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Related post: NADPH Oxidase Genes - Leto Human Phagocyte Granule Proteins - Rosenberg Page 7-1 7-5 7-6 7-7 7-8 7-9 7-10 7-11 7-12 7-13 7-14 7-15 PHS-NIH Summary Statement LABORATORY OF HOST DEFENSES National Institute of Allergy and Infectious Diseases October 1, 1991 to September 30, 1992 Introduction : The focus of work in the Laboratory of* Host Defenses is (1) to study the basic mechanisms of protection against bacterial and fungal infection; (2) to study the physiology, biochemistry and molecular biology of phagocytic cells (blood neutrophils, monocytes, eosinophils, and fixed tissue macrophages) in host defense against bacteria and fungi; (3) to determine the role and effect of cytokines on Anacin Tablet both phagocytic cells and upon the general process of inflammation; (4) to investigate the cellular, biochemical and genetic basis of diseases leading to recun-ent bacterial and fungal infections, particularly diseases affecting phagocytic cells function (chronic granulomatous diseases, hyper-IgE-recurrent infection [Job's] syndrome, specific granule deficiency, leukocyte adhesion deficiency, cyclic neutropenia and others); (5) to develop new animal models of human diseases which lead to recurrent infections; and (6) to develop new treatments for host defense defects leading to recurrent infections including new antibiotics or cytokine therapy or prophylaxis against infection, new diagnostic approaches for infections, and the development of gene therapy for such inherited immune deficiencies. During the past year the Laboratory has continued to expand upon clinical studies in patient Buy Anacin Online cohorts collected at NIH over more than 20 years and performed studies in patients and normal volunteers regarding the physiology and biochemistry of phagocytic cells and cytokines in infection and inflammation. The oxidative microbicidal superoxide-generating NADPH oxidase, the microbicidal granule proteins, and the chemoattractant receptors of phagocytic cells were studied. Clinical Studies : A study completed in the previous year demonstrating the efficacy of prophylactic y- interferon to reduce infection frequency in patients with chronic granulomatous diseases (CGD) entered phase IV this year following FDA approval of this treatment. This phase IV study is aimed at determining the long term safety for the patients and the continued effect of y-interferon on both phagocytic cells and the inflammatoiy process. This treatment appears to be without Anacin Aspirin adverse effects. A new double-blinded randomized trial was initiated to determine whether prophylactic oral itraconazole can reduce fungal infections in CGD. In related studies on the patient group with CGD, data was collated and published relating to infections with unusual fungal organisms, and also the urological, orthopedic, and surgical anaesthetic considerations related to CGD. We also demonstrated that use of steroids Buy Anacin is effective in controlling the granuloma complications of CGD. We have also developed new molecular biology probes, functional assays, and antibodies which yield more rapid and accurate 7 - 1 diagnosis of CGD and determination of genetic subtypes of this disease. In particular specific restriction length polymorphisms were identified in the p67phox CGD gene which Anacin Tablets can be used for genetic diagnosis. In studies of patients with Mycobacterium avium intracellulare (MAI) a family group with likely X-linked susceptibility to MAI was identified, with possible lymphocyte defect. A protocol is in progress which is examining the use of y-interferon to enhance host defense against MAI in this patient group. These studies may yield important information regarding the use of this cytokine in infections with MAI. Studies of the use of y-interferon in altering the humoral and cellular defects seen in HyperlgE-recurrent infection syndrome (HIE) are in progress. This and other studies of the use of y-interferon in tieatment of MAI and CGD noted above will yield important information about the use of this cytokine in various infection syndromes. Clinical studies of normal volunteers and patients were initiated to determine the systemic and local changes in cytokines and phagocytic cells in response to both local inflammation modelled by experimental skin blisters and/or in response to bacterial endotoxin as a model of bacterial infections. The time course of several cytokines in blisters was documented. Patients with HIE had a ten-fold normal increase in tumor necrosis factor in local lesions yet showed normal systemic responses to endotoxin. High levels of tumor necrosis factor in pulmonary tissues of HIE patients during staphylococcal pneumonia might occur and cause the extensive tissue damage seen in this disease. In other studies administration of endotoxin to normal volunteers was associated with four-fold increases in circulating hematopoietic progenitor cells. This may reflect an important role for circulating progenitors in bacterial infections. Furthermore, endotoxin itself or the cytokines increased by endotoxin, such as IL6, may be useful agents to enhance the yield of progenitor cells harvested from patients for gene therapy, a major future direction for the laboratory. Studies of a patient with neutrophil specific granule deficiency demonstrated that this patient has a defect in expression of all eosinophil granule proteins except eosinophil peroxidase, but demonstrated increases of this defective eosinophil population in response to administration of granulocyte-macrophage colony stimulating factor. This demonstrates that the lesion of specific granule deficiency extends to a defect of eosinophil granule protein production, but that actual production of these cells is unaffected. These studies demonstrate that there is a genetic regulatory element or elements common to both eosinophil and neutrophil granule development. Pre-clinical studies of the development of new treatments : Studies have been initiated to develop methods of gene transfer of normal genes for the phagocyte NADPH oxidase into hematopoietic progenitor cells of CGD patients defective in such genes. These studies are aimed at gene therapy for CGD. Anacin 3 Defective retroviruses free of helper virus activity were developed which were capable of transferring expression of normal oxidase genes in CGD cells defective in such genes. Transfer was associated with
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