NEUTROPHILS AND G-CSF IN RHEUMATOID ARTHRITIS

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Polymorphonuclear neutrophilic granulocytes (PMNs) are the predominant cells that are present in the synovial fluid of inflammatory arthritis and that accumulate at the pannus/cartilage junction in RA. G-CSF is a potent chemoattracant, activator, and survival factor for PMN that may be contributing to PMN accumulation and activation within inflamed joints and its attendant joint destruction. G-CSF can be detected I the synovial fluid of most inflamed joints and its administration to some patients with Felty~s syndrome results in acute flares of RA. The hypothesis we wish to examine in this proposal is that G-CSF contributes to recruitment and activation of PMNs in inflamed joints and contributes to joint inflammation and destruction. To that end, the Specific Aims in the proposal are: AIM I: To determine the consequences of intraarticular G-CSF production on PMN recruitment and activation and cartilage damage in the antigen-induced-arthritis rabbit model. AIM II: To determine the factors modulating G-CSF production in rabbit models of arthritis focusing on Il-1. AIM III: To develop reagents that block G-CSF signaling and to examine their effects on PMN activation, joint inflammation, and cartilage damage in rabbit models of arthritis. The overall goal of these investigations are to develop therapies targeting the effect of G-CSF on PMN that may attenuate the influx of PMNs and their activation in the inflamed joint. These agents might also prove useful in other clinical situations in which G-CSF- mediated PMN infiltration contributes to disease.