Clinical Studies Of Abnormal Host Defense

宿主防御异常的临床研究

• 批准号: 6984867
• 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/6984867
• 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-?. 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-? adverse events and no discernable effect on growth and development. The overall mortality was 6.6% over 9 years. Thus, interferon-? prophylaxis for CGD appears effective and well tolerated over a prolonged period of time.

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，该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-？的长期临床安全性和有效性。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。没有危及生命的干扰素-？不良事件，对生长和发育没有明显影响。9年来总死亡率为6.6%。因此，干扰素-？对于CGD的预防似乎是有效的，并且在较长的时间内耐受性良好。