Clinical Studies Of Abnormal Host Defense

宿主防御异常的临床研究

• 批准号: 7189401
• 负责人: JOHN I GALLIN
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 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/7189401
• 关键词: Chediak Higashi syndrome; calcium flux; cellular pathology; chemoprevention; chronic granulomatous disease; clinical trials; drug screening /evaluation; enzyme linked immunosorbent assay; human subject; human therapy evaluation; hydrogen peroxide; hyperglobulinemia; immunogenetics; inflammation; interferon alpha; itraconazole; longitudinal human study; mycosis; neutrophil; nucleic acid sequence; opportunistic infections; patient /disease registry; patient oriented research; phagocytic dysfunction

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.

该项目的目的是研究异常宿主防御的患者；确定其异常的原因；并为其潜在疾病的有效疗法以及与疾病过程相关的威胁生命的感染。 LHD具有研究吞噬细胞功能异常的患者的悠久传统。这些研究包括早期描述临床，功能和在某些情况下，中性粒细胞特异性颗粒缺乏症患者的分子缺陷，儿童慢性肉芽肿（CGD），白细胞粘附缺乏症以及超抗蛋白质 - E Hyproukocyte粘附缺乏症和综合征超抗蛋白 - E和复发性感染和伊拉克-4缺陷。多年来，已经收集了许多患者的同类，我们将继续在NIH遵循。 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.所有这些患者都是希望来自患者样本的研究人员的国家资源，可用于涉及壁内或壁外科学家的临床研究方案。现在，我们拥有EB病毒从大多数患者中转化的B细胞，我们很高兴与其他壁内或壁外同事共享这些B细胞系。我们继续监视和扩展这些同类的患者，这些患者是对异常宿主防御的免疫操纵的长期研究模型的模型。 今年，我们完成了一项长期研究，对76名CGD患者进行了一项不受控制的开放标签随访研究，以评估干扰素 - 伽马NIH方案92-I-86的长期临床安全性和功效，这是对儿童慢性肉芽肿性疾病患者的重组干扰素的IV期研究）。我们跟踪患者长达9年（328例患者年）。严重感染是每年0.3（细菌0.18；真菌0.12）。轻度不良事件是常见但在大多数患者中忍受的（38％的患者发烧。但是，由于不良事件（3）或患者偏爱（15）或转移到另一项试验（8），有些患者撤回了。试验期间患者出生的儿童健康。没有生命的不良事件，对Interferon Gamma不利事件，对成长和发育的不良影响，因此对6.6年的持久性影响。6.6年6月6日。 CGD在长时间内看起来有效且耐受性良好。 其他研究与中性粒细胞所用的机制识别和消毒微生物，尤其是通过Toll样受体（TLR）以及随之而来的细胞反应的编排，例如激活呼吸爆发和动员PMN的氧气独立系统的激活，例如CateliciDIDIDIDIDIDIDIDIDIDIDIDIDIDIDIDIDIDIDIDIDIDIDIDIDIDIDIDIDIDIDIDIDIDIDIDIDIRID抗生素蛋白质蛋白质蛋白质蛋白质。与Janyce Sugui和June Kwong-Chung合作，在NIAID的临床传染病实验室中进行了一项重大项目，调查了PMN介导的正常和CGD中性粒细胞对烟曲霉的杀害。如前所述，我们发现CGD嗜中性粒细胞的曲霉菌杀死有缺陷。但是，CGD和正常嗜中性粒细胞杀死曲霉孢子是可比的。研究正在利用DNA微阵列技术来识别响应于PMN攻击的曲霉基因。 （Kol Zarember） 在HEK293三晶剂中研究了对野生型和突变体IRAK-4物种与IL-1R，IRAK-1和MYD88的野生型和突变体IRAK-4种与IL-1R，IRAK-1和MYD88的患者的研究。 IL-1引起IL-1R，激活的IRAK-1，MYD88和WILDTYPE之间的强烈相互作用，但没有突变的IRAK-4。截短的IRAK-4蛋白质与MyD88的组成性相互作用更加强烈，并钝化IL-1诱导的IRAK-1和MYD88募集到IL-1R。因此，IL-1诱导的IRAK-1和MYD88与IL-1RI的降低可能是由IRAK-4突变蛋白固换MYD88引起的。