IDDM is a T cell-mediated autoimnmune disease characterized by infiltration of the islet cells of the pancreas by immune cells and progressive destruction of insulin secreting pancreatic beta cells. An increasing body of evidence from animal models supports the hypothesis the Th1 lymphocytes are pivotal to the development of IDDM. Increased expression of Th1 type cytokines have been observed during the development of IDDM in NOD mice. Additional support for the involvement of a Th1 response is the observation that inhibition of Th1 cytokines by one or more approaches, delays and/or reduces the incidence of diabetes in NOD mice. NF-kb is a transcription factor involved in the regulation of expression of a number of genes, including IL-1 beta, IL-2, IL-6, IL-12, IFNgamma, TNFalpha, and iNOS. Due to the ubiquitous nature of this transcription factor and its regulatory role in the activation of many of the proinflammatory and Th1 cytokines known to be pivotal to the development of IDDM, the investigators propose that strategies aimed at the attenuation of NF-kb could lead to the prevention and/or treatment of IDDM. The long-range goal is to understand the pathophysiology of IDDM and to develop new strategies for the prevention and/or treatment of the disease. The investigators propose in this application to investigate the role of NF-kb in the development of insulitis and diabetes. The central hypothesis of this proposal is that NF-kb over-expression is a pivotal and essential event in the development of insulitis and diabetes in the NOD mouse. To critically evaluate the hypothesis, the investigators will pursue two specific aims. First, the investigators will determine if inhibition of NF-kb activation reduces the incidence of diabetes and the severity of insulitis in the NOD mouse. Second, to examine potential mechanisms, the investigators will determine if inhibition of NF-kb activation decreases proinflammatory and Th1 cytokines as well as iNOS levels in NOD mice. The work proposed is significant because it will reveal whether neutralization of a pathogenic mechanism that is common to many of the diabetogenic cytokines can be used as an effective therapy to prevent IDDM. In addition, the basic science information the investigators will acquire will provide insight into the role of NF-kb in the pathogenesis of diabetes and may facilitate our development of strategies for treatment of IDDM and possibly other autoimmune diseases.
| Breuel, Kevin F; Kougias, Panagiotis; Rice, Peter J et al. (2004) Anterior pituitary cells express pattern recognition receptors for fungal glucans: implications for neuroendocrine immune involvement in response to fungal infections. Neuroimmunomodulation 11:1-9 |
