IN VIVO ROLE OF CRP IN TRANSGENIC MICE

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The overall objective of this program is to define the role of C reactive protein (CRP) in host defense mechanisms. It has been hypothesized, based largely on in vitro studies, that CRP functions during the early preimmune stages following inflammatory stimulus. A clear role for CRP during the course of inflammatory response in vivo has not been established. In the prior funding period the principal investigator has generated transgenic mice which express rabbit CRP with either a metallothionein (MTT) or PEPCK promoter which has made possible expression of CRP independent of inflammatory stimuli. These transgenic animals have been used in three mouse models of inflammation which include the systemic effects of LPS and PAF, a model of alveolar inflammation and a model of monoarticular arthritis. In all three systems CRP expressing transgenic mice have shown reproducible antiinflammatory effects. The present proposal is to extend the studies on the mechanisms of CRP as a participant in inflammation, The working hypotheses are that the effects of CRP are dependent on its ability to bind phosphocholine (PC), CRP can influence expression of cytokines and adhesion molecules, and antiinflammatory effects on antigen enduced arthritis are mediated by inhibition of T cell activation during the afferent arm of the immune process. These hypotheses will be tested by: 1) producing transgenic mice expressing a mutant CRP which has been designed to be incapable of PC binding; 2) measuring the effects of CRP on inflammatory cytokine gene expression in monocytes, splenocytes and neutrophils; and 3) manipulating the level of CRP before, during and after the initiation of the immune response in a model of arthritis to determine the effect of CRP on T cell activation.