Clinical Investigations In Infectious And Autoimmune Dis

感染性和自身免疫性疾病的临床研究

• 批准号: 6677482
• 负责人: SHARON M WAHL
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6677482
• 关键词: AIDS therapy; HIV infections; aging; aphthous stomatitis; chemotherapy; clinical trials; drug screening /evaluation; elastases; estrogens; fibronectins; gene targeting; genetically modified animals; hormone therapy; human subject; human therapy evaluation; human tissue; inflammation; laboratory mouse; leukocytes; mucosal immunity; patient oriented research; thalidomide; topical drug application; wound healing

Immunocompromised patients demonstrate a wide variety of idiopathic cutaneous and mucosal lesions including dermatitis, gastrointestinal and genital tract ulcerations, and recurrent aphthous stomatitis. One objective of this research program is to evaluate the pathogenesis of mucosal inflammation associated with immune dysregulation in HIV-infected patients with aphthous lesions. A randomized, controlled clinical trial using topical thalidomide was initiated which serves as a vehicle for several lines of inquiry directed towards investigating the pathogenesis and treatment of oral aphthous ulcers, which are spontaneous, recurrent mucosal ulcerations of unknown etiology, and which are persistent and debilitating in persons with HIV/AIDS.Dose related healing in response to topical thalidomide without adverse effects. Based on the impressive healing response, topical thalidomide appears to be an effective alternative to oral thalidomide treatment for aphthous ulcers in pateints with HIV infection. In addition to mucosal lesions, temporomandibular joint disease and cutaneous lesions may also become chronic and debilitating, and efforts are focusing on characterizing the underlying pathogenesis. The delayed cutaneous healing response in the aged, characterized by a predominance of neutrophils and excess elastase, can be mimicked in animal models including ovariectomized rodents and secretory leukocyte protease inhibitor(SLPI) knockout mice. Using these models of cutaneous and oral wounds, delayed healing can be reversed by the topical application of TNF antagonists, SLPI and synthetic fibronectin peptides. Based on the successful topical delivery of these and other agents in reversing human nonhealing wounds, other novel approaches for inhibiting the persistent leukocyte recruitment and overabundant elastase released at the inflammatory site will be evaluated for their efficacy in facilitating the healing process.

免疫功能低下的患者表现出各种各样的特发性皮肤和粘膜损害，包括皮炎、胃肠道和生殖道溃疡以及复发性口腔炎。这项研究的目标之一是评估与免疫失调相关的粘膜炎症的发病机制，这些炎症与HIV感染的口疮患者有关。一项使用局部沙利度胺的随机对照临床试验被启动，作为研究口腔口疮的发病机制和治疗的载体，口腔口疮是一种原因不明的自发性复发性粘膜溃疡，在HIV/艾滋病患者中持续存在并使人虚弱。局部使用沙利度胺后，与愈合相关的溃疡没有不良反应。基于令人印象深刻的愈合反应，局部应用沙利度胺似乎是治疗HIV感染患者口腔溃疡的有效替代方案。除了粘膜损害，颞颌关节疾病和皮肤损害也可能成为慢性和衰弱的，努力集中在表征潜在的发病机制。老年人皮肤愈合延迟反应的特点是中性粒细胞占优势和弹性蛋白酶过度，可以在动物模型上模拟，包括去卵巢的啮齿动物和分泌性白细胞蛋白酶抑制物(SLPI)基因敲除的小鼠。使用这些皮肤和口腔创伤模型，局部应用肿瘤坏死因子拮抗剂、SLPI和合成纤维连接蛋白多肽可以逆转延迟愈合。基于这些药物和其他药物在逆转人类不可愈合伤口方面的成功局部给药，将评估其他抑制炎症部位持续的白细胞募集和过多的弹性蛋白酶释放的新方法在促进愈合过程中的有效性。