Anti CD40L therapy in inflammatory bowel disease

炎症性肠病（IBD），分类为克罗恩病（CD）或溃疡性结肠炎（UC），是一种病因不明的复杂疾病，具有一系列临床特征，在受影响的受试者中表现出很大的差异。然而，大多数患者将需要免疫抑制剂和/或免疫调节剂，这些药物在有效维持缓解和预防疾病复发方面并不普遍成功。最近对免疫反应基本机制的深入了解，以及将这些概念扩展到CD和UC的研究，已经发现了新的治疗靶点，通过关注关键的生物学途径，这些靶点可能在IBD治疗中更有效。最近，有研究表明，参与抗原呈递的共刺激信号似乎通过T细胞上一种名为CD40配体（CD40L）的辅助分子的上调来影响免疫反应。分子CD40和CD40L之间的相互作用似乎在CD4 T细胞介导的反应中发挥作用，这些反应表征了包括炎症性肠病在内的各种自身免疫介导的疾病状态。基于这些CD40-CD40L活性的生物学考虑，我们认为人类。IBD，包括CD和UC，可能会从针对CD40-CD40L通路的治疗中受益。因此，我们建议在炎症性肠病患者中进行人源化抗CD40L抗体的临床试验，其具体目的如下：1)确定抗CD40L抗体治疗对类固醇耐药或难治性CD和UC患者的毒性和潜在益处。2)确定抗cd40l抗体治疗的类固醇耐药或难治性CD和UC患者的临床和组织学疾病缓解的发生率。3)确定抗cd40l抗体治疗12个月后持续临床缓解的患者比例。

Inflammatory bowel diseases (IBD), categorized as Crohn's disease (CD) or ulcerative colitis (UC), are complex disorders of unknown etiology with a spectrum of clinical features which exhibit great variation among affected subjects. The majority of patients, however, will required immunosuppressive and/or immunomodulatory agents which are not universally successful in effective maintaining remission and preventing disease relapse. Recent insights into the basic mechanisms of immune responses and the extension of these concepts to CD and UC have led to the identification of new therapeutic targets which may be more efficacious in IBD therapy by focusing on critical biologic pathways. More recently, it has been suggested that co-stimulatory signals involved in antigen presentation appear to affect immune responses through the up- regulation of an accessory molecule named CD40 ligand (CD40L) on T cells. The interaction between the molecule CD40 and CD40L appears to play a role in CD4 T cell-mediated responses that characterize a variety of autoimmune-mediated disease states including inflammatory bowel disease. Based upon these biologic considerations of CD40-CD40L activity, we believe that human. IBD, both CD and UC, may be diseases which would benefit clinically from therapy directed at the CD40-CD40L pathway. We therefore propose a clinical trial of a humanized anti- CD40L antibody in study subjects with inflammatory bowel disease with the following specific aims: 1) To determine any toxicity and potential benefit from anti-CD40L antibody therapy in patients with steroid-resistant or refractory CD and UC. 2) To determine the incidence of clinical and histologic disease remission in patients with steroid-resistant or refractory CD and UC treated with anti-CD40L antibody therapy. 3) To determine the proportion of patients who remain in sustained clinical remission 12 months after anti-CD40L antibody therapy.