"The NOD and C3H-IL10 knockout mice: Animal models for autoimmune Type 1 diabetes and colitis"

This meeting will be held at the MBC Offices, located on the ninth floor of One Cambridge Center, Cambridge, MA 02142.

Meeting Overview

The NOD mouse model of autoimmune Type 1 diabetes and the C3H-IL10 knockout mouse model of colitis: two complex disease models characterized by defects in innate immunity but with opposite effects of microbial challenge on disease development.

Mouse models of complex diseases in humans typically entail an interaction between a susceptible genotype and an environmental factor(s). Microbial factors are commonly implicated in inflammatory diseases. The NOD/LtJ mouse is an excellent polygenic model for autoimmune, T cell-mediated Type 1 diabetes in humans. To achieve a high penetrance of the diabetes susceptibility genes (e.g., high diabetes incidence), NOD mice must be maintained at high barrier status; exposure of young mice to either bacterial or viral reagents suppresses diabetes development. The mechanism relates to the finding that there are multiple deficiencies in the components of the innate immune system (dendritic cells, and macrophages) manifested by impaired maturation. Immunostimulatory challenge of the innate immune system promotes maturation and, hence, a more normal immunoregulatory communication between the innate and adaptive arms of the immune system.

C3H/HeJBir made genetically deficient in IL-10 develop a juvenile-onset enterocolitis with features resembling Crohn's disease in humans. As yet incompletely-defined components of the enteric flora are essential for disease initiation and progression; if raised at full barrier status, the stock is colitis-free. A major genetic locus was discovered (Cdcs1) distinguishing susceptible IL-10 deficient C3H/HeJBir from B6 mice. Studies in vitro using either macrophages or dendritic cells from these two stocks showed that the innate immune responses of the colitis-susceptible strain was hypo-functional when challenged by bacterial ligands of toll-like receptors. Similar to the NOD mouse diabetes model, this hypo-function was associated with a compensatory hyper-activation of the adaptive immune responsesâ�"but in this case to bacterial antigens rather than to beta cell autoantigens.

Presenter

Edward H. Leiter, Senior Staff Scientist, The Jackson Laboratory, Bar Harbor, ME