Accelerated arthritis in E and P selectin deficient mice

描述(申请人提供)：黏附分子的表达决定了启动的炎症反应的类型，因此设计用于抑制黏附分子功能的治疗药物的开发似乎非常值得。然而，我们的初步数据表明，选择性黏附分子抑制可能会放大某些炎症反应。因此，代偿性黏附分子的表达可能在这种体内环境中发挥作用，并可能以类似于细胞因子网络的方式发挥作用。例如，众所周知，IL-13具有许多类似于IL-4的特性。同样，IL-15具有IL-2的冗余特性，而IL-1β具有与IL-18相似的特性。可能随着免疫系统变得更加复杂，进化出了内置的备份机制，削弱了任何一种细胞因子的整体重要性。因此，正如细胞因子网络观察到的那样，某些黏附分子可以弥补缺失或拮抗的黏附分子。总体而言，这项建议将通过将黏附分子表达、单核细胞调节和白细胞募集联系起来，为炎症的启动和维持提供新的见解。这些研究将证明靶向黏附分子作为治疗类风湿关节炎和其他炎症性疾病的潜在治疗策略所涉及的复杂性。虽然普遍的教条认为IL-1β调节选择素，但这项研究提出了一个新的假设，即在体内，E-和P-选择素调节IL-1β的产生和CIA的发育。

DESCRIPTION (provided by applicant): Adhesion molecule expression dictates the type of inflammatory response initiated, therefore the development of therapeutics designed at inhibiting adhesion molecule function seem very worthwhile. However, our preliminary data indicates that selective adhesion molecule inhibition may amplify certain inflammatory responses. Thus, compensatory adhesion molecule expression may be functioning in this in vivo environment and may work in a similar fashion as cytokine networks. For example, it is well established that IL-13 has many properties similar to IL-4. Likewise, IL-15 has redundant properties to IL-2, and IL-1beta has similar properties to IL-18. It may be that as the immune system became more sophisticated, there evolved built in backup mechanisms, attenuating the overall importance of any 1 cytokine. Therefore, as observed with cytokine networks, certain adhesion molecules may compensate for missing or antagonized ones. Overall, this proposal will provide novel insight pertaining to the initiation and maintenance of inflammation by linking adhesion molecule expression, monokine regulation, and leukocyte recruitment. These studies will demonstrate the complexity involved in targeting adhesion molecules as a potential therapeutic strategy for the treatment of RA and other inflammatory disorders. While common dogma suggests IL-1beta regulates selectins, this study proposes the novel hypothesis that in vivo E- and P-selectins regulate IL-1beta production and CIA development.