TREATMENT INTERVENTIONS FOR HEMORRHAGIC COLITIS

描述 本申请的广泛目的是使用一种新的动物模型， 肠出血性大肠杆菌（EHEC）感染，以制定预防措施 以及预防和治疗肠出血性大肠杆菌病的治疗方案。 最严重的 肠和肾表现由毒素介导的损害引起， 血管内皮，伴组织水肿，炎性浸润，细胞因子 产生和血管血栓。 战略将侧重于预防， 或限制志贺样毒素（SLT）与血管 通过中和血管室内的毒素来保护内皮： 在肠腔内结合毒素，清除产毒微生物; 和/或抑制促炎细胞因子的作用。 目前， 没有针对肠出血性大肠杆菌的疫苗，也没有有效的 如果暴露于EHEC，则采取干预措施预防或治疗出血性结肠炎 发生。 只有支持性护理可用于预防 EHEC感染的严重并发症。 旨在防止 SLT与其内皮受体的相互作用应防止或 改善靶器官（肠道、CNS和肾脏）的损伤 大肠杆菌菌株RDEC-H19 A感染家兔后将作为 EHEC疾病的动物模型。 这款RDEC H19 A，由 将026：H11肠出血性大肠杆菌的毒素转化噬菌体H19 A转移至 兔肠道致病性E. coliRDEC-1，是一种附着和消失的家兔 病原体 该菌株产生高水平的志贺样毒素I（SLT-I）， 定殖盲肠和结肠，并诱导兔肠道疾病， 类似人类肠出血性大肠杆菌病的病理变化。 我们最近的工作 表明RDEC-I中连接/删除相互作用的基因 与肠出血性大肠杆菌高度同源 菌株; 026：H11和0157：7血清型。 初步数据显示 防止这种感染的血管并发症， 通过全身性抗-IgM抗体或通过对 病原体 本申请的具体目的（1-5）是使用这种动物模型， 感染：测试被动给予免疫球蛋白的能力 具有抗毒性活性，以预防EHEC疾病;测试 预防肠出血性大肠杆菌病的腔内毒素受体类似物;确定 抗生素治疗对病程的影响是有益还是有害 确定抗炎策略，特别是 IL-1受体拮抗剂（IL-1 ra）可以改变疾病;制定策略 使用毒素、粘附和体细胞免疫进行针对EHEC的主动免疫 抗原;并扩展动物模型以测试类似的策略 针对表达SLT-II的EHEC菌株。 我们假设，基于 初步数据，旨在限制毒素相互作用的方法， 血管内皮最好在动物模型中发育。 这些 这些策略可以随后应用于EHEC的管理 感染

DESCRIPTION The broad aim of this application is to use a new animal model of enterohemorrhagic Escherichia coli (EHEC) infection to develop prophylactic and therapeutic regimens to prevent and treat EHEC disease. The most severe intestinal and renal manifestations result from toxin-mediated damage to vascular endothelium, with tissue edema, inflammatory infiltrates, cytokine production and vascular thrombi. Strategies will be focused on preventing, or limiting, the interaction of Shiga-like toxins (SLTs) with the vascular endothelium by neutralizing toxin within the vascular compartment by: binding toxin in the gut lumen; eliminating the toxin-producing organisms; and/or inhibiting the action of pro-inflammatory cytokines. At present, there is no vaccine for EHEC, neither are there established effective interventions to prevent or treat hemorrhagic colitis if exposure to EHEC occurs. Only supportive care is available to prevent the development of the severe complications of EHEC infection. Strategies aimed at preventing the inter-action of SLTs with their endothelial receptors should prevent or ameliorate damage in target organs (gut, CNS and kidney) Escherichia coli strain RDEC-H19A infection of rabbits will serve as the animal model of EHEC disease for these studies. This RDEC H19A, produced by the transfer of the toxin-converting phage H19A of an 026:H11 EHEC to the rabbit entero-pathogenic E. coli RDEC-1, is an attaching and effacing rabbit pathogen. This strain produces high levels of Shiga-like toxin I (SLT-I), colonizes cecum and colon, and induces intestinal disease in rabbits with pathologic changes resembling human EHEC disease. Our recent work demonstrates that the genes for attaching/effacing interactions in RDEC-I are highly homologous to those in enterohemorrhagic Escherichia coli strains; both of 026:H11 and 0157:7 serotypes. Preliminary data indicate that protection against the vascular complications of this infection can be prevented by systemic anti-SLT antibody, or by mucosal immunity to the pathogen. Specific aims (1-5) of the application are to use this animal model of infection to: test the ability of passively administered immunoglobulin with anti-toxic activity to prevent EHEC disease; test the ability of intraluminal toxin-receptor analogs to prevent EHEC disease; determine whether antibiotic therapy has beneficial or harmful effects on the course of disease; determine whether anti-inflammatory strategies, in particular IL-I receptor antagonist (IL-lra), can alter the disease; develop strategies for active immunization against EHEC using the toxins, adhesions and somatic antigens of EHEC; and to extend the animal model to test similar strategies against EHEC strains expressing SLT-II. We hypothesize, based on preliminary data, that approaches designed to limit toxin interactions with vascular endothelium can best be developed in an animal model. These strategies could subsequently be applied to the management of EHEC infection.