The broad objective of these investigations is to establish the molecular, cellular and genetic basis of the acute and chronic granulomatous inflammation induced by the peptidoglycan-polysaccharide polymers isolated from group A streptococcal cell walls (PG-APS). These well-characterized PG-APS polymers are resistant to biodegradation, immunogenic and capable of modulating the immune response. Injection of a susceptible strain of rat with a PG-APS polymer of appropriate size and structure will induce a prolonged, remittent, chronic erosive arthritis which resembles many features of human inflammatory arthritis. This experimental model provides a defined structure upon which to focus study of the etiology of human rheumatoid and reactive arthritides, and an opportunity to examine in vivo the function of a variety of inflammatory mediator in evolving inflammation of joints. The first specific aim is designed to test the capacity of several highly purified cytokine or eicosanoid mediators to cause reactivation of erosive synovitis which has been initiated by PG-APS. Another experimental approach will involve testing the effect of specific inhibitors of cytokines or arachidonic acid metabolites on recurrence of arthritis induced by PG=APS or lipopolysaccharide. The effect of long term administration of nonsteroidal anti-inflammatory agents and steroids on progression of experimental chronic remittent erosive arthritis induced by PG-APS will also be examined. Another specific aim is to characterize an interleukin 1 inhibitor produced by rat macrophages stimulated by PG-APS and to determine its role in regulation of joint inflammation induced by PG-APS.
Showing the most recent 10 out of 14 publications
