Clinical Studies Of Abnormal Host Defense

本课题的目的是研究宿主防御异常患者；确定其异常的原因；并为他们的潜在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患者方面有着悠久的传统。这些研究包括对中性粒细胞特异性颗粒缺乏症、儿童慢性肉芽肿病（CGD）、白细胞粘附缺乏症和高免疫球蛋白e综合征、复发性感染和IRAK-4缺乏症患者的临床、功能和某些情况下的分子缺陷的早期描述。多年来，我们一直在NIH跟踪收集患者队列。目前，我们随访了150多例CGD患者，约40例高免疫球蛋白- e复发感染综合征患者，30例其他吞噬细胞功能障碍综合征患者，包括白细胞粘附不足，循环中性粒细胞减少症，中性粒细胞特异性颗粒缺乏和Chediak-Higashi综合征和IRAK-4缺乏症。所有这些患者都是希望从患者身上获得样本的研究人员的国家资源，并可用于涉及校内或校外科学家的临床研究方案。我们现在从大多数患者身上获得了EB病毒转化的B细胞，我们很高兴与其他校内或校外的同事分享这些B细胞系。我们继续监测和扩大这些患者的队列，作为长期研究异常宿主防御的免疫操作的模型。例如，今年我们发现，对细菌脂多糖（LPS）和IL-1没有反应的患者具有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，这些观察对其他为这些患者和有相关问题的患者提供患者护理的人有用。

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.