GENETIC MOUSE MODELS FOR CHRONIC INFLAMMATORY DISEASE

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Systemic lupus erythematosus, Wegener's granulomatosis, and polyarteritis nodosa are chronic inflammatory diseases that have vasculitis as a major component. The pathogenesis of vasculitis in these and other disorders involves a complex interaction among inflammatory, genetic, and environmental factors. Evidence from both patient studies and in vitro models supports a central role for leukocyte/endothelial cell adhesion molecules, such as ICAM-1 and its beta2 integrin counterreceptors, in the development of vasculitis. However, the specific mechanisms by which ICAM-1 mediates vasculititic lesion formation are not clear. This project will use a straightforward genetic approach using the MRL/MpJ-Faslpr mouse model to define the ICAM-1-dependent pathways responsible for mediating vasculitis. MRL/MpJ-Faslpr mice containing mutations in ICAM-1, LFA-l, Mac-1 and P150/95 have now been generated and will be used to investigate the roles of leukocyte/endothelial interactions in lesion formation in vivo. The specific aims are to: (i) define, by comprehensive qualitative and quantitative analysis, the effects of ICAM-1 deficiency on development and progression, organ distribution, and inflammatory characteristics of lesions of vasculitis in MRL/MpJ-Faslpr mice; (ii) define the relative contributions of ICAM-1 in mediating neutrophil, lymphocyte, and monocyte adhesion to MRL/MpJ-Faslpr endothelial cells; (iii) determine the roles of ICAM-1 in neutrophil-mediated damage to MRL/MpJ-Faslpr endothelial cells; and (iv) determine whether MRL/MpJ-Faslpr mice with null mutations in the ICAM-1 ligands CD11a (LFA-1), CD11b (Mac-1), or CD11c (p150/95) will alter development and progression, organ distribution, or inflammatory characteristics of lesions of vasculitis. Upon successful completion of these aims, detailed mechanistic information regarding the roles of ICAM-1 in mediating leukocyte/endothelial adhesion and damage during the development of vasculitis will be obtained. In addition, new insights will be gained towards the general understanding of the pathogenesis of vasculitis as well as other leukocyte-mediated vascular injuries such as transplantation arteriosclerosis, and other reperfusion injuries. There have been many requests for these mutant mice or materials derived from these models; therefore, these models are contributing significantly to ongoing research that is relevant to several NIH institutes, including NIAMS, NHLBI, and NIAID.