scholarly journals Chronic granulomatous disease. Expression of the metabolic defect by in vitro culture of bone marrow progenitors.

1980 ◽  
Vol 66 (3) ◽  
pp. 599-602 ◽  
Author(s):  
P E Newburger ◽  
M S Kruskall ◽  
J M Rappeport ◽  
S H Robinson ◽  
M E Chovaniec ◽  
...  
Keyword(s):  
Bone Marrow ◽  
In Vitro Culture ◽  
Chronic Granulomatous Disease ◽  
Granulomatous Disease ◽  
Disease Expression ◽  
Metabolic Defect

Long-Term Follow-Up of Patients Treated by Gene Therapy for X-Linked Chronic Granulomatous Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 194-194 ◽  
Author(s):  
Marion G. Ott ◽  
Manuel Grez ◽  
Stefan Stein ◽  
Ulrich Siler ◽  
Ulrike Koehl ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Bone Marrow ◽  
Chronic Granulomatous Disease ◽  
Ex Vivo ◽  
Therapeutic Option ◽  
High Morbidity ◽  
Granulomatous Disease ◽  
Phagocytic Cells

Abstract Chronic granulomatous disease (CGD) is a primary immunodeficiency in which phagocytic cells of affected patients have impaired antimicrobial activity due to a defect in the production of reactive oxygen species (ROS). CGD is caused by mutations in any one of four genes encoding for the subunits of the NADPH oxidase complex. Although curable by HSC transplantation, this strategy is usually limited only to patients with HLA-matched sibling or unrelated donors, as mismatched transplantation is associated with high morbidity and mortality due to graft failure and slow immune reconstitution. A therapeutic alternative for CGD patients is the genetic modification of autologous HSC. In January 2004 we initiated a Phase I/II clinical trial for X-CGD patients including conditioning with busulfan (8 mg/kg/total dose) prior to infusion of genetically modified HSC. G-CSF mobilized CD34+ cells from 2 adult patients (25 and 26 years) were transduced ex-vivo with a monocistronic gp91phox retroviral vector. Therapeutically significant gene marking levels were detected in neutrophils of both patients with up to 60% functionally corrected phagocytes 14 months after gene therapy. This high correction resulted from an unexpected but temporarily restricted expansion of gene transduced myeloid cells in vivo. In contrast gene marking levels in B-cells has remained constant at a level of 20%, while gene marking in T-cells is below 5%. Gene marking in bone marrow was detected at levels between 30% and 40% one year after transplantation of gene modified cells. Killing assays in vitro have demonstrated antibacterial and antifungal activity in gene transduced phagocytes and both patients recovered of Staph. aureus and Aspergillus fumigatus infections after gene therapy. Our results suggest that gene therapy in combination with bone marrow conditioning is a therapeutic option for inherited diseases affecting the myeloid compartment and can be successfully used to treat CGD.

NORMAL GRANULOCYTE INFUSION THERAPY FOR ASPERGILLOSIS IN CHRONIC GRANULOMATOUS DISEASE

PEDIATRICS ◽  
1973 ◽  
Vol 51 (2) ◽  
pp. 230-233
Author(s):  
Andrew A. Raubitschek ◽  
Alan S. Levin ◽  
Daniel P. Stites ◽  
Edward B. Shaw ◽  
H. Hugh Fudenberg
Keyword(s):  
Adverse Effects ◽  
Chronic Granulomatous Disease ◽  
Blood Cells ◽  
White Blood Cells ◽  
Infusion Therapy ◽  
Granulomatous Disease ◽  
Transient Improvement ◽  
Life Threatening ◽  
Granulocyte Function

An 8-year-old boy with chronic granulomatous disease (CGD) was admitted in moribund condition with aspergillus pneumonia. Because of the gravity of the situation, normal granulocyte infusions were used as adjuncts to the more conventional antimicrobial therapy. White blood cells, derived from a total of 58 units of whole blood obtained by leukophoresis of the father, were given in two separate doses. The first dose, totaling 2.8 x 1010 granulocytes, was coincident with significant improvement, and the second, totaling 3.0 x 1010 granulocytes, was coincident with the onset of clinical improvement and interim recovery. Transient improvement in in vitro granulocyte function was noted in cells taken from the patient's blood immediately after infusion. No adverse effects of the infusions were noted in either the patient or the donor. Although it is impossible to divorce the therapeutic effect of the granulocyte infusions from the more conventional therapy, we conclude that normal granulocyte infusions can be considered a valid adjunct in children with CGD who are suffering from a life-threatening infection.

Decreased Nitroblue Tetrazolium Dye Reduction in the Phagocytes of Patients Receiving Prednisone

PEDIATRICS ◽  
1970 ◽  
Vol 45 (5) ◽  
pp. 861-865
Author(s):  
Denis R. Miller ◽  
Henry G. Kaplan
Keyword(s):  
Chronic Granulomatous Disease ◽  
Nitroblue Tetrazolium ◽  
Quantitative Assay ◽  
Granulomatous Disease ◽  
Host Defenses ◽  
Dye Reduction ◽  
Slide Test ◽  
Intracellular Metabolism

Nitroblue tetrazolium (NBT) dye reduction by leukocytes of 21 patients receiving prednisone was significantly decreased. Nineteen percent of the patients had values similar to those found in children with chronic granulomatous disease, and 57% had heterozygous-range NBT dye reduction. A qualitative NBT dye reduction "slide test" correlated well with the quantitative assay. The uptake of particles by the phagocytes of steroid-treated patients appeared normal. The exact mechanism of corticosteroid action remains unknown. The decreased dye reduction observed in vitro suggests an induced defect of intracellular metabolism which may be related to known alterations of host defenses which occur in patients receiving these hormones.

STUDIES OF POLYMORPHONUCLEAR LEUKOCYTES FROM PATIENTS WITH CHRONIC GRANULOMATOUS DISEASE OF CHILDHOOD: BACTERICIDAL CAPACITY FOR STREPTOCOCCI

PEDIATRICS ◽  
1968 ◽  
Vol 41 (3) ◽  
pp. 591-599
Author(s):  
Edward L. Kaplan ◽  
Throstur Laxdal ◽  
Paul G. Quie
Keyword(s):  
Chronic Granulomatous Disease ◽  
Polymorphonuclear Leukocytes ◽  
Gram Negative Bacteria ◽  
Granulomatous Disease ◽  
Gram Negative ◽  
Modified Method ◽  
Bactericidal Capacity ◽  
Normal Manner ◽  
Streptococcal Species

Polymorphonuclear leukocytes (PMNs) from children with chronic granulomatous disease of childhood have been shown to readily phagocytize staphylococci and certain gram-negative bacteria, but they demonstrate an impaired intracellular bactericidal capacity for these organisms. The in vitro phagocytic and bactericidal capacities of PMNs from three patients with this disease for four species of streptococci (Streptococcus faecalis, Streptococcus viridans, microaerophlic streptococci, and Streptococcus pyogenes) were tested by the modified method of Maaloe. The PMNs obtained from the patients phagocytized and killed the four species of streptococci in a normal manner while still showing the defect for Staph. aureus and S. marcescens. Morphologic examination of coverslip preparations of PMNs revealed minimal post-phagocytic degranulation and vacuole formation when either staphylococci and serratia or the streptococcal species were tested. This suggests that different intracellular mechanisms may be responsible for the streptococcal killing. These observations are in accord with the clinical courses of these patients, who rarely have serious streptococcal infections in contrast to the frequent and life-threatening infections caused by staphylococci and some gram-negative bacteria.

Leprosy (Hansen’s disease)

2010 ◽  
pp. 836-848
Author(s):  
Diana N.J. Lockwood
Keyword(s):  
Public Health ◽  
Chronic Granulomatous Disease ◽  
Health Problem ◽  
Disease Transmission ◽  
Public Health Problem ◽  
Mycobacterium Leprae ◽  
Granulomatous Disease ◽  
Important Public Health Problem ◽  
Important Public Health

Leprosy is a chronic granulomatous disease caused by Mycobacterium leprae, an acid-fast intracellular organism not yet cultivated in vitro. It is an important public health problem worldwide, with an estimated 4 million people disabled by the disease. Transmission of M. leprae is only partially understood, but untreated lepromatous patients discharge abundant organisms from their nasal mucosa into the environment....

scholarly journals Interferon-gamma improves splicing efficiency of CYBB gene transcripts in an interferon-responsive variant of chronic granulomatous disease due to a splice site consensus region mutation

Blood ◽  
2000 ◽  
Vol 95 (11) ◽  
pp. 3548-3554 ◽  
Author(s):  
Antonio Condino-Neto ◽  
Peter E. Newburger
Keyword(s):  
B Cell ◽  
Chronic Granulomatous Disease ◽  
Cell Line ◽  
Interferon Gamma ◽  
Granulomatous Disease ◽  
First Intron ◽  
Cybb Gene ◽  
Nuclear Rna ◽  
Ifn Γ

Abstract X-linked chronic granulomatous disease (CGD) derives from defects in the CYBB gene, which encodes the gp91-phox component of NADPH oxidase. We studied the molecular basis of the disease in a kindred with variant CGD, due to a single base substitution at the sixth position of CYBB first intron. The patients' phagocytes have been shown previously to greatly increase superoxide release in response to interferon-gamma (IFN-γ) in vitro and in vivo. We examined CYBB gene expression in an Epstein-Barr virus (EBV)-transformed B-cell line from 1 patient in this kindred. These cells showed markedly decreased levels of CYBB transcripts in total RNA (5% of normal) and nuclear RNA (1.4% of normal), despite equal CYBB transcription rates in the CGD and control cells. Incubation with IFN-γ produced a 3-fold increase in CYBBtotal messenger RNA (mRNA) levels in the patient's cells, and decreased nuclear transcripts to undetectable levels. Reverse transcriptase–polymerase chain reaction analysis of RNA splicing revealed a preponderance of unspliced CYBB transcripts in the patient's nuclear RNA. In vitro incubation with IFN-γ increased by 40% the ratio of spliced relative to unspliced CYBB mRNA in nuclei from the CGD B-cell line. Total RNA harvested from the same patient's monocytes, on and off therapy with IFN-γ, showed a similar improvement in splicing. We conclude that IFN-γ partially corrects a nuclear processing defect due to the intronic mutation in theCYBB gene in this kindred, most likely by augmentation of nuclear export of normal transcripts, and improvement in the fidelity of splicing at the first intron.

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