TREATMENT INTERVENTIONS FOR HEMORRHAGIC COLITIS

出血性结肠炎的治疗干预措施

• 批准号: 2518577
• 负责人: EDGAR C. BOEDEKER
• 金额: $ 19.59万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-30 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2518577
• 关键词: Escherichia coli infections; active immunization; antibiotics; antitoxins; cytokine receptors; exotoxins; gastrointestinal disorder chemotherapy; gastrointestinal pharmacology; interleukin 1; laboratory rabbit; microorganism culture; nonhuman therapy evaluation; passive immunization; peptide analog; ulcerative colitis; vascular endothelium

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.

描述 这个应用程序的主要目标是使用一种新的动物模型 肠出血性大肠埃希菌(EHEC)感染预防措施的开发 以及预防和治疗EHEC疾病的治疗方案。最严重的 肠道和肾脏的表现是由毒素介导的损害引起的 血管内皮细胞，伴有组织水肿、炎性浸润、细胞因子 产生血栓和血管血栓。战略将侧重于预防， 限制志贺样毒素(SLT)与血管的相互作用 通过中和血管隔间内的毒素，使血管内皮细胞： 结合肠腔内的毒素；清除产生毒素的微生物； 和/或抑制促炎细胞因子的作用。目前， 目前还没有针对EHEC的疫苗，也没有公认的有效疫苗 如果暴露于EHEC，预防或治疗出血性结肠炎的干预措施 发生。只有支持性的护理才能防止 肠出血性大肠杆菌感染的严重并发症。旨在防止经济衰退的战略 SLT与其内皮受体的相互作用应防止或 改善靶器官(肠道、中枢神经系统和肾脏)的损害 大肠埃希菌RDEC-H19A株感染兔将作为 用于这些研究的EHEC病的动物模型。这款RDEC H19A，由 O26：H11肠出血性肠出血性大肠杆菌H19A噬菌体的转移 兔肠道致病性大肠杆菌RDEC-1是一种依附消失型兔 病原体。该菌株产生高水平的志贺样毒素I(SLT-I)， 在盲肠和结肠定植，并诱导兔肠道疾病 类似于人类EHEC病的病理变化。我们最近的工作 证明了RDEC-I中附着/消除相互作用的基因 与肠出血性大肠埃希氏菌高度同源 菌株；均为026：H11和0157：7血清型。初步数据显示 对这种感染的血管并发症的保护可以是 通过全身性抗SLT抗体或粘膜免疫来预防 病原体。 应用程序的具体目标(1-5)是使用该动物模型 感染：测试被动注射免疫球蛋白的能力 具有抗毒素活性，可预防肠出血性肠出血性大肠杆菌病；检测 用于预防EHEC疾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 疾病；确定抗炎策略，特别是 白介素I受体拮抗剂(IL-LRA)，可改变疾病；制定策略 使用毒素、粘连和体细胞主动免疫EHEC EHEC的抗原；并扩展动物模型以测试类似的策略 对表达SLT-II的EHEC菌株的抑制作用。我们假设，基于 初步数据，旨在限制毒素与 血管内皮细胞最适合在动物模型中发育。这些 随后可将战略应用于EHEC的管理 感染。