NEUTROPHILS AND G-CSF IN RHEUMATOID ARTHRITIS

中性粒细胞(PMN)是 关节滑液中的优势细胞 炎症性关节炎和血管膜/软骨积聚 RA的交界处。G-CSF是一种强大的趋化剂、激活剂和 可能对PMN起作用的PMN的生存因素 炎症关节及其伴发部位的蓄积和活化 联合毁灭。关节滑液中可检测到G-CSF 最易发炎的关节及其对某些患者的治疗 Felty~S综合征导致类风湿性关节炎急性发作。我们的假设是 希望在这项提案中检查的是G-CSF对 炎症关节中中性粒细胞的募集和激活 导致关节发炎和破坏。为此， 该建议的具体目标是： 目的I：确定关节内注射G-CSF的后果 中性粒细胞募集活化与软骨损伤的研究进展 在抗原诱导的兔关节炎模型上。 目的II：确定G-CSF产生的调节因素。 以IL-1为核心的兔关节炎模型。 目的III：开发阻断G-CSF信号转导的试剂 检查它们对PMN激活、关节炎症和 兔关节炎模型的软骨损伤。 这些研究的总体目标是开发治疗方法。 靶向G-CSF对中性粒细胞的抑制作用 中性粒细胞及其在发炎关节中的激活。这些特工 可能在其他临床情况下也被证明是有用的，在这些情况下，G-CSF- 介导性PMN的渗入有助于疾病的发生。

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.