Clinical Studies Of Abnormal Host Defense

该项目的目的是研究宿主防御异常的患者;确定其异常的原因;并为其潜在的疾病和与疾病过程相关的危及生命的感染设计有效的治疗方法。LHD在研究吞噬细胞功能异常的患者方面有着悠久的传统。这些研究包括早期描绘中性粒细胞特异性颗粒缺乏症、儿童慢性肉芽肿病（CGD）、白细胞粘附缺陷和高免疫球蛋白-E综合征、复发性感染和IRAK-4缺乏症患者的临床、功能和分子缺陷。多年来，我们一直在收集患者队列，并在NIH继续跟踪。目前，我们随访了150多例CGD患者，约40例高免疫球蛋白-E复发性感染综合征患者，以及30例其他吞噬细胞功能障碍综合征患者，包括白细胞粘附缺陷，周期性中性粒细胞减少症，中性粒细胞特异性颗粒缺乏症和Chediak-Higashi综合征和IRAK-4缺乏症。所有这些患者都是研究人员希望从患者身上获得样本的国家资源，并可用于涉及校内或校外科学家的临床研究方案。我们现在有EB病毒转化的B细胞从我们的大多数病人，我们一直很高兴地分享这些B细胞系与其他内部或外部的同事。我们将继续监测和扩大这些患者队列，这些患者将作为异常宿主防御的免疫操纵的长期研究的模型。例如，今年我们发现，对细菌脂多糖（LPS）和IL-1没有反应的患者存在IRAK-4基因缺陷。此外，我们继续对这些患者进行重要的临床观察，这些观察对为这些患者和有相关问题的患者提供患者护理的其他人有用。 2003年，我们完成了一项为期10年的CGD患者双盲临床试验，证明伊曲康唑预防性治疗可预防这些患者严重和浅表真菌感染，且无明显毒性。基于这些研究，我们建议将伊曲康唑添加到CGD管理中使用的常规药物方案中。在其他研究中，我们调查了CGD中过度肉芽肿形成的基础。我们发现，CGD中性粒细胞比正常中性粒细胞产生100倍多的IL-8化学引诱物和增加的IL-8 mRNA，当用化学引诱物fmet-leu-phe刺激时，这种增加被加入生理浓度的过氧化氢逆转，这在CGD中是不存在的。这种IL-8的异常调节可能有助于CGD中过度肉芽肿的形成。

The purpose of this project is to study patients with abnormal host defense; to determine the cause of their abnormality; and to devise effective therapies for their underlying disorder and the life-threatening infections associated with their disease processes. The LHD has a long tradition of investigating patients with abnormalities of phagocytic cell function. These studies include early delineation of the clinical, functional, and in some cases, the molecular defects of patients with neutrophil specific granule deficiency, chronic granulomatous disease of childhood (CGD), leukocyte adhesion deficiency and the syndrome of hyperimmunoglobulin-E and recurrent infections and IRAK-4 deficiency. Cohorts of patients have been collected over the years which we continue to follow at NIH. Currently we follow over 150 patients with CGD, about 40 patients with the hyperimmunoglobulin-E recurrent infection syndrome, and 30 patients with other phagocyte dysfunction syndromes, including leukocyte adhesion deficiency, cyclic neutropenia, neutrophil specific granule deficiency and Chediak-Higashi syndrome and IRAK-4 deficiency. All these patients serve as a national resource for investigators desiring samples from patients and are available for clinical research protocols involving intramural or extramural scientists. We now have EB virus transformed B cells from most of our patients and we have been pleased to share these B cell lines with other intramural or extramural colleagues. We continue to monitor and expand these cohorts of patients who serve as models for long term studies of the immunological manipulation of the abnormal host defenses. For example, this year we showed that a patient who fails to respond to bacterial lipopolysaccharide (LPS) and IL-1 has a defect of the IRAK-4 gene. In addition, we continue to make important clinical observations on these patients which are of use to others providing patient care for these patients and patients with related problems. In 2003 we completed a ten year double blind clinical trial in patients with CGD and demonstrated that itraconazole prophylaxis prevents serious and superficial fungal infections in these patients without significant toxicity. Based on these studies we recommended that itraconazole be added to the regimen of routine medicines used in the management of CGD. In other studies we investigated the basis for excessive granuloma formation in CGD. We showed that CGD neutrophils make 100 fold more IL-8 chemoattractant and increased IL-8 mRNA than normal neutrophils when stimulated with the chemoattractant fmet-leu-phe and this increase is reversed by addition of physiological concentrations of hydrogen peroxide, which is absent in CGD. This abnormal regulation of IL-8 may contribute to the excess granuloma formation in CGD.