ANTI-CD44 IMMUNOTHERAPY IN ARTHRITIS

这项研究计划涉及抗CD-44的治疗用途。 用于治疗实验性炎症和人类的单抗 类风湿关节炎(RA)。这是一种基本的研究方法， 抗CD44治疗对关节影响的综合研究 发炎。在不久的将来，在拉什医疗中心，合作 与风湿科(内科)和我们的 研究小组(生物化学和整形外科)，我们 正计划将抗CD44免疫疗法引入到患有 类风湿关节炎。治疗方案及疗效评价 临床疗效将在很大程度上取决于从 这项研究。 最近我们报道了CD44与透明质酸的相互作用。 酸(HA)在维持组织肿胀方面起着重要作用 将炎性白细胞的交通引导到 实验性关节炎小鼠的炎症(自然医学。1：558-563， 1995年)。我们证明了注射单抗IM7.8.1 (单抗IM7)，针对CD44，消除关节肿胀和白细胞 关节炎症小鼠滑膜组织的浸润性改变。这 抗体诱导表面CD44受体丢失(脱落) 白细胞和滑膜细胞。CD44的损失，以及 受体结合的HA和来自滑膜的相关水，导致 组织肿胀减少，CD44缺乏的白细胞将不再 能够识别HA并迁移到富含HA的细胞外 发炎的滑膜间隙。 我们的初步结果表明，抗体IM7与人发生交叉反应 CD44并诱导人白细胞和滑膜细胞CD44的丢失 在体外，就像在小鼠系统中所显示的那样。这 因此，抗体有可能被引入作为一种治疗方法。 治疗人类类风湿性关节炎的药物。我们对动物模型的开创性研究 揭示了抗炎性关节炎的基本机制 然而，这种免疫疗法的许多其他方面应该是 在人类应用之前进行了探索。我们将鉴定CD44亚型 在维持关节炎症方面发挥主导作用，并设计 针对参与炎症反应的细胞的窄幅免疫治疗 流程。我们将研究与抗CD44相关的调控机制 在活体动物模型和体外对人类细胞的治疗。最后， 我们将探讨抗CD44治疗对T细胞功能的影响。 体内的免疫、造血和生殖系统。我们相信 这些研究将有助于理解CD44在细胞周期中的作用。 炎症和提高抗CD44的临床安全性和有效性 类风湿关节炎的免疫治疗。

This research proposal concerns the therapeutic use of anti-CD-44 monoclonal for the treatment of experimental inflammatory and human rheumatoid arthritic (RA). This is a basic research approach to a comprehensive study on the effects of anti-CD44 treatment upon joint inflammation. In the near future at Rush Medical Center, in collaboration with the Section of Rheumatology (Department of Internal Medicine) and our research groups (Departments of Biochemistry and Orthopedic Surgery), we are planning to introduce anti-CD44 immunotherapy to patients with rheumatoid arthritis. The protocol of treatment and the evaluation of clinical efficacy will be largely based upon the information obtained from this study. Recently we have reported that the interaction of CD44 with hyaluronic acid (HA) plays a major role in maintaining tissue swelling as well as in directing the traffic of inflammatory leukocytes to the site of inflammation in mice with experimental arthritis (Nature Med. 1:558-563, 1995). We demonstrated that the injection of monoclonal antibody IM7.8.1 (mAb IM7), directed to CD44, eliminates joint swelling and leukocyte infiltration in the synovial tissue of mice with joint inflammation. This antibody induces the loss (shedding of the CD44 receptor from the surface of both leukocytes and synovial cells. The loss of CD44, along with receptor-bound HA and associated water from the synovium, results in a decrease of tissue swelling, and CD44-deficient leukocytes will no longer be able to recognize HA and migrate into the HA-rich extracellular compartment of the inflamed synovium. Our preliminary results show that antibody IM7 cross-reacts with human CD44 and induces the loss of CD44 from human leukocytes and synovial cells in vitro as it has been similarly shown in the murine system. This antibody has a potential, therefore, to be introduced as a therapeutic agent for the treatment of human RA. Our pioneer study on animal models of inflammatory arthritis has revealed the basic mechanism of anti-CD44 treatment, however, many other aspects of this immunotherapy should be explored before human application. We will identify CD44 isoforms which play dominant roles in the maintenance of joint inflammation and design a narrow-range immunotherapy targeted to cells involved in inflammatory processes. We will study the regulatory mechanisms, linked to anti-CD44 treatment, in animal models in vivo and on human cells in vitro. Finally, we will investigate the effects of anti-CD44 therapy on the functions of the immune, hemopoietic and reproductive systems in vivo. We believe that these studies will contribute to the understanding of the role of CD44 in inflammation and increase the clinical safety and efficacy of anti-CD44 immunotherapy in RA.