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1.
Clin Pharmacokinet ; 2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-31131436

RESUMO

BACKGROUND AND OBJECTIVE: Alemtuzumab (Campath®) is used to prevent graft-versus-host disease and graft failure following pediatric allogeneic hematopoietic cell transplantation. The main toxicity includes delayed immune reconstitution, subsequent viral reactivations, and leukemia relapse. Exposure to alemtuzumab is highly variable upon empirical milligram/kilogram dosing. METHODS: A population pharmacokinetic (PK) model for alemtuzumab was developed based on a total of 1146 concentration samples from 206 patients, aged 0.2-19 years, receiving a cumulative intravenous dose of 0.2-1.5 mg/kg, and treated between 2003 and 2015 in two centers. RESULTS: Alemtuzumab PK were best described using a two-compartment model with a parallel saturable and linear elimination pathway. The linear clearance pathway, central volume of distribution, and intercompartmental distribution increased with body weight. Blood lymphocyte counts, a potential substrate for alemtuzumab, did not impact clearance. CONCLUSION: The current practice with uniform milligram/kilogram doses leads to highly variable exposures in children due to the non-linear relationship between body weight and alemtuzumab PK. This model may be used for individualized dosing of alemtuzumab.

2.
Pediatr Blood Cancer ; 66(8): e27787, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31034760

RESUMO

The molecular detection of minimal residual disease (MRD) is standard of care in acute lymphoblastic leukemia to personalize the stratification of patients to appropriate intensity chemotherapy regimens. High-throughput sequencing (HTS) techniques are driving changes to MRD methodologies. Our study demonstrates HTS can identify suitable diagnostic markers, even in cases where traditional screening has been unsuccessful. Markers identified by HTS were used to track MRD using standard real-time quantitative PCR. We show, with six patient examples, clinical benefits of utilizing HTS to screen diagnostic samples and its necessity when traditional screening techniques fail. This is practical evidence that current MRD diagnostic marker screening should be replaced by an HTS approach.

3.
Blood ; 133(24): 2586-2596, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31015189

RESUMO

DiGeorge syndrome (DGS) is a primary immunodeficiency characterized by various degrees of T-cell deficiency. In partial DGS (pDGS), other risk factors could predispose to recurrent infections, autoimmunity, and allergy. The aim of this study was to assess the effect of different factors in the development of infections, autoimmunity, and/or allergy in patients with pDGS. We studied 467 pDGS patients in follow-up at Great Ormond Street Hospital. Using a multivariate approach, we observed that palatal anomalies represent a risk factor for the development of recurrent otitis media with effusion. Gastroesophageal reflux/dysphagia and asthma/rhinitis represent a risk factor for the development of recurrent upper respiratory tract infections. Allergy and autoimmunity were associated with persistently low immunoglobulin M levels and lymphopenia, respectively. Patients with autoimmunity showed lower levels of CD3+, CD3+CD4+, and naïve CD4+CD45RA+CD27+ T lymphocytes compared with pDGS patients without autoimmunity. We also observed that the physiological age-related decline of the T-cell number was slower in pDGS patients compared with age-matched controls. The age-related recovery of the T-cell number depended on a homeostatic peripheral proliferation of T cells, as suggested by an accelerated decline of the naïve T lymphocytes in pDGS as well as a more skewed T-cell repertoire in older pDGS patients. These evidences suggest that premature CD4+ T-cell aging and lymphopenia induced spontaneous peripheral T-cell proliferation might contribute to the pathogenesis of autoimmunity in patients with pDGS. Infections in these patients represent, in most of the cases, a complication of anatomical or gastroenterological anomalies rather than a feature of the underlying immunodeficiency.

4.
J Allergy Clin Immunol ; 144(1): 280-293, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30731121

RESUMO

BACKGROUND: Mismatched stem cell transplantation is associated with a high risk of graft loss, graft-versus-host disease (GvHD), and transplant-related mortality. Alternative graft manipulation strategies have been used over the last 11 years to reduce these risks. OBJECTIVE: We investigated the outcome of using different graft manipulation strategies among children with primary immunodeficiencies. METHODS: Between 2006 and 2017, 147 patients with primary immunodeficiencies received 155 mismatched grafts: 30 T-cell receptor (TCR) αß/CD19-depleted grafts, 43 cord blood (CB) grafts (72% with no serotherapy), 17 CD34+ selection with T-cell add-back grafts, and 65 unmanipulated grafts. RESULTS: The estimated 8-year survival of the entire cohort was 79%, transplant-related mortality was 21.7%, and the graft failure rate was 6.7%. Posttransplantation viral reactivation, grade II to IV acute graft-versus-host disease (aGvHD), and chronic graft-versus-host disease (cGvHD) complicated 49.6%, 35%, and 15% of transplantations, respectively. Use of TCRαß/CD19 depletion was associated with a significantly lower incidence of grade II to IV aGvHD (11.5%) and cGvHD (0%), although with a greater incidence of viral reactivation (70%) in comparison with other grafts. T-cell immune reconstitution was robust among CB transplants, although with a high incidence (56.7%) of grade II to IV aGvHD. Stable full donor engraftment was significantly greater at 80% among TCRαß+/CD19+-depleted and CB transplants versus 40% to 60% among the other groups. CONCLUSIONS: Rapidly accessible CB and haploidentical grafts are suitable alternatives for patients with no HLA-matched donor. Cord transplantation without serotherapy and TCRαß+/CD19+-depleted grafts produced comparable survival rates of around 80%, although with a high rate of aGvHD with the former and a high risk of viral reactivation with the latter that need to be addressed.

5.
Front Immunol ; 9: 2547, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30455696

RESUMO

Spectratyping assays are well recognized as the clinical gold standard for assessing the T cell receptor (TCR) repertoire in haematopoietic stem cell transplant (HSCT) recipients. These assays use length distributions of the hyper variable complementarity-determining region 3 (CDR3) to characterize a patient's T cell immune reconstitution post-transplant. However, whilst useful, TCR spectratyping is notably limited by its resolution, with the technique unable to provide data on the individual clonotypes present in a sample. High-resolution clonotype data are necessary to provide quantitative clinical TCR assessments and to better understand clonotype dynamics during clinically relevant events such as viral infections or GvHD. In this study we developed and applied a CDR3 Next Generation Sequencing (NGS) methodology to assess the TCR repertoire in cord blood transplant (CBT) recipients. Using this, we obtained comprehensive TCR data from 16 CBT patients and 5 control cord samples at Great Ormond Street Hospital (GOSH). These were analyzed to provide a quantitative measurement of the TCR repertoire and its constituents in patients post-CBT. We were able to both recreate and quantify inferences typically drawn from spectratyping data. Additionally, we demonstrate that an NGS approach to TCR assessment can provide novel insights into the recovery of the immune system in these patients. We show that NGS can be used to accurately quantify TCR repertoire diversity and to provide valuable inference on clonotypes detected in a sample. We serially assessed the progress of T cell immune reconstitution demonstrating that there is dramatic variation in TCR diversity immediately following transplantation and that the dynamics of T cell immune reconstitution is perturbed by the presence of GvHD. These findings provide a proof of concept for the adoption of NGS TCR sequencing in clinical practice.

6.
Artigo em Inglês | MEDLINE | ID: mdl-30298747

RESUMO

BACKGROUND: In this study, we aimed to quantify KREC (kappa-deleting recombination excision circles) levels and naïve B-cell output in healthy HIV-uninfected children, compared with HIV-infected South African children, before and after starting ART (anti-retroviral therapy). SETTING: Samples were acquired from a Child Wellness Clinic (n=288 HIV-uninfected South African children, 2 weeks - 12 years) and the Children with HIV and Early Antiretroviral Therapy (CHER) trial (n=153 HIV-infected South African children, 7 weeks - 8 years). METHODS: Naïve B-cell output was estimated using a mathematical model combining KREC levels to reflect B-cell emigration into the circulation, flow cytometry measures of naïve un-switched B-cells to quantify total body naïve B-cells, and their rates of proliferation using the intracellular marker Ki67. RESULTS: Naïve B-cell output increases from birth to 1 year, followed by a decline and plateau into late childhood. HIV-infected children on or off ART had higher naïve B-cell outputs than their uninfected counterparts (p=0.01 and p=0.04). CONCLUSIONS: This is the first study to present reference ranges for measurements of KRECs and naïve B-cell output in healthy and HIV-infected children. Comparison between HIV-uninfected healthy children and HIV-infected children suggest that HIV may increase naïve B-cell output. Further work is required to fully understand the mechanisms involved and clinical value of measuring naïve B-cell output in children. .

8.
Front Immunol ; 9: 1372, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29988398

RESUMO

Juvenile dermatomyositis (JDM) is a rare form of childhood autoimmune myositis that presents with proximal muscle weakness and skin rash. B cells are strongly implicated in the pathogenesis of the disease, but the underlying mechanisms are unknown. Therefore, the main objective of our study was to investigate mechanisms driving B cell lymphocytosis and define pathological features of B cells in JDM patients. Patients were recruited through the UK JDM Cohort and Biomarker study. Peripheral blood B cell subpopulations were immunophenotyped by flow cytometry. The results identified that immature transitional B cells were significantly expanded in active JDM, actively dividing, and correlated positively with disease activity. Protein and RNAseq analysis revealed high interferon alpha (IFNα) and TLR7-pathway signatures pre-treatment. Stimulation of B cells through TLR7/8 promoted both IL-10 and IL-6 production in controls but failed to induce IL-10 in JDM patient cells. Interrogation of the CD40-CD40L pathway (known to induce B cell IL-10 and IL-6) revealed similar expression of IL-10 and IL-6 in B cells cultured with CD40L from both JDM patients and controls. In conclusion, JDM patients with active disease have a significantly expanded immature transitional B cell population which correlated with the type I IFN signature. Activation through TLR7 and IFNα may drive the expansion of immature transitional B cells in JDM and skew the cells toward a pro-inflammatory phenotype.

9.
J Mol Diagn ; 20(3): 381-388, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29474984

RESUMO

Certain blood components and anticoagulants interfere with the PCR process and subsequent analysis. Here we demonstrate that reliable test results can be obtained for chimerism analysis despite omitting a DNA-extraction step and performing PCR and fragment analysis directly on bone marrow, whole blood, and individual cell fractions. For chimerism analysis, direct-tissue PCR is possible with the use of a robust, commercially available PCR mix containing a DNA polymerase capable of DNA amplification directly from the sample without the need for pretreatment. A total of 178 chimerism samples were processed directly, and results were compared to those obtained from the corresponding DNA sample. No differences were observed between the two sets of results. For the cell fraction-purity assessment, commercially available PCR kits were used directly on T and B cells without the use of any additional lysing agent. A total of 53 purity samples and their corresponding DNA samples were analyzed and showed a correlation similar to that obtained for the chimerism samples. The results show that chimerism testing and associated cell fraction-purity assessment can be performed reliably without the need for prior DNA extraction and that this method can easily be integrated into existing routine laboratory procedures.

11.
J Agric Food Chem ; 65(34): 7294-7304, 2017 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-28388055

RESUMO

An extraction method using acidified methanol based on the quick polar pesticide (QuPPe) method using suppressed ion chromatography coupled to mass spectrometry was developed and validated for the direct analysis of polar pesticides, without the need for derivatization or ion pairing, in cereals and grapes. The method was robust, and results for glyphosate, aminomethyl phosphonic acid (AMPA), N-acetyl-AMPA, glufosinate, 3-methylphosphinicopropionic acid (3-MPPA), N-acetyl glufosinate, ethephon, chlorate, perchlorate, fosetyl aluminum, and phosphonic acid at three concentration levels (typically 0.01, 0.05, and 0.1 mg/kg) were compliant with SANTE/11945/2015 guideline method performance criteria. Cereal-based infant food proved to be a more challenging matrix and validated only for glyphosate, chlorate, and perchlorate at 0.005, 0.01, and 0.05 mg/kg. The developed method enables the multiresidue analysis of 12 ionic pesticides and relevant metabolites in a single analysis. Until now, the analysis of these compounds required several different single-residue methods using different chromatographic conditions. This multiresidue approach offers the possibility of more cost-effective and more efficient monitoring of polar ionic pesticides and contaminants that are of concern to food regulation bodies and consumers.


Assuntos
Cromatografia Líquida/métodos , Contaminação de Alimentos/análise , Resíduos de Praguicidas/química , Espectrometria de Massas em Tandem/métodos , Grão Comestível/química , Resíduos de Praguicidas/isolamento & purificação , Praguicidas/química
12.
J Allergy Clin Immunol ; 140(6): 1660-1670.e16, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28400115

RESUMO

BACKGROUND: Thymus transplantation is a promising strategy for the treatment of athymic complete DiGeorge syndrome (cDGS). METHODS: Twelve patients with cDGS underwent transplantation with allogeneic cultured thymus. OBJECTIVE: We sought to confirm and extend the results previously obtained in a single center. RESULTS: Two patients died of pre-existing viral infections without having thymopoiesis, and 1 late death occurred from autoimmune thrombocytopenia. One infant had septic shock shortly after transplantation, resulting in graft loss and the need for a second transplant. Evidence of thymopoiesis developed from 5 to 6 months after transplantation in 10 patients. Median circulating naive CD4 counts were 44 × 106/L (range, 11-440 × 106/L) and 200 × 106/L (range, 5-310 × 106/L) at 12 and 24 months after transplantation and T-cell receptor excision circles were 2,238/106 T cells (range, 320-8,807/106 T cells) and 4,184/106 T cells (range, 1,582-24,596/106 T cells). Counts did not usually reach normal levels for age, but patients were able to clear pre-existing infections and those acquired later. At a median of 49 months (range, 22-80 months), 8 have ceased prophylactic antimicrobials, and 5 have ceased immunoglobulin replacement. Histologic confirmation of thymopoiesis was seen in 7 of 11 patients undergoing biopsy of transplanted tissue, including 5 showing full maturation through to the terminal stage of Hassall body formation. Autoimmune regulator expression was also demonstrated. Autoimmune complications were seen in 7 of 12 patients. In 2 patients early transient autoimmune hemolysis settled after treatment and did not recur. The other 5 experienced ongoing autoimmune problems, including thyroiditis (3), hemolysis (1), thrombocytopenia (4), and neutropenia (1). CONCLUSIONS: This study confirms the previous reports that thymus transplantation can reconstitute T cells in patients with cDGS but with frequent autoimmune complications in survivors.


Assuntos
Doenças Autoimunes/imunologia , Síndrome de DiGeorge/terapia , Transplante de Órgãos , Complicações Pós-Operatórias/imunologia , Linfócitos T/imunologia , Timo/transplante , Doenças Autoimunes/etiologia , Células Cultivadas , Criança , Pré-Escolar , Síndrome de DiGeorge/imunologia , Europa (Continente) , Feminino , Humanos , Reconstituição Imune , Lactente , Masculino , Técnicas de Cultura de Órgãos , Transplante Homólogo , Resultado do Tratamento
13.
J Chromatogr A ; 1496: 37-44, 2017 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-28366571

RESUMO

Direct analysis in real time (DART) was evaluated for the determination of a number of highly polar pesticides using the Quick Polar Pesticides Extraction (QuPPe) method. DART was hyphenated to high resolution mass spectrometry (HRMS) in order to get the required selectivity that allows the determination of these compounds in complex samples such as lettuce and celery. Experimental parameters such as desorption temperature, scanning speed, and distances between the DART ion source and MS inlet were optimized. Two different mass analyzers (Orbitrap and QTOF) and two accessories for sample introduction (Dip-it® tips and QuickStrip™ sample cards) were evaluated. An extra clean-up step using primary-secondary amine (PSA) was included in the QuPPe method to improve sensitivity. The main limitation found was in-source fragmentation, nevertheless QuPPe-DART-HRMS proved to be a fast and reliable tool with quantitative capabilities for at least seven compounds: amitrole, cyromazine, propamocarb, melamine, diethanolamine, triethanolamine and 1,2,4-triazole. The limits of detection ranged from 20 to 60µg/kg. Recoveries for fortified samples ranged from 71 to 115%, with relative standard deviations <18%.


Assuntos
Apium/química , Alface/química , Praguicidas/análise , Praguicidas/química , Calibragem , Resíduos de Praguicidas/análise , Resíduos de Praguicidas/química , Resíduos de Praguicidas/isolamento & purificação , Praguicidas/isolamento & purificação , Temperatura Ambiente , Fatores de Tempo
14.
Sci Transl Med ; 9(374)2017 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-28123068

RESUMO

Autologous T cells engineered to express chimeric antigen receptor against the B cell antigen CD19 (CAR19) are achieving marked leukemic remissions in early-phase trials but can be difficult to manufacture, especially in infants or heavily treated patients. We generated universal CAR19 (UCART19) T cells by lentiviral transduction of non-human leukocyte antigen-matched donor cells and simultaneous transcription activator-like effector nuclease (TALEN)-mediated gene editing of T cell receptor α chain and CD52 gene loci. Two infants with relapsed refractory CD19+ B cell acute lymphoblastic leukemia received lymphodepleting chemotherapy and anti-CD52 serotherapy, followed by a single-dose infusion of UCART19 cells. Molecular remissions were achieved within 28 days in both infants, and UCART19 cells persisted until conditioning ahead of successful allogeneic stem cell transplantation. This bridge-to-transplantation strategy demonstrates the therapeutic potential of gene-editing technology.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Linfócitos T/citologia , Nucleases dos Efetores Semelhantes a Ativadores de Transcrição/genética , Alemtuzumab/uso terapêutico , Antígenos CD19/metabolismo , Antígeno CD52/metabolismo , Ensaios de Uso Compassivo , Feminino , Edição de Genes , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Lentivirus/genética , Recidiva Local de Neoplasia , Receptores de Antígenos de Linfócitos T/genética , Indução de Remissão , Transplante de Células-Tronco , Efetores Semelhantes a Ativadores de Transcrição , Transplante Homólogo
15.
J Allergy Clin Immunol ; 139(2): 634-642.e5, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27522155

RESUMO

BACKGROUND: Signaling through the T-cell receptor (TCR) is critical for T-cell development and function. Linker for activation of T cells (LAT) is a transmembrane adaptor signaling molecule that is part of the TCR complex and essential for T-cell development, as demonstrated by LAT-deficient mice, which show a complete lack of peripheral T cells. OBJECTIVE: We describe a pedigree affected by a severe combined immunodeficiency phenotype with absent T cells and normal B-cell and natural killer cell numbers. A novel homozygous frameshift mutation in the gene encoding for LAT was identified in this kindred. METHODS: Genetic, molecular, and functional analyses were used to identify and characterize the LAT defect. Clinical and immunologic analysis of patients was also performed and reported. RESULTS: Homozygosity mapping was used to identify potential defective genes. Sanger sequencing of the LAT gene showed a mutation that resulted in a premature stop codon and protein truncation leading to complete loss of function and loss of expression of LAT in the affected family members. We also demonstrate loss of LAT expression and lack of TCR signaling restoration in LAT-deficient cell lines reconstituted with a synthetic LAT gene bearing this severe combined immunodeficiency mutation. CONCLUSION: For the first time, the results of this study show that inherited LAT deficiency should be considered in patients with combined immunodeficiency with T-cell abnormalities.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Membrana/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Deleção de Sequência/genética , Imunodeficiência Combinada Severa/genética , Linfócitos T/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Apoptose , Sinalização do Cálcio/genética , Diferenciação Celular , Consanguinidade , Feminino , Genótipo , Homozigoto , Humanos , Células Jurkat , Ativação Linfocitária , Masculino , Proteínas de Membrana/genética , Paquistão , Linhagem , Receptores de Antígenos de Linfócitos T/genética , Transgenes/genética
16.
J Allergy Clin Immunol ; 138(4): 1152-1160, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27241891

RESUMO

BACKGROUND: Reduced-intensity conditioning (RIC) regimens are increasingly being used in the transplantation of patients with primary immunodeficiency disorders (PIDs), but there are no large studies looking at long-term lineage-specific chimerism. OBJECTIVES: We sought to analyze long-term chimerism and event-free survival in children undergoing transplantation for PIDs using RIC with fludarabine and melphalan (Flu/Melph) and to study the effect of donor type and stem cell source. METHODS: One hundred forty-two children underwent transplantation with RIC by using Flu/Melph and for PIDs by using bone marrow (n = 93) or peripheral blood stem cells (PBSCs; n = 49). Donors were matched unrelated donors (n = 72), mismatched unrelated donors (n = 37), matched sibling donors (n = 14), matched family donors (n = 12), and mismatched family donors (n = 7). RESULTS: Overall survival at a median follow-up of 7.5 years was 78%, irrespective of stem cell source or donor type. When bone marrow was used as the stem cell source, 26% of patients ended up with very low levels of donor chimerism (<10% donor), especially in the myeloid lineage. Event-free survival in this group was significantly lower compared with that in the rest of the group (25% vs 70%, P < .001). With the use of PBSCs, more than 90% of patients achieved complete donor chimerism or high-level mixed chimerism (>50% donor chimerism) in all lineages. CONCLUSIONS: On the basis of our experience, we would suggest that PBSCs should be the stem cell source of choice in children with PIDs undergoing transplantation with Flu/Melph RIC from a matched donor source. This is most likely to ensure sustained high-level donor chimerism.


Assuntos
Quimerismo , Intervalo Livre de Doença , Síndromes de Imunodeficiência/terapia , Melfalan/uso terapêutico , Transplante de Células-Tronco/normas , Células-Tronco/citologia , Vidarabina/análogos & derivados , Linhagem da Célula , Quimioterapia Combinada , Seguimentos , Humanos , Síndromes de Imunodeficiência/tratamento farmacológico , Síndromes de Imunodeficiência/mortalidade , Lactente , Recém-Nascido , Vidarabina/uso terapêutico
18.
Clin Immunol ; 161(2): 174-9, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26255240

RESUMO

Severe combined immunodeficiency (SCID) arises from a number of different genetic defects, one of the most common being mutations in the gene encoding adenosine deaminase (ADA). In the UK, ADA deficient SCID compromises approximately 20% of all known cases of SCID. We carried out a retrospective analysis of the ADA gene in 46 known ADA deficient SCID patients on whom DNA had been stored. Here, we report a high frequency of two previously reported mutations and provide a link between the mutations and patient ethnicity within our patient cohort. We also report on 9 novel mutations that have been previously unreported.


Assuntos
Adenosina Desaminase/deficiência , Adenosina Desaminase/genética , Agamaglobulinemia/genética , Mutação/genética , Imunodeficiência Combinada Severa/genética , DNA/genética , Genótipo , Humanos , Lactente , Recém-Nascido , Estudos Retrospectivos , Reino Unido
19.
J Clin Immunol ; 35(4): 366-72, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25875700

RESUMO

PURPOSE: Adenosine deaminase (ADA) deficiency is a systemic disorder of purine metabolism. Deficiency of the purine salvage enzyme ADA leads to the build-up of the toxic metabolites, deoxyadenosine triphosphate and deoxyadenosine. ADA is ubiquitously expressed in all tissues of the body but most profoundly affects lymphocyte development and function leading to severe combined immunodeficiency (SCID). Unlike most other forms of SCID, ADA deficiency also results in non-immunologic manifestations. Associations between ADA deficiency and sensorineural hearing loss, behavioural abnormalities, non-infectious pulmonary disease and skeletal dysplasia are all recognised, and affect the long term outcome for these patients. Identification of new non-immunological manifestations and clinical presentations of ADA deficiency is essential to allow early optimisation of supportive care. METHODS AND RESULTS: Here we report four patients with ADA deficiency whose presenting feature was haemolytic uremic syndrome (HUS). 3 of 4 patients were diagnosed with ADA deficiency only after developing HUS, and one diagnosis was made post mortem, after a sibling was diagnosed with SCID. Shiga-toxigenic organisms were not isolated from any of the patients. 2 patients made a good recovery from their HUS with supportive treatment and initiation of PEG-ADA. Both remain well on enzyme replacement with mild or no residual renal impairment. CONCLUSIONS: Clinicians should be aware of this previously unreported non-immunologic manifestation of ADA deficiency.


Assuntos
Adenosina Desaminase/deficiência , Agamaglobulinemia/diagnóstico , Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Imunodeficiência Combinada Severa/diagnóstico , Adenosina Desaminase/genética , Agamaglobulinemia/tratamento farmacológico , Criança , Diagnóstico Diferencial , Evolução Fatal , Feminino , Genótipo , Humanos , Lactente , Masculino , Mutação , Imunodeficiência Combinada Severa/tratamento farmacológico
20.
Pediatr Transplant ; 18(6): 609-16, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24977928

RESUMO

For infants with SCID the ideal conditioning regimen before allogeneic HCT would omit cytotoxic chemotherapy to minimize short- and long-term complications. We performed a prospective pilot trial with alemtuzumab monotherapy to overcome NK-cell mediated immunologic barriers to engraftment. We enrolled four patients who received CD34-selected haploidentical cells, two of whom failed to engraft donor T cells. The two patients who engrafted had delayed T-cell reconstitution, despite rapid clearance of circulating alemtuzumab. Although well-tolerated, alemtuzumab failed to overcome immunologic barriers to donor engraftment. Furthermore, alemtuzumab may slow T-cell development in patients with SCID in the setting of a T-cell depleted graft.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Imunodeficiência Combinada Severa/terapia , Alemtuzumab , Anticorpos Monoclonais Humanizados/efeitos adversos , California , Quimioterapia Adjuvante , Criança , Teste de Histocompatibilidade , Humanos , Lactente , Masculino , Projetos Piloto , Estudos Prospectivos , Imunodeficiência Combinada Severa/tratamento farmacológico , Imunodeficiência Combinada Severa/imunologia , Condicionamento Pré-Transplante , Transplante Homólogo , Resultado do Tratamento
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