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ABSTRACT: We describe a family with 12 members carrying a heterozygous germline FAS c.3G>T start codon mutation leading to FAS haploinsufficiency. One patient had autoimmune lymphoproliferative syndrome (ALPS), one had recovered from ALPS, and ten mutation-positive relatives (MPRs) were healthy. FAS-mediated apoptosis and surface expression of FAS in single-positive T cells were lower for MPRs but did not discriminate between them and the ALPS patient. However, double-negative (DN) T cells of the ALPS patient had no FAS expression due to somatic loss of heterozygosity. Our results in this kindred suggest that FAS haploinsufficiency does not cause ALPS-FAS, but that modifying genetic events are crucial for its pathogenesis. FAS surface expression on DN T cells should be assessed routinely and FAS haploinsufficient patients should be followed as its potential for lymphomagenesis is not well defined and a second hit might occur later on.
Clinical Immunology 03/2013; 147(1):61-68. · 4.05 Impact Factor
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Annals of Hematology 12/2012; · 2.62 Impact Factor
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Luyan Liu,
Satoshi Okada,
Xiao-Fei Kong,
Alexandra Y Kreins,
Sophie Cypowyj,
Avinash Abhyankar,
Julie Toubiana,
Yuval Itan,
Magali Audry,
Patrick Nitschke, [......],
Matias Oleastro,
Amos Etzioni,
Claudia Traidl-Hoffmann,
Ellen D Renner,
Laurent Abel,
Capucine Picard,
László Maródi,
Stéphanie Boisson-Dupuis,
Anne Puel,
Jean-Laurent Casanova
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ABSTRACT: Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity.
Journal of Experimental Medicine 08/2011; 208(8):1635-48. · 13.85 Impact Factor
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The Journal of allergy and clinical immunology 06/2011; 128(3):686-7; author reply 687-8. · 9.17 Impact Factor
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ABSTRACT: We describe a previously symptom-free 13-year-old boy with dominant partial interferon-γ receptor-1 deficiency and unusual varicella-zoster virus reactivation. This case supports the unsettled notion that some interferon-γ R-deficient patients are at enhanced risk for viral disease.
The Pediatric Infectious Disease Journal 03/2011; 30(3):265-6. · 3.58 Impact Factor
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Dirk Roos,
Douglas B Kuhns,
Anne Maddalena, Joachim Roesler,
Juan Alvaro Lopez,
Tadashi Ariga,
Tadej Avcin,
Martin de Boer,
Jacinta Bustamante,
Antonio Condino-Neto, [......],
Irina Kondratenko,
Karin van Leeuwen,
Harry L Malech,
László Marodi,
Hiroyuki Nunoi,
Marie-José Stasia,
Anna Maria Ventura,
Carl T Witwer,
Baruch Wolach,
John I Gallin
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ABSTRACT: Chronic granulomatous disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. The disease is caused by a lack of superoxide production by the leukocyte enzyme NADPH oxidase. Superoxide is used to kill phagocytosed micro-organisms in neutrophils, eosinophils, monocytes and macrophages. The leukocyte NADPH oxidase is composed of five subunits, of which the enzymatic component is gp91-phox, also called Nox2. This protein is encoded by the CYBB gene on the X chromosome. Mutations in this gene are found in about 70% of all CGD patients. This article lists all mutations identified in CYBB in the X-linked form of CGD. Moreover, apparently benign polymorphisms in CYBB are also given, which should facilitate the recognition of future disease-causing mutations.
Blood Cells Molecules and Diseases 10/2010; 45(3):246-65. · 2.35 Impact Factor
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ABSTRACT: Complement C2 deficiency (C2D) is associated with increased susceptibility to pneumococcal infections and SLE-like autoimmunity. We report a novel pediatric C2D phenotype consisting of immune-complex mediated leukocytoclastic vasculitis, polyclonal B cell activation associated destructive follicular bronchiolitis, and disturbed humoral immune responses including dysgammaglobulinemia and specific antibody deficiency. We provide a detailed histological, immunological, and genetic evaluation and discuss the pathophysiology of C2D as a complex disorder at the interface between innate and adaptive humoral immunity. Finally, we describe the efficient clinical response to the effective treatment with rituximab, implicating B cell depletion as a therapeutic strategy for the autoimmune manifestations of this primary immunodeficiency disorder.
Arthritis care & research. 10/2010; 63(3):454-9.
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ABSTRACT: The granule enzyme myeloperoxidase (MPO) plays an important role in neutrophil antimicrobial responses. However, the severity of immunodeficiency in patients carrying mutations in MPO is variable. Serious microbial infections, especially with Candida species, have been observed in a subset of completely MPO-deficient patients. Here we show that neutrophils from donors who are completely deficient in MPO fail to form neutrophil extracellular traps (NETs), indicating that MPO is required for NET formation. In contrast, neutrophils from partially MPO-deficient donors make NETs, and pharmacological inhibition of MPO only delays and reduces NET formation. Extracellular products of MPO do not rescue NET formation, suggesting that MPO acts cell-autonomously. Finally, NET-dependent inhibition of Candida albicans growth is compromised in MPO-deficient neutrophils. The inability to form NETs may contribute in part to the host defense defects observed in completely MPO-deficient individuals.
Blood 10/2010; 117(3):953-9. · 9.90 Impact Factor
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Lena F Schimke,
Julie Sawalle-Belohradsky, Joachim Roesler,
Andreas Wollenberg,
Anita Rack,
Michael Borte,
Nikolaus Rieber,
Reinhold Cremer,
Eberhart Maass,
Roland Dopfer, [......],
Manfred Hoenig,
Annette F Jansson,
Angela Roesen-Wolff,
Bianca Schaub,
Reinhard Seger,
Harry R Hill,
Hans D Ochs,
Troy R Torgerson,
Bernd H Belohradsky,
Ellen D Renner
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ABSTRACT: Hyper-IgE syndromes (HIES) are primary immunodeficiency disorders characterized by Staphylococcus aureus abscesses, recurrent pneumonia, increased serum IgE levels, and eczema. The association of heterozygous signal transducer and activator of transcription 3 (STAT3) mutations with autosomal dominant (AD)-HIES allows the differentiation of AD-HIES from disorders associated with eczema and increased serum IgE levels, such as other primary immunodeficiencies and atopic dermatitis.
To facilitate early diagnosis of AD-HIES to initiate appropriate therapy.
The clinical phenotype (suggested by a National Institutes of Health [NIH] score of >or=40 points), STAT3 genotype, and T(H)17 cell counts were compared in a cohort of 78 patients suspected of having HIES.
Heterozygous STAT3 missense mutations and in-frame deletions were identified in 48 patients, all but 2 with an NIH score >or=40 points. Patients with STAT3 mutations with HIES showed significantly lower T(H)17 cell counts compared with patients with wild-type STAT3 and control subjects. Only 1 patient with wild-type STAT3 had both an NIH score >or=40 points and abnormal T(H)17 cell counts (<or=0.2% of CD4(+) cells), with this exception being identified with a homozygous dedicator of cytogenesis 8 protein (DOCK8) mutation. Pathologic shedding of primary teeth was present in 3 patients with wild-type STAT3 and 33 patients with STAT3 mutations. Internal abscesses and severe infections were exclusively seen in patients with STAT3 mutations, who also had increased pneumatocele formation and skeletal or connective tissue manifestations compared with patients with wild-type STAT3.
We expanded the number of STAT3 mutations and validated that the NIH score sensitively identifies patients with HIES. Based on our patient cohort, we propose key findings that, when combined with T(H)17 cell numbers, predict patients with AD-HIES with STAT3 mutations, supporting early diagnosis of AD-HIES.
The Journal of allergy and clinical immunology 09/2010; 126(3):611-7.e1. · 9.17 Impact Factor
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Folke Freudenberg,
Uwe Wintergerst,
Angela Roesen-Wolff,
Michael H Albert,
Christine Prell,
Brigitte Strahm,
Sibylle Koletzko,
Stephan Ehl,
Dirk Roos,
Alberto Tommasini,
Alessandro Ventura,
Bernd H Belohradsky,
Reinhard Seger, Joachim Roesler,
Tayfun Güngör
The Journal of allergy and clinical immunology 04/2010; 125(4):943-946.e1. · 9.17 Impact Factor
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Dirk Roos,
Douglas B Kuhns,
Anne Maddalena,
Jacinta Bustamante,
Caroline Kannengiesser,
Martin de Boer,
Karin van Leeuwen,
M Yavuz Köker,
Baruch Wolach, Joachim Roesler,
Harry L Malech,
Steven M Holland,
John I Gallin,
Marie-José Stasia
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ABSTRACT: Chronic granulomatous Disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. The disease is caused by mutations in the genes encoding the components of the leukocyte NADPH oxidase. This enzyme produces superoxide, which is essential in the process of intracellular pathogen killing by phagocytic leukocytes. Four of the five genes involved in CGD are autosomal; these are CYBA, encoding p22-phox, NCF2, encoding p67-phox, NCF1, encoding p47-phox, and NCF4, encoding p40-phox. This article lists all mutations identified in these genes in the autosomal forms of CGD. Moreover, polymorphisms in these genes are also given, which should facilitate the recognition of future disease-causing mutations.
Blood Cells Molecules and Diseases 02/2010; 44(4):291-9. · 2.35 Impact Factor
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Danielle T Avery,
Elissa K Deenick,
Cindy S Ma,
Santi Suryani,
Nicholas Simpson,
Gary Y Chew,
Tyani D Chan,
Umamainthan Palendira,
Jacinta Bustamante,
Stéphanie Boisson-Dupuis, [......], Joachim Roesler,
Peter D Arkwright,
Pravin Hissaria,
D Sean Riminton,
Melanie Wong,
Robert Brink,
David A Fulcher,
Jean-Laurent Casanova,
Matthew C Cook,
Stuart G Tangye
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ABSTRACT: Engagement of cytokine receptors by specific ligands activate Janus kinase-signal transducer and activator of transcription (STAT) signaling pathways. The exact roles of STATs in human lymphocyte behavior remain incompletely defined. Interleukin (IL)-21 activates STAT1 and STAT3 and has emerged as a potent regulator of B cell differentiation. We have studied patients with inactivating mutations in STAT1 or STAT3 to dissect their contribution to B cell function in vivo and in response to IL-21 in vitro. STAT3 mutations dramatically reduced the number of functional, antigen (Ag)-specific memory B cells and abolished the ability of IL-21 to induce naive B cells to differentiate into plasma cells (PCs). This resulted from impaired activation of the molecular machinery required for PC generation. In contrast, STAT1 deficiency had no effect on memory B cell formation in vivo or IL-21-induced immunoglobulin secretion in vitro. Thus, STAT3 plays a critical role in generating effector B cells from naive precursors in humans. STAT3-activating cytokines such as IL-21 thus underpin Ag-specific humoral immune responses and provide a mechanism for the functional antibody deficit in STAT3-deficient patients.
Journal of Experimental Medicine 01/2010; 207(1):155-71. · 13.85 Impact Factor
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Marcus Gentsch,
Aneta Kaczmarczyk,
Karin van Leeuwen,
Martin de Boer,
Magdalena Kaus-Drobek,
Marie-Claire Dagher,
Petra Kaiser,
Peter D Arkwright,
Manfred Gahr,
Angela Rösen-Wolff,
Matthias Bochtler,
Elizabeth Secord,
Pamela Britto-Williams,
Gulam Mustafa Saifi,
Anne Maddalena,
Ghassan Dbaibo,
Jacinta Bustamante,
Jean-Laurent Casanova,
Dirk Roos, Joachim Roesler
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ABSTRACT: Mutations that impair expression or function of the components of the phagocyte NADPH oxidase complex cause chronic granulomatous disease (CGD), which is associated with life-threatening infections and dysregulated granulomatous inflammation. In five CGD patients from four consanguineous families of two different ethnic backgrounds, we found similar genomic homozygous deletions of 1,380 bp comprising exon 5 of NCF2, which could be traced to Alu-mediated recombination events. cDNA sequencing showed in-frame deletions of phase zero exon 5, which encodes one of the tandem repeat motifs in the tetratricopeptide (TPR4) domain of p67-phox. The resulting shortened protein (p67Delta5) had a 10-fold reduced intracellular half-life and was unable to form a functional NADPH oxidase complex. No dominant negative inhibition of oxidase activity by p67Delta5 was observed. We conclude that Alu-induced deletion of the TPR4 domain of p67-phox leads to loss of function and accelerated degradation of the protein, and thus represents a new mechanism causing p67-phox-deficient CGD.
Human Mutation 12/2009; 31(2):151-8. · 5.69 Impact Factor
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J Merlijn van den Berg,
Elsbeth van Koppen,
Anders Ahlin,
Bernd H Belohradsky,
Ewa Bernatowska,
Lucien Corbeel,
Teresa Español,
Alain Fischer,
Magdalena Kurenko-Deptuch,
Richard Mouy,
Theoni Petropoulou, Joachim Roesler,
Reinhard Seger,
Marie-José Stasia,
Niels H Valerius,
Ron S Weening,
Baruch Wolach,
Dirk Roos,
Taco W Kuijpers
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ABSTRACT: CGD is an immunodeficiency caused by deletions or mutations in genes that encode subunits of the leukocyte NADPH oxidase complex. Normally, assembly of the NADPH oxidase complex in phagosomes of certain phagocytic cells leads to a "respiratory burst", essential for the clearance of phagocytosed micro-organisms. CGD patients lack this mechanism, which leads to life-threatening infections and granuloma formation. However, a clear picture of the clinical course of CGD is hampered by its low prevalence (approximately 1:250,000). Therefore, extensive clinical data from 429 European patients were collected and analyzed. Of these patients 351 were males and 78 were females. X-linked (XL) CGD (gp91(phox) deficient) accounted for 67% of the cases, autosomal recessive (AR) inheritance for 33%. AR-CGD was diagnosed later in life, and the mean survival time was significantly better in AR patients (49.6 years) than in XL CGD (37.8 years), suggesting a milder disease course in AR patients. The disease manifested itself most frequently in the lungs (66% of patients), skin (53%), lymph nodes (50%), gastrointestinal tract (48%) and liver (32%). The most frequently cultured micro-organisms per episode were Staphylococcus aureus (30%), Aspergillus spp. (26%), and Salmonella spp. (16%). Surprisingly, Pseudomonas spp. (2%) and Burkholderia cepacia (<1%) were found only sporadically. Lesions induced by inoculation with BCG occurred in 8% of the patients. Only 71% of the patients received antibiotic maintenance therapy, and 53% antifungal prophylaxis. 33% were treated with gamma-interferon. 24 patients (6%) had received a stem cell transplantation. The most prominent reason of death was pneumonia and pulmonary abscess (18/84 cases), septicemia (16/84) and brain abscess (4/84). These data provide further insight in the clinical course of CGD in Europe and hopefully can help to increase awareness and optimize the treatment of these patients.
PLoS ONE 02/2009; 4(4):e5234. · 4.09 Impact Factor
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ABSTRACT: Patients with chronic granulomatous disease (CGD) suffer from severe bacterial and fungal infections and deregulated inflammation, which are often associated with granuloma formation. We describe a 2-year-old boy who was seemingly healthy at the age of 1 year when a conventional chest radiograph was taken to exclude pulmonary aspiration of a piece of apple. Incidentally, a space-occupying mediastinal mass was revealed that was further evaluated by magnetic resonance imaging. Varying solid and also cystic, septated parts of the mass could be discerned and it was considered to be a teratoma. Removal of the mass by surgery was arduous because of adhesiveness to surrounding areas and led to severe complications. Unexpectedly, histopathologic examination revealed massive acute granulomatous inflammation with liquefied thymic cysts. X-linked CGD was subsequently diagnosed by a dihydrorhodamine 123 assay and sequencing of the CYBB gene (hotspot mutation c.742-743insA). This is the third example that we are aware of, where CGD granulomas were mistaken for neoplasms. The other 2 patients were initially believed to have tumors of the stomach and the urinary bladder, respectively. All patients initially received inadequate treatment. We discuss possible strategies to avoid such tragic confusions.
Journal of Pediatric Hematology/Oncology 01/2009; 30(12):877-80. · 1.16 Impact Factor
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Joachim Roesler
Seminars in Immunopathology 08/2008; 30(3):365; author reply 367-8. · 6.27 Impact Factor
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ABSTRACT: Patients with chronic granulomatous disease (CGD) cannot generate reactive oxygen metabolites, and suffer from severe recurrent infections and dysregulated inflammation. Haematopoietic stem cell transplantation is the only established option for definitive cure for patients with a suitable donor and is indicated when conventional prophylaxis and therapy with antimicrobial medication fail. Gene therapy has the potential to cure CGD, and several clinical trials have been conducted since 1997. Whereas initial studies resulted in low and short-term engraftment of CGD-corrected cells, recent trials demonstrated clinical benefit when engraftment was enhanced by busulfan conditioning prior to infusion of gene-corrected cells. However, the progress in gene therapy has been hampered by the appearance of insertional mutagenesis causing leukaemia in a trial for patients with X-linked severe combined immunodeficiency and by the emergence of dominant clones in a recent trial for the X-linked form of CGD. These findings stimulated the development of modified vector systems that demonstrate reduced genotoxicity in vitro and in animal models. New gene therapy protocols that allow efficient gene transfer and durable expression but limit the risk for insertional mutagenesis are envisioned to become an important therapeutic option for patients with CGD.
Expert opinion on biological therapy 01/2008; 7(12):1799-809. · 3.22 Impact Factor
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ABSTRACT: We report on a 6-year-old boy with chronic granulomatous disease (CGD) complicated by chronic inflammatory reactions with formation of large pulmonary granuloma as well as intracerebral lesions. Bone marrow transplantation (BMT) from an unrelated donor led to stable reconstitution, to rapid resolution of pulmonary granuloma, and to rapid resolution of intracerebral lesions.
European Journal of Pediatrics 09/2007; 166(8):785-8. · 1.88 Impact Factor
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Lysann Mauch,
Andreas Lun,
Maurice R G O'Gorman,
John S Harris,
Ilka Schulze,
Arturo Zychlinsky,
Tobias Fuchs,
Uta Oelschlägel,
Sebastian Brenner,
Dolphe Kutter,
Angela Rösen-Wolff, Joachim Roesler
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ABSTRACT: The flow cytometric dihydrorhodamine 123 (DHR) assay is used as a screening test for chronic granulomatous disease (CGD), but complete myeloperoxidase (MPO) deficiency can also lead to a strongly decreased DHR signal. Our aim was to devise simple laboratory methods to differentiate MPO deficiency (false positive for CGD) and NADPH oxidase abnormalities (true CGD).
We measured NADPH-oxidase and MPO activity in neutrophils from MPO-deficient patients, CGD patients, NADPH-oxidase-transfected K562 cells and cells with inhibited and substituted MPO.
Eosinophils from MPO-deficient individuals retain eosinophilic peroxidase and therefore generate a normal DHR signal. The addition of recombinant human MPO enhances the DHR signal when simply added to a suspension of MPO-deficient cells but not when added to NADPH-oxidase-deficient (CGD) cells. Lucigenin-enhanced chemiluminescence (LCL) is increased in neutrophils from MPO-deficient patients, whereas neutrophils from patients with CGD show a decreased response.
A false-positive result caused by MPO deficiency can be easily ascertained because, unlike cells from a CGD patient, cells from MPO-deficient patients (a) contain functionally normal eosinophils, (b) show a significant enhancement of the DHR signal following addition of rhMPO, and (c) generate a strong LCL signal.
Clinical Chemistry 06/2007; 53(5):890-6. · 7.91 Impact Factor
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Sebastian Brenner,
Martin F Ryser,
Uimook Choi,
Narda Whiting-Theobald,
Eberhard Kuhlisch,
Gilda Linton,
Elizabeth Kang,
Romy Lehmann,
Angela Rosen-Wolff,
Andrew G Rudikoff,
Ann M Farese,
Thomas J Macvittie, Joachim Roesler,
Mitchell E Horwitz,
Harry L Malech
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ABSTRACT: We have recently reported that the RD114-pseudotyped MFGS-gp91phox vector achieves unprecedented levels of correction of the NADPH-oxidase gp91phox (approved gene symbol CYBB) defect in CD34(+) cells from patients with X-linked chronic granulomatous disease in the NOD/SCID mouse model. Considering clinical use of this vector, we transplanted autologous mobilized peripheral blood CD34(+) progenitor cells, transduced with the RD114-MFGS-gp91phox vector, into two healthy rhesus macaques following nonmyeloablative conditioning. The moderately high levels of in vivo marking seen in the first months following transduction decreased and stabilized at about 8 months posttransplant. Marking for both healthy animals after 15 months was 0.3 to 1.3 vector copies per 100 cells in lymphocytes, neutrophils, and monocytes. Vector insertion analyses performed by linear amplification-mediated PCR and sequencing identified 32 and 45 separate insertion sites in the animals. Identical insertion sites were found in myeloid cells and lymphocytes, demonstrating the successful transduction of lymphomyeloid progenitors. Some inserts landed in the vicinity of genes controlling cell cycle and proliferation. Statistical analyses of insertion sites 1 year posttransplant suggest a high diversity of insertion sites despite low marking.
Molecular Therapy 09/2006; 14(2):202-11. · 6.87 Impact Factor
