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1.
Am J Hum Genet ; 105(3): 549-561, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31447097

RESUMO

FOXN1 is the master regulatory gene of thymic epithelium development. FOXN1 deficiency leads to thymic aplasia, alopecia, and nail dystrophy, accounting for the nude/severe combined immunodeficiency (nu/SCID) phenotype in humans and mice. We identified several newborns with low levels of T cell receptor excision circles (TRECs) and T cell lymphopenia at birth, who carried heterozygous loss-of-function FOXN1 variants. Longitudinal analysis showed persistent T cell lymphopenia during infancy, often associated with nail dystrophy. Adult individuals with heterozygous FOXN1 variants had in most cases normal CD4+ but lower than normal CD8+ cell counts. We hypothesized a FOXN1 gene dosage effect on the function of thymic epithelial cells (TECs) and thymopoiesis and postulated that these effects would be more prominent early in life. To test this hypothesis, we analyzed TEC subset frequency and phenotype, early thymic progenitor (ETP) cell count, and expression of FOXN1 target genes (Ccl25, Cxcl12, Dll4, Scf, Psmb11, Prss16, and Cd83) in Foxn1nu/+ (nu/+) mice and age-matched wild-type (+/+) littermate controls. Both the frequency and the absolute count of ETP were significantly reduced in nu/+ mice up to 3 weeks of age. Analysis of the TEC compartment showed reduced expression of FOXN1 target genes and delayed maturation of the medullary TEC compartment in nu/+ mice. These observations establish a FOXN1 gene dosage effect on thymic function and identify FOXN1 haploinsufficiency as an important genetic determinant of T cell lymphopenia at birth.

2.
Sci Transl Med ; 11(495)2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31167928

RESUMO

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenic disorder caused by AIRE mutations, presents with several autoimmune diseases. Among these, endocrine organ failure is widely recognized, but the prevalence, immunopathogenesis, and treatment of non-endocrine manifestations such as pneumonitis remain poorly characterized. We enrolled 50 patients with APECED in a prospective observational study and comprehensively examined their clinical and radiographic findings, performed pulmonary function tests, and analyzed immunological characteristics in blood, bronchoalveolar lavage fluid, and endobronchial and lung biopsies. Pneumonitis was found in >40% of our patients, presented early in life, was misdiagnosed despite chronic respiratory symptoms and accompanying radiographic and pulmonary function abnormalities, and caused hypoxemic respiratory failure and death. Autoantibodies against BPIFB1 and KCNRG and the homozygous c.967_979del13 AIRE mutation are associated with pneumonitis development. APECED pneumonitis features compartmentalized immunopathology, with accumulation of activated neutrophils in the airways and lymphocytic infiltration in intraepithelial, submucosal, peribronchiolar, and interstitial areas. Beyond APECED, we extend these observations to lung disease seen in other conditions with secondary AIRE deficiency (thymoma and RAG deficiency). Aire-deficient mice had similar compartmentalized cellular immune responses in the airways and lung tissue, which was ameliorated by deficiency of T and B lymphocytes. Accordingly, T and B lymphocyte-directed immunomodulation controlled symptoms and radiographic abnormalities and improved pulmonary function in patients with APECED pneumonitis. Collectively, our findings unveil lung autoimmunity as a common, early, and unrecognized manifestation of APECED and provide insights into the immunopathogenesis and treatment of pulmonary autoimmunity associated with impaired central immune tolerance.

3.
Nat Immunol ; 20(3): 350-361, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30718914

RESUMO

Despite the known importance of zinc for human immunity, molecular insights into its roles have remained limited. Here we report a novel autosomal recessive disease characterized by absent B cells, agammaglobulinemia and early onset infections in five unrelated families. The immunodeficiency results from hypomorphic mutations of SLC39A7, which encodes the endoplasmic reticulum-to-cytoplasm zinc transporter ZIP7. Using CRISPR-Cas9 mutagenesis we have precisely modeled ZIP7 deficiency in mice. Homozygosity for a null allele caused embryonic death, but hypomorphic alleles reproduced the block in B cell development seen in patients. B cells from mutant mice exhibited a diminished concentration of cytoplasmic free zinc, increased phosphatase activity and decreased phosphorylation of signaling molecules downstream of the pre-B cell and B cell receptors. Our findings highlight a specific role for cytosolic Zn2+ in modulating B cell receptor signal strength and positive selection.


Assuntos
Agamaglobulinemia/imunologia , Linfócitos B/imunologia , Proteínas de Transporte de Cátions/imunologia , Zinco/imunologia , Agamaglobulinemia/genética , Agamaglobulinemia/metabolismo , Animais , Linfócitos B/metabolismo , Proteínas de Transporte de Cátions/deficiência , Proteínas de Transporte de Cátions/genética , Pré-Escolar , Citosol/imunologia , Citosol/metabolismo , Modelos Animais de Doenças , Retículo Endoplasmático/imunologia , Retículo Endoplasmático/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Lactente , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Linhagem , Zinco/metabolismo
6.
Dermatitis ; 27(5): 293-302, 2016 Sep-Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27649353

RESUMO

BACKGROUND: Little is known about the epidemiology of allergic contact dermatitis (ACD) in US children. More widespread diagnostic confirmation through epicutaneous patch testing is needed. OBJECTIVE: The aim was to quantify patch test results from providers evaluating US children. METHODS: The study is a retrospective analysis of deidentified patch test results of children aged 18 years or younger, entered by participating providers in the Pediatric Contact Dermatitis Registry, during the first year of data collection (2015-2016). RESULTS: One thousand one hundred forty-two cases from 34 US states, entered by 84 providers, were analyzed. Sixty-five percent of cases had one or more positive patch test (PPT), with 48% of cases having 1 or more relevant positive patch test (RPPT). The most common PPT allergens were nickel (22%), fragrance mix I (11%), cobalt (9.1%), balsam of Peru (8.4%), neomycin (7.2%), propylene glycol (6.8%), cocamidopropyl betaine (6.4%), bacitracin (6.2%), formaldehyde (5.7%), and gold (5.7%). CONCLUSIONS: This US database provides multidisciplinary information on pediatric ACD, rates of PPT, and relevant RPPT reactions, validating the high rates of pediatric ACD previously reported in the literature. The registry database is the largest comprehensive collection of US-only pediatric patch test cases on which future research can be built. Continued collaboration between patients, health care providers, manufacturers, and policy makers is needed to decrease the most common allergens in pediatric consumer products.


Assuntos
Dermatite Alérgica de Contato/epidemiologia , Sistema de Registros , Adolescente , Alérgenos/efeitos adversos , Bacitracina/efeitos adversos , Bálsamos/efeitos adversos , Betaína/efeitos adversos , Betaína/análogos & derivados , Criança , Pré-Escolar , Cobalto/efeitos adversos , Dermatite Alérgica de Contato/diagnóstico , Dermatite Alérgica de Contato/etiologia , Feminino , Formaldeído/efeitos adversos , Ouro/efeitos adversos , Humanos , Lactente , Recém-Nascido , Masculino , Neomicina/efeitos adversos , Níquel/efeitos adversos , Testes do Emplastro , Perfumes/efeitos adversos , Propilenoglicol/efeitos adversos , Estudos Retrospectivos , Estados Unidos/epidemiologia
7.
J Clin Immunol ; 36(6): 600-9, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27342758

RESUMO

PURPOSE: This phase 4, multicenter, open-labeled, single-sequence, crossover study in pediatric patients (ages 2 to 16) with primary immunodeficiency disease (PID) evaluated the pharmacokinetics, safety, and tolerability for subcutaneously (SC) administered 10 % caprylate/chromatography purified human immune globulin injection (IGIV-C, GAMUNEX®) compared with intravenously (IV) administered IGIV-C. METHODS: This study included a screening phase, run-in phase (where required), IV treatment phase, SC treatment phase, and end of study/early termination visit. Eligible patients receiving a stable dose of IGIV-C entered into the IV phase to receive two IV infusions of IGIV-C (200-600 mg/kg per infusion) every 3-4 weeks. The weekly SC dose of IGIV-C was calculated using a conversion factor of 1.37 times the prior IV dose. RESULTS: Twelve subjects between the ages of 2 and 16 years participated in the clinical study with the median age being 11 years old. The adjusted weekly mean AUC0-τ,IV was 216,873.7 h*mg/dL for the IV phase versus a mean AUC0-τ,SC of 230,830.0 h*mg/dL for the SC phase. The mean (range) C trough was 997.2 (784-1320) mg/dL in the IV phase and 1325.0 (1077-1690) mg/dL in the SC phase. During the SC phase, 100.0 % of the patients (n = 11) experienced treatment-emergent adverse events (TEAEs) that were local infusion reactions and 9 patients (81.8 %) had TEAEs that were non-infusion site reactions. The majority of TEAEs were mild or moderate in severity. CONCLUSION: In pediatric patients with PID, SC-administered IGIV-C provides comparable overall serum exposure to total IgG to that produced by IV-administered IGIV-C. We have concluded that weekly SC administration of 10 % IGIV-C based on a dose conversion factor of 1.37 is safe and well-tolerated in pediatric patients with PID. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01465958. https://clinicaltrials.gov/ct2/show/NCT01465958?term=NCT01465958.&rank=1.


Assuntos
Imunoglobulinas Intravenosas/farmacologia , Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/tratamento farmacológico , Adolescente , Anticorpos Neutralizantes/sangue , Área Sob a Curva , Infecções Bacterianas/etiologia , Criança , Pré-Escolar , Monitoramento de Medicamentos , Feminino , Humanos , Síndromes de Imunodeficiência/sangue , Síndromes de Imunodeficiência/diagnóstico , Reação no Local da Injeção/etiologia , Masculino , Resultado do Tratamento
8.
J Clin Immunol ; 36(6): 583-9, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27279130

RESUMO

PURPOSE: The previous studies with Flebogamma(®) 5 % DIF intravenous immunoglobulin (IVIG) contained insufficient numbers of pediatric subjects to fully warrant a pediatric indication by the FDA. The objective of this study was to evaluate the efficacy, safety, and pharmacokinetics of Flebogamma® 5 % DIF for replacement therapy in children (age 2-16) with primary immunodeficiency diseases (PIDD). METHODS: IVIG was administered at eight clinical sites to 24 subjects with well-defined PIDD at a dose of 300-800 mg/kg every 21-28 days for 12 months. The pharmacokinetics endpoint in this study was the dose-adjusted increment of the serum IgG trough levels. RESULTS: The calculated serious bacterial infection rate was 0.05/subject/year. The incidence of adverse events considered potentially related to IVIG during or within 72 h after completing an infusion was within the FDA guidance threshold of <40 % at each time point. Dose-adjusted incremental IgG levels remained approximately equal to or slightly greater than pre-study IgG levels (between 800 and 1000 mg/dL throughout) when the subjects were treated with IVIG therapy other than Flebogamma(®) DIF 5 % indicating no evidence of a different pharmacokinetic profile in this pediatric population if compared to those profiles in previous Flebogamma studies in predominately adult populations. CONCLUSIONS: Flebogamma(®) 5 % DIF is efficacious and safe, has adequate pharmacokinetic properties, is well-tolerated, and maintains the profile of Flebogamma(®) 5 % for the treatment of children with primary humoral immunodeficiency diseases.


Assuntos
Imunoglobulinas Intravenosas/administração & dosagem , Síndromes de Imunodeficiência/tratamento farmacológico , Adolescente , Infecções Bacterianas/etiologia , Criança , Pré-Escolar , Feminino , Humanos , Imunoglobulinas Intravenosas/efeitos adversos , Imunoglobulinas Intravenosas/farmacocinética , Síndromes de Imunodeficiência/diagnóstico , Masculino , Fatores de Tempo , Resultado do Tratamento
9.
Biol Blood Marrow Transplant ; 17(4): 534-41, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20457269

RESUMO

Preliminary studies using directed-donor ex vivo expanded human mesenchymal stem cells (hMSCs) have shown promise in the treatment of acute graft-versus-host disease (aGVHD). However, their production is cumbersome and standardization is difficult. We describe the first experience of using a premanufactured, universal donor, formulation of hMSCs (Prochymal) in children (n = 12; 10 boys; 9 Caucasian; age range: 0.4-15 years) with treatment-resistant grade III and IV aGVHD who received therapy on compassionate use basis between July 2005 and June 2007 at 5 transplant centers. All patients had stage III or IV gut (GI) symptoms and half had additional liver and/or skin involvement. Disease was refractory to steroids in all cases and additionally to a median of 3 other immunosuppressive therapies. The hMSCs (8 × 10(6)cells/kg/dose in 2 patients and 2 × 10(6)cells/kg/dose in the rest) were infused intravenously over 1 hour twice a week for 4 weeks. Partial and mixed responders received subsequent weekly therapy for 4 weeks. HLA or other matching was not needed. The hMSCs were started at a median of 98 days (range: 45-237) posttransplant. A total of 124 doses were administered, with a median of 8 doses (range: 2-21) per patient. Overall, 7 (58%) patients had complete response, 2 (17%) partial response, and 3 (25%) mixed response. Complete resolution of GI symptoms occurred in 9 (75%) patients. Two patients relapsed after initial response and showed partial response to retreatment. The cumulative incidence of survival at 100 days from the initiation of Prochymal therapy was 58%. Five of 12 patients (42%) were still alive after a median follow-up of 611 days (range: 427-1111) in surviving patients. No infusional or other identifiable acute toxicity was seen in any patient. Multiple infusions of hMSCs were well tolerated and appeared to be safe in children. Clinical responses, particularly in the GI system, were seen in the majority of children with severe refractory aGVHD. Given the favorable results observed in a patient population with an otherwise grave prognosis, we conclude that hMSCs hold potential for the treatment of aGVHD, and should be further studied in phase III trials in pediatric and adult patients.


Assuntos
Células-Tronco Adultas , Técnicas de Cultura de Células , Doença Enxerto-Hospedeiro/terapia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Doença Aguda , Adolescente , Adulto , Células Cultivadas , Criança , Pré-Escolar , Ensaios de Uso Compassivo , Intervalo Livre de Doença , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/mortalidade , Neoplasias Hematológicas/mortalidade , Humanos , Lactente , Masculino , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de Tempo , Transplante Homólogo
10.
Diabetes ; 59(10): 2558-68, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20622174

RESUMO

OBJECTIVE: To test the graft-promoting effects of mesenchymal stem cells (MSCs) in a cynomolgus monkey model of islet/bone marrow transplantation. RESEARCH DESIGN AND METHODS: Cynomolgus MSCs were obtained from iliac crest aspirate and characterized through passage 11 for phenotype, gene expression, differentiation potential, and karyotype. Allogeneic donor MSCs were cotransplanted intraportally with islets on postoperative day (POD) 0 and intravenously with donor marrow on PODs 5 and 11. Recipients were followed for stabilization of blood glucose levels, reduction of exogenous insulin requirement (EIR), C-peptide levels, changes in peripheral blood T regulatory cells, and chimerism. Destabilization of glycemia and increases in EIR were used as signs of rejection; additional intravenous MSCs were administered to test the effect on reversal of rejection. RESULTS: MSC phenotype and a normal karyotype were observed through passage 11. IL-6, IL-10, vascular endothelial growth factor, TGF-ß, hepatocyte growth factor, and galectin-1 gene expression levels varied among donors. MSC treatment significantly enhanced islet engraftment and function at 1 month posttransplant (n = 8), as compared with animals that received islets without MSCs (n = 3). Additional infusions of donor or third-party MSCs resulted in reversal of rejection episodes and prolongation of islet function in two animals. Stable islet allograft function was associated with increased numbers of regulatory T-cells in peripheral blood. CONCLUSIONS: MSCs may provide an important approach for enhancement of islet engraftment, thereby decreasing the numbers of islets needed to achieve insulin independence. Furthermore, MSCs may serve as a new, safe, and effective antirejection therapy.


Assuntos
Diabetes Mellitus Experimental/cirurgia , Transplante das Ilhotas Pancreáticas/fisiologia , Transplante de Células-Tronco Mesenquimais/métodos , Animais , Antígenos CD/análise , Glicemia/metabolismo , Diferenciação Celular , Meios de Cultura , Diabetes Mellitus Experimental/sangue , Fator de Crescimento Epidérmico/genética , Fatores de Transcrição Forkhead/análise , Galectina 1/genética , Fator de Crescimento de Hepatócito/genética , Antígenos de Histocompatibilidade Classe II/análise , Teste de Histocompatibilidade , Interleucinas/genética , Cariotipagem , Macaca fascicularis/imunologia , Macaca fascicularis/fisiologia , Complexo Principal de Histocompatibilidade , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/fisiologia , Fenótipo , RNA/genética , RNA/isolamento & purificação , Fator de Crescimento Transformador beta/genética , Transplante Homólogo
11.
J Allergy Clin Immunol ; 124(3): 536-43, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19683336

RESUMO

BACKGROUND: Mutations in serine protease inhibitor Kazal-type 5 (SPINK5), encoding the serine protease inhibitor lympho-epithelial Kazal-type 5 related inhibitor (LEKTI), cause Comèl-Netherton syndrome, an autosomal-recessive disease characterized by congenital ichthyosis, bamboo hair, and atopic diathesis. Despite increased frequency of infections, the immunocompetence of patients with Comèl-Netherton syndrome has not been extensively investigated. OBJECTIVE: To define Comèl-Netherton syndrome as a primary immunodeficiency disorder and to explore the benefit of intravenous immunoglobulin replacement therapy. METHODS: We enrolled 9 patients with Comèl-Netherton syndrome, sequenced SPINK5, and analyzed LEKTI expression by immunohistochemistry. Immune function was assessed by measuring cognate immunity, serum cytokine levels, and natural killer cell cytotoxicity. RESULTS: All patients presented with recurrent skin infections caused predominantly by Staphylococcus aureus. All but 1 reported recurrent respiratory tract infections; 78% had sepsis and/or pneumonia; 67% had recurrent gastrointestinal disease and failure to thrive. Mutations in SPINK5-including 6 novel mutations-were identified in 8 patients. LEKTI expression was decreased or absent in all patients. Immunologic evaluation revealed reduced memory B cells and defective responses to vaccination with Pneumovax and bacteriophage phiX174, characterized by impaired antibody amplification and class-switching. Immune dysregulation was suggested by a skewed T(h)1 phenotype and elevated proinflammatory cytokine levels, whereas serum concentrations of the chemokine (C-C motif) ligand 5 and natural killer cell cytotoxicity were decreased. Treatment with intravenous immunoglobulin resulted in remarkable clinical improvement and temporarily increased natural killer cell cytotoxicity. CONCLUSION: These data provide new insights into the immunopathology of Comèl-Netherton syndrome and demonstrate that this multisystem disorder, characterized by lack of LEKTI expression in epithelial cells, is complicated by cognate and innate immunodeficiency that responds favorably to intravenous immunoglobulin therapy.


Assuntos
Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Proteínas Secretadas Inibidoras de Proteinases/genética , Infecções Cutâneas Estafilocócicas/genética , Infecções Cutâneas Estafilocócicas/imunologia , Staphylococcus aureus , Linfócitos B/imunologia , Linfócitos B/metabolismo , Criança , Pré-Escolar , Citocinas/sangue , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Masculino , Mutação , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Proteínas Secretadas Inibidoras de Proteinases/biossíntese , Proteínas Secretadas Inibidoras de Proteinases/metabolismo , Inibidor de Serinopeptidase do Tipo Kazal 5 , Infecções Cutâneas Estafilocócicas/tratamento farmacológico , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
12.
Rev Assoc Med Bras (1992) ; 54(5): 426-9, 2008 Sep-Oct.
Artigo em Português | MEDLINE | ID: mdl-18989563

RESUMO

OBJECTIVE: A biochemical marker for detection of acute cellular rejection following small intestine transplantation has been sought. Citrulline, a non- protein amino acid synthesized mainly by functioning enterocytes, has been proposed. Trial sensitivity has been reportedly high but with low specificity. Thus, the goal was to determine, in a sufficiently large analysis, the significant value of citrulline level in the post-transplant setting, which would correlate with complications such as rejection and infection. METHODS: Since March, 2004 2,135 dried blood spot (DBS) citrulline samples were obtained from 57 small intestine transplant recipients three months or more after post-transplant, i.e., once the expected period of recovery in the citrulline levels had occurred. RESULTS: Using a <13 vs. > 13 micromoles/L cut off point, sensitivity of DBS citrulline for the detection of moderate or severe ACR was extremely high (96.4%). Furthermore, specificity estimates (given the absence of ACR and these particular infections), while controlling for time-to-DBS sample were reasonably high (54%-74% in children and 83%-88% in adults), and the negative predictive value (NPV) was >99%. CONCLUSION: Citrulline is a non-invasive marker to evaluate problems of the intestinal graft after three months post-transplant. Due to the high NPV, a moderate or severe ACR can be ruled out, based exclusively on knowledge of a high value for DBS citrulline.


Assuntos
Citrulina/sangue , Rejeição de Enxerto/diagnóstico , Intestinos/transplante , Adulto , Biomarcadores/sangue , Criança , Rejeição de Enxerto/sangue , Humanos , Valor Preditivo dos Testes , Valores de Referência
13.
Rev. Assoc. Med. Bras. (1992) ; 54(5): 426-429, set.-out. 2008. tab
Artigo em Português | LILACS | ID: lil-495904

RESUMO

OBJETIVO: Analisar, numa ampla amostra, o valor crítico da citrulina que confirma a presença das principais complicações do enxerto: rejeição e infecção. MÉTODOS: Foram coletadas 2135 amostras de citrulina sérica, na forma de gota de sangue seca, de 57 doentes submetidos a transplante de intestino/multivisceral no Jackson Memorial Hospital na Universidade de Miami, de março de 2004 a abril de 2006. Todas as amostras são do pós-operatório três meses em diante, passada a conhecida curva de elevação da citrulina após a recuperação das lesões causadas pela isquemia e reperfusão do pós-transplante. RESULTADOS: Utilizando um valor limite menor que 13 µmoles/L, a sensibilidade da citrulina foi de 96,4 por cento para detectar rejeicão celular aguda (RCA) moderada ou grave. A especificidade para as complicações mais freqüentes, rejeição e infecção foi de 54 por cento-74 por cento nas crianças e 83 por cento-88 por cento nos adultos, e o valor preditivo negativo (VPN) foi > 99 por cento. CONCLUSÃO: A citrulina pode ser utilizada como método não-invasivo para avaliar a evolução do enxerto intestinal após três meses do TI. Os episódios de RCA moderado e grave podem ser afastados quando o valor da citrulina for maior que 13 µmoles/L devido ao alto valor preditivo negativo.


OBJECITIVE: A biochemical marker for detection of acute cellular rejection following small intestine transplantation has been sought. Citrulline, a non- protein amino acid synthesized mainly by functioning enterocytes, has been proposed. Trial sensitivity has been reportedly high but with low specificity. Thus, the goal was to determine, in a sufficiently large analysis, the significant value of citrulline level in the post-transplant setting, which would correlate with complications such as rejection and infection. METHODS: Since March, 2004 2,135 dried blood spot (DBS) citrulline samples were obtained from 57 small intestine transplant recipients three months or more after post-transplant, i.e., once the expected period of recovery in the citrulline levels had occurred. RESULTS: Using a <13 vs. > 13 µmoles/L cut off point, sensitivity of DBS citrulline for the detection of moderate or severe ACR was extremely high (96.4 percent). Furthermore, specificity estimates (given the absence of ACR and these particular infections), while controlling for time-to-DBS sample were reasonably high (54 percent-74 percent in children and 83 percent-88 percent in adults), and the negative predictive value (NPV) was >99 percent. CONCLUSION: Citrulline is a non-invasive marker to evaluate problems of the intestinal graft after three months post-transplant. Due to the high NPV, a moderate or severe ACR can be ruled out, based exclusively on knowledge of a high value for DBS citrulline.


Assuntos
Adulto , Criança , Humanos , Citrulina/sangue , Rejeição de Enxerto/diagnóstico , Intestinos/transplante , Biomarcadores/sangue , Rejeição de Enxerto/sangue , Valor Preditivo dos Testes , Valores de Referência
14.
Transplantation ; 84(9): 1077-81, 2007 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-17998860

RESUMO

BACKGROUND: Serum citrulline is a marker for acute cellular rejection (ACR) after intestinal transplantation; however, its clinical utility has not yet been established. The goal of this study was to determine clearcut serum levels beyond which the diagnosis of acute rejection could be supported or refuted, and predictors of citrulline levels posttransplant from which more accurate estimates of sensitivity and specificity could be obtained. METHODS: Since March 2004, we obtained 2135 dried blood spot (DBS) citrulline samples from 57 intestinal transplant recipients at or beyond 3 months posttransplant. Stepwise linear regression was performed to determine the most significant multivariable predictors of the patient's DBS citrulline level. RESULTS: Seven characteristics were associated with a significantly lower citrulline in multivariable analysis: presence of mild, moderate, or severe ACR; presence of bacteremia or respiratory infection; pediatric age; and time from transplant to DBS sample (P<0.00001 in each case). Using a <13 vs. > or =13 micromoles/L cutoff point, the sensitivity for detecting moderate or severe ACR and the negative predictive value were high (96.4% and >99% respectively). Specificity was 54% to 74% in children and 83% to 88% in adults. CONCLUSIONS: Citrulline levels <13 micromoles/L should alert the clinical team that a serious problem (rejection or infection) could be looming in a previously stable intestinal recipient. Levels > =13 micromoles/L practically rule out moderate or severe rejection.


Assuntos
Citrulina/sangue , Rejeição de Enxerto/diagnóstico , Intestinos/transplante , Doença Aguda , Biomarcadores/sangue , Feminino , Rejeição de Enxerto/sangue , Humanos , Masculino , Estudos Retrospectivos , Sensibilidade e Especificidade
15.
J Spinal Cord Med ; 30 Suppl 1: S35-40, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17874685

RESUMO

BACKGROUND/OBJECTIVE: Adipose-derived stem cells (ADSCs) are mesenchymal stem cells (MSCs) that can be extracted from adipose tissue and obtained by a less invasive method and in larger quantities compared with bone marrow-derived MSCs. The objective of this study was to harvest ADSCs from piglets and to explore their neuronal differentiation potential. METHODS: Adipose tissue from piglet facial or abdominal fat was digested with collagenase type XI, followed by filter and centrifugation; the isolated adipose stromal cells were cultured in dishes. MSC markers were measured by flow cytometry; 2 to 5 passage cells were used for in vitro differentiation. Adipogenic, chondrogenic, osteogenic, and neuronal differentiation was induced by incubation of the ADSCs with different induction media. RESULTS: ADSCs were easily expanded to beyond 15 passages, maintaining the undifferentiated state and exhibiting MSC characteristics and markers CD29, CD44, and CD90. ADSCs differentiated into other mesodermal cells including adipocytes, chondrocytes, and osteocytes. These cells were induced to differentiate into neuron-like cells as evidenced by neuronal morphology and the presence of neuronal markers including microtubule-associated protein 2, neuronal nuclear antigen, and beta-tubulin III. CONCLUSIONS: ADSCs can be readily obtained from a small amount fat tissue and expanded in culture. Adipose tissue may be an alternative source of stem cell therapy for nervous system injury.


Assuntos
Tecido Adiposo/citologia , Diferenciação Celular/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Neurônios/fisiologia , Células-Tronco/fisiologia , Animais , Animais Recém-Nascidos , Antígenos CD/metabolismo , Células Cultivadas , Citometria de Fluxo , Suínos , Fatores de Tempo
16.
Ann Surg ; 246(3): 436-44; discussion 445-6, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17717447

RESUMO

OBJECTIVES: To describe the effect of the splenic allograft in human multivisceral transplantation. SUMMARY BACKGROUND DATA: We performed transplants of the spleen as part of a multivisceral graft in an attempt to decrease both the risk of infection from an asplenic state and the risk of rejection by a possible tolerogenic effect. To our knowledge, this is the first report of human splenic transplantation in a large series. METHODS: All primary multivisceral recipients who received a donor spleen (N = 60) were compared with those who did not receive a spleen (N = 81). RESULTS: Thirty-five of 60 (58%) are alive in the spleen group, and 39 of 81 (48%) are alive in control group (P = 0.98). In univariate analysis, splenic recipients showed superiority in freedom-from-any rejection (P = 0.02) and freedom-from-moderate or severe rejection (P = 0.007). No significant differences were observed in analyses of infectious complications between the spleen and control groups. Both platelet and leukocyte counts became normal in splenic patients, whereas these counts were significantly increased in nonsplenic recipients. Observed incidence of graft versus host disease (GVHD) was 8.25% (5 of 60) in the spleen group and 6.2% (5 of 81) in the control group (P = 0.70). Increased incidence of autoimmune hemolysis was observed in the spleen group. CONCLUSIONS: Allograft spleen can be transplanted within a multivisceral graft without significantly increasing the risk of GVHD. The allogenic spleen seems to show a protective effect on small bowel rejection. Further investigation with longitudinal follow-up is required to precisely determine the immunologic and hematologic effects of the allograft spleen.


Assuntos
Baço/transplante , Vísceras/transplante , Adolescente , Adulto , Contagem de Células Sanguíneas , Criança , Pré-Escolar , Feminino , Rejeição de Enxerto/epidemiologia , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/epidemiologia , Humanos , Imunossupressão/métodos , Incidência , Lactente , Tempo de Internação , Transtornos Linfoproliferativos/etiologia , Masculino , Complicações Pós-Operatórias/epidemiologia , Modelos de Riscos Proporcionais , Análise de Sobrevida , Transplante Homólogo , Resultado do Tratamento
17.
Transplantation ; 83(12): 1611-9, 2007 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-17589345

RESUMO

BACKGROUND: We update more favorable 10-year deceased donor kidney transplant survival in 63 recipients infused perioperatively with donor vertebral body bone marrow (DBMC-i) vs. 219 noninfused controls having equivalent immunosuppression and demographics. We questioned if this was associated with putatively regulatory FoxP3 mRNA and cell phenotypes (CD4+CD25+high percentages and high DC2:DC1 ratios) in DBMC-i vs. noninfused controls. METHODS: Baseline studies were performed on peripheral blood lymphocytes (PBLs) vs. marrow in normal laboratory volunteers of CD4+CD25+high percentages and DC2:DC1 by flow cytometry, and FoxP3 mRNA in CD3+ cells by real-time polymerase chain reaction. Similar studies were performed on PBL of the majority of the 10-year patients remaining with graft function: 21 (of the remaining 37) DBMC-i vs. 55 (of the remaining 105) controls. RESULTS: In normal subjects, all parameters were significantly higher in marrow than in PBL, supporting our previous reports of ex vivo DBMC immunoregulation. At 9.8+/-.02 years posttransplant in DBMC-i vs. controls, death-censored percent graft failure was 17.5% vs. 32.9% (P=0.02) with 247.6+/-24 vs. 79.9+/-3.1 (mean+/-SE) FoxP3 copies/5,000 CD3+ cells (P=0.0001). PBL CD4+CD25+high percentages were lower, but DC2:DC1 values higher in both recipient groups than in end-stage renal disease patients who had lower FoxP3 levels (40.8+/-5.9, P<0.0001), consistent with non-CD4+CD25+high T regulatory cells generated long-term posttransplant. Individual higher FoxP3 values correlated with higher iliac crest chimerism in DBMC-i, but not in controls (with 50-fold lower chimerism). In chronically rejecting controls, FoxP3 was further decreased. CONCLUSIONS: Peritransplant DBMC-i has higher 10-year renal transplant acceptance, chimerism, and FoxP3 mRNA in thus-far unclarified regulatory cell phenotypes.


Assuntos
Transplante de Medula Óssea/fisiologia , Fatores de Transcrição Forkhead/metabolismo , Transplante de Rim/fisiologia , RNA Mensageiro/genética , Medula Óssea/imunologia , Transplante de Medula Óssea/imunologia , Complexo CD3/imunologia , Citometria de Fluxo , Seguimentos , Humanos , Imunofenotipagem , Falência Renal Crônica/cirurgia , Transplante de Rim/imunologia , Linfócitos T/imunologia , Transcrição Genética
18.
Mov Disord ; 22(11): 1664-6, 2007 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-17588239

RESUMO

X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disorder caused by a mutation in the Bruton agammaglobulinemia tyrosine kinase gene that results in severe B-cell deficiency. So far, neurological complications of XLA have been primarily related to acute and/or chronic central nervous system enteroviral infections. In the last few years a progressive neurodegenerative syndrome of unknown etiology has been described in XLA patients. We describe and present a video of an XLA patient who developed a fatal dementing, dystonia-Parkinsonism syndrome 14 years into his immune disorder. Physician awareness of this rare syndrome may lead to its better characterization and management.


Assuntos
Distúrbios Distônicos/tratamento farmacológico , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Transtornos Parkinsonianos/tratamento farmacológico , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/tratamento farmacológico , Adolescente , Encéfalo/patologia , Distúrbios Distônicos/complicações , Distúrbios Distônicos/patologia , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Transtornos Parkinsonianos/complicações , Transtornos Parkinsonianos/patologia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/complicações , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/patologia
19.
Pediatr Dermatol ; 24(2): 172-6, 2007 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17461818

RESUMO

Pemphigus foliaceus is an autoimmune disease that clinically manifests with cutaneous blisters of the superficial skin. The nonendemic or sporadic form of this entity is rare in children and typically presents with a milder, more localized rash that usually follows a benign course of short duration. We describe an affected patient atypical in both her young age and the severity of skin findings. Our patient presented with a full body exfoliative erythroderma at 21 months of age. After an extensive work-up to determine the etiology of her exfoliative erythroderma, direct and indirect immunofluorescence studies confirmed the diagnosis of pemphigus foliaceus. Rituximab therapy was initiated based on the patient's refractory disease course to multiple immunosuppressive agents. Rituximab is a therapeutic monoclonal antibody targeting CD20, an integral membrane protein highly expressed on the surface of pre-B lymphocytes and activated mature B lymphocytes. The patient's skin exhibited marked clinical improvement after the start of rituximab infusions over 12 weeks. Her initial desmoglein 1 antibody level was greater than 1:1280, which decreased to 1:16 after seven rituximab treatments. She has had no skin flares since initiating treatment with rituximab therapy. Based on this clinical and serologic response, the use of rituximab may be helpful in the treatment of pediatric pemphigus foliaceus refractory to mainstays of therapy.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Dermatite Esfoliativa/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Pênfigo/tratamento farmacológico , Pênfigo/patologia , Anticorpos Monoclonais Murinos , Dermatite Esfoliativa/etiologia , Dermatite Esfoliativa/patologia , Feminino , Humanos , Lactente , Pênfigo/complicações , Rituximab
20.
Transplantation ; 80(12): 1729-33, 2005 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-16378068

RESUMO

BACKGROUND: Citrulline concentrations have been proposed as a marker for intestinal allograft rejection. We instituted dried blood spot (DBS) specimen monitoring of citrulline to simplify sample collection posttransplant. This study demonstrates the correlation between plasma and dried blood spot specimen citrulline concentrations after intestinal transplantation. METHODS: Plasma and DBS samples were analyzed by hydrophilic interaction chromatography tandem mass spectrometry. Comparison of the strength of linear correlation was made according to the type of surgery, sonication time, DBS citrulline levels, and the time interval between the blood sample collection and the assay date. RESULTS: A very strong linear correlation exists between the plasma and DBS citrulline concentrations (r=0.87; P<0.001). The correlation between plasma and DBS citrulline concentrations was maintained when evaluating only the intestinal transplant recipients. There was no significant difference in the strength of linear correlation according to sonication time, cirtrulline concentrations, or length of time to assay date. CONCLUSIONS: DBS citrulline monitoring will ease sample collection following intestinal transplantation and improve the ability to detect intestinal dysfunction and rejection by a noninvasive means.


Assuntos
Citrulina/sangue , Intestinos/transplante , Transplante Homólogo/fisiologia , Adulto , Idoso , Coleta de Amostras Sanguíneas/métodos , Criança , Pré-Escolar , Feminino , Hepatectomia , Humanos , Lactente , Transplante de Fígado/fisiologia , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica/métodos
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