves immunoregulation to prevent type 1 diabetes. Eur J Immunol 41:1399-409 |
| Libbey, Jane E; Fujinami, Robert S (2011) Experimental autoimmune encephalomyelitis as a testing paradigm for adjuvants and vaccines. Vaccine 29:3356-62 |
| Fousteri, Georgia; Dave, Amy; Morin, Bret et al. (2011) Nasal cardiac myosin peptide treatment and OX40 blockade protect mice from acute and chronic virally-induced myocarditis. J Autoimmun 36:210-20 |
| van Belle, Tom L; Coppieters, Ken T; von Herrath, Matthias G (2011) Type 1 diabetes: etiology, immunology, and therapeutic strategies. Physiol Rev 91:79-118 |
| Bresson, Damien; Fousteri, Georgia; Manenkova, Yulia et al. (2011) Antigen-specific prevention of type 1 diabetes in NOD mice is ameliorated by OX40 agonist treatment. J Autoimmun 37:342-51 |
| Van Belle, Tom L; Esplugues, Enric; Liao, Jeanette et al. (2011) Development of autoimmune diabetes in the absence of detectable IL-17A in a CD8-driven virally induced model. J Immunol 187:2915-22 |
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