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.
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