NEUTROPHILS AND G-CSF IN RHEUMATOID ARTHRITIS

嗜多形核粒细胞（PMNs）是 主要细胞存在于滑液中， 炎症性关节炎和血管翳/软骨处积聚 在RA的交界处。 G-CSF是一种有效的化学引诱剂，激活剂， 可能导致PMN的PMN存活因素 炎症关节内的积聚和激活及其伴随物 共同毁灭。 G-CSF可在患者的滑液中检测到， 大多数关节炎和它的管理，以一些患者 类风湿性关节炎急性发作是February综合征的结果。 假设我们 我希望在这项提案中审查的是，G-CSF有助于 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， 该提案的具体目标是： 目的I：确定关节内注射G-CSF的后果 生产对PMN募集和激活以及软骨损伤的影响 在抗原诱导的关节炎兔模型中。 目的II：确定调节G-CSF产生的因素， 以IL-1为重点的兔关节炎模型。 目的III：开发阻断G-CSF信号传导的试剂， 检查它们对PMN激活、关节炎症和 在兔关节炎模型中的软骨损伤。 这些研究的总体目标是开发治疗方法 靶向G-CSF对PMN的作用，可能会减弱内流 以及它们在发炎关节中的激活。 这些试剂 也可能在其他临床情况下证明是有用的，其中G-CSF- 介导的PMN浸润有助于疾病。

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.