Clinical Studies Of Abnormal Host Defense

这个项目的目的是研究宿主防御异常的患者；确定他们异常的原因；并为他们潜在的疾病和与他们的疾病过程相关的危及生命的感染设计有效的治疗方法。LHD调查吞噬细胞功能异常患者的传统由来已久。这些研究包括中性粒细胞特殊颗粒缺乏症、儿童慢性肉芽肿性疾病(CGD)、白细胞黏附缺陷、高免疫球蛋白E综合征、反复感染和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。多年来已经收集了患者队列，我们在NIH继续跟踪调查。目前，我们跟踪观察了150多名CGD患者，约40名高免疫球蛋白-E反复感染综合征患者，以及30名其他吞噬细胞功能障碍综合征患者，包括白细胞黏附缺陷、循环中性粒细胞减少、中性粒细胞特异性颗粒缺陷以及Chediak-Higashi综合征和IRAK-4缺陷。所有这些患者都是希望从患者身上获取样本的研究人员的全国性资源，并可用于涉及院内或院外科学家的临床研究方案。我们现在有来自我们大多数患者的EB病毒转化的B细胞，我们很高兴与其他壁内外同事分享这些B细胞系。我们继续监测和扩大这些患者队列，这些患者作为长期研究异常宿主防御的免疫操纵的模型。 今年，我们完成了一项对76名CGD患者的长期研究，这些患者参加了一项非对照、开放标签的随访研究，以评估干扰素-伽玛方案92-I-86的长期临床安全性和有效性(重组干扰素在儿童慢性肉芽肿病患者中的IV期研究)。我们对患者进行了长达9年的跟踪调查(328个患者年)。严重感染为0.3例/病人年(细菌0.18例，真菌0.12例)。轻微的不良反应很常见，但在大多数患者中是可以耐受的(38%的患者发烧。但一些患者因不良事件(3例)或患者偏好(15例)而退出，或转至另一试验(8例)。患者在试验期间所生的孩子是健康的。没有出现危及生命的干扰素-伽马不良事件，也没有对生长和发育的明显影响。9年来总死亡率为6.6%。因此，干扰素-伽玛预防CGD似乎是有效的，并在较长时间内耐受性良好。 其他研究涉及中性粒细胞识别和杀灭入侵微生物的机制，特别是Toll样受体(TLRs)，以及随后的细胞反应协调，如激活呼吸爆发和动员PMN的氧依赖系统，如Catelicidin抗菌蛋白家族。NIAID临床传染病实验室与Janyce Sugui和jun Kwong-chung合作完成的一个重大项目研究了PMN介导的正常和CGD中性粒细胞对烟曲霉菌的杀灭作用。正如之前报道的那样，我们发现CGD中性粒细胞对曲霉菌丝的杀灭存在缺陷。然而，CGD对曲霉孢子的杀灭作用与正常中性粒细胞相当。目前正在进行利用DNA微阵列技术识别曲霉菌基因的研究，这些基因是针对PMN攻击而调节的。(Kol Zarember) 在一名反复感染和IRAK-4缺乏的患者中，研究了野生型和突变型IRAK-4物种与HEK293转基因细胞中Toll样受体途径的IL-1R、IRAK-1和MyD88的相互作用。IL-1可诱导IL-1R与野生型IRAK-1、MYD88相互作用，但不能与突变型IRAK-4相互作用。截短的IRAK-4蛋白与MyD88有更强的结构性相互作用，并钝化IL-1诱导的IRAK-1和MyD88向IL-1R的募集。因此，减少IL-1诱导的IRAK-1和MyD88与IL-1RI的结合可能是由于IRAK-4突变蛋白对MyD88的隔离。

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. This year we completed a long term study in 76 CGD patients enrolled in an uncontrolled, open label follow-up study to assess the long-term clinical safety and efficacy of interferon-gamma NIH Protocol 92-I-86, A phase IV study of recombinant interferon in patients with chronic granulomatous disease of childhood). We followed patients for up to 9 years (328 patient years). Serious infections were 0.3 per patient year (bacterial 0.18; fungal 0.12). Mild adverse events were common but tolerable in most patients (fever in 38% of patients. But some patients withdrew because of the adverse events (3) or patient preference (15), or for transfer to another trial (8). Children born to patients during the trial were healthy. There were no life-threatening interferon-gamma adverse events and no discernable effect on growth and development. The overall mortality was 6.6% over 9 years. Thus, interferon-gamma prophylaxis for CGD appears effective and well tolerated over a prolonged period of time. Other studies related to the mechanisms used by neutrophils to recognize and sterilize invading microbes, especially by the Toll-like receptors (TLRs), and consequent orchestration of cellular responses such as activation of the respiratory burst and mobilization of oxygen-independent systems of the PMN, such as the Catelicidin family of antimicrobial proteins. A major project done in collaboration with Janyce Sugui and June Kwong-Chung in NIAID's Laboratory of Clinical Infectious Diseases investigated PMN-mediated killing of Aspergillus fumigatus by normal and CGD neutrophils. As previously reported, we found CGD neutrophils have defective killing of aspergillus hyphae. However, killing of aspergillus spores by CGD and normal neutrophils were comparable. Studies are underway utilizing DNA microarray technology to identify aspergillus genes that are regulated in response to PMN attack. (Kol Zarember) Studies in a patient with recurrent infections and IRAK-4 deficiency interactions of wildtype and mutant IRAK-4 species with IL-1R, IRAK-1, and MyD88 of the Toll-like receptor pathway were studied in HEK293 tranfectants. Il-1 induced a strong interaction between the IL-1R, activated IRAK-1, MYD88 and wildtype, but not mutant IRAK-4. Truncated IRAK-4 proteins constitutively interacted more strongly with MyD88 and blunted IL-1 induced recruitment of IRAK-1 and MyD88 to the IL-1R. Thus, decreased IL-1 induced association of IRAK-1 and MyD88 with the IL-1RI may result from sequestration of MyD88 by IRAK-4 mutant proteins.