Assuntos
Granuloma/diagnóstico , Janus Quinase 3/genética , Mutação , Imunodeficiência Combinada Severa/genética , Dermatopatias/diagnóstico , Linfócitos B/imunologia , Linfócitos B/metabolismo , Biópsia , Pré-Escolar , Diagnóstico Diferencial , Feminino , Expressão Gênica , Humanos , Imunofenotipagem , Janus Quinase 3/metabolismo , Imunodeficiência Combinada Severa/diagnóstico , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
OBJECTIVE: To investigate the clinical manifestations at diagnosis and during follow-up in patients with 22q11.2 deletion syndrome to better define the natural history of the disease. STUDY DESIGN: A retrospective and prospective multicenter study was conducted with 228 patients in the context of the Italian Network for Primary Immunodeficiencies. Clinical diagnosis was confirmed by cytogenetic or molecular analysis. RESULTS: The cohort consisted of 112 males and 116 females; median age at diagnosis was 4 months (range 0 to 36 years 10 months). The diagnosis was made before 2 years of age in 71% of patients, predominantly related to the presence of heart anomalies and neonatal hypocalcemia. In patients diagnosed after 2 years of age, clinical features such as speech and language impairment, developmental delay, minor cardiac defects, recurrent infections, and facial features were the main elements leading to diagnosis. During follow-up (available for 172 patients), the frequency of autoimmune manifestations (P = .015) and speech disorders (P = .002) increased. After a median follow-up of 43 months, the survival probability was 0.92 at 15 years from diagnosis. CONCLUSIONS: Our data show a delay in the diagnosis of 22q11.2 deletion syndrome with noncardiac symptoms. This study provides guidelines for pediatricians and specialists for early identification of cases that can be confirmed by genetic testing, which would permit the provision of appropriate clinical management.
Assuntos
Anormalidades Múltiplas/diagnóstico , Deficiências do Desenvolvimento/epidemiologia , Síndrome de DiGeorge/diagnóstico , Progressão da Doença , Monitorização Fisiológica/métodos , Anormalidades Múltiplas/epidemiologia , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Cromossomos Humanos Par 22/genética , Diagnóstico Tardio , Deficiências do Desenvolvimento/diagnóstico , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/terapia , Diagnóstico Precoce , Feminino , Seguimentos , Testes Genéticos , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Prospectivos , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Fatores de Tempo , Adulto JovemRESUMO
Therapeutic HIV immunization is intended to induce new HIV-specific cellular immune responses and to reduce viral load, possibly permitting extended periods without antiretroviral drugs. A multigene, multi-subtype A, B, C HIV-DNA vaccine (HIVIS) has been used in clinical trials in both children and adults with the aim of improving and broadening the infected individuals' immune responses. Despite the different country locations, different regimens and the necessary variations in assays performed, this is, to our knowledge, the first attempt to compare children's and adults' responses to a particular HIV vaccine. Ten vertically HIV-infected children aged 4-16 years were immunized during antiretroviral therapy (ART). Another ten children were blindly recruited as controls. Both groups continued their antiretroviral treatment during and after vaccinations. Twelve chronically HIV-infected adults were vaccinated, followed by repeated structured therapy interruptions (STI) of their antiretroviral treatment. The adult group included four controls, receiving placebo vaccinations. The HIV-DNA vaccine was generally well tolerated, and no serious adverse events were registered in any group. In the HIV-infected children, an increased specific immune response to Gag and RT proteins was detected by antigen-specific lymphoproliferation. Moreover, the frequency of HIV-specific CD8+ T-cell lymphocytes releasing perforin was significantly higher in the vaccinees than the controls. In the HIV-infected adults, increased CD8+ T-cell responses to Gag, RT and viral protease peptides were detected. No augmentation of HIV-specific lymphoproliferative responses were detected in adults after vaccination. In conclusion, the HIV-DNA vaccine can elicit new HIV-specific cellular immune responses, particularly to Gag antigens, in both HIV-infected children and adults. Vaccinated children mounted transient new HIV-specific immune responses, including both CD4+ T-cell lymphoproliferation and late CD8+ T-cell responses. In the adult cohort, primarily CD8+ T-cell responses related to MHC class I alleles were noted. However, no clinical benefits with respect to viral load reduction were ascribable to the vaccinations alone. No severe adverse effects related to the vaccine were found in either cohort, and no virological failures or drug resistances were detected.
RESUMO
SUBJECTS: Twenty vertically HIV-infected children, 6-16 years of age, with stable viral load control and CD4+ values above 400 cells/mm(3). INTERVENTION: Ten subjects continued their ongoing antiretroviral treatment (ART, Group A) and 10 were immunized with a HIV-DNA vaccine in addition to their previous therapy (ART and vaccine, Group B). The genetic vaccine represented HIV-1 subtypes A, B and C, encoded Env, Rev, Gag and RT and had no additional adjuvant. Immunizations took place at weeks 0, 4 and 12, with a boosting dose at week 36. Monitoring was performed until week 60 and extended to week 96. RESULTS: Safety data showed good tolerance of the vaccine. Adherence to ART remained high and persistent during the study and did not differ significantly between controls and vaccinees. Neither group experienced either virological failure or a decline of CD4+ counts from baseline. Higher HIV-specific cellular immune responses were noted transiently to Gag but not to other components of the vaccine. Lymphoproliferative responses to a virion antigen HIV-1 MN were higher in the vaccinees than in the controls (pâ=â0.047), whereas differences in reactivity to clade-specific Gag p24, RT or Env did not reach significance. Compared to baseline, the percentage of HIV-specific CD8+ lymphocytes releasing perforin in the Group B was higher after the vaccination schedule had been completed (pâ=â0.031). No increased CD8+ perforin levels were observed in control Group A. CONCLUSIONS: The present study demonstrates the feasibility, safety and moderate immunogenicity of genetic vaccination in vertically HIV-infected children, paving the way for amplified immunotherapeutic approaches in the pediatric population. TRIAL REGISTRATION: clinicaltrialsregister.eu _2007-002359-18IT.
Assuntos
Vacinas contra a AIDS/uso terapêutico , Infecções por HIV/terapia , Infecções por HIV/transmissão , Transmissão Vertical de Doenças Infecciosas , Vacinas de DNA/uso terapêutico , Vacinas contra a AIDS/efeitos adversos , Vacinas contra a AIDS/imunologia , Adolescente , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Linfócitos T CD8-Positivos/imunologia , Criança , Feminino , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Infecções por HIV/virologia , HIV-1/imunologia , Humanos , Masculino , Resultado do Tratamento , Vacinação , Vacinas de DNA/efeitos adversos , Vacinas de DNA/imunologia , Carga ViralRESUMO
BACKGROUND: This Phase IV study evaluated the safety and immunogenicity of a two-dose, MF59®-adjuvanted (Novartis Vaccines, Marburg, Germany), monovalent, A/H1N1 pandemic influenza vaccination schedule in Human Immunodeficiency Virus (HIV) positive children and young adults. METHODS: A total of 83 children infected with HIV-1, and 37 non-immunocompromised, age-matched controls were enrolled. All participants received two vaccine doses administered three weeks apart. Antibody responses were assessed by haemagglutination assay at baseline, three weeks after each vaccine dose, and six months after immunization. Vaccines were evaluated according to European influenza vaccine licensure criteria. RESULTS: The investigational vaccine was well tolerated. After the first vaccine dose, seroconversion rates were significantly lower in HIV-positive patients (60%) than controls (82%), with GMTs of 419 and 600, respectively. No significant differences in seroconversion rates were observed between the two study groups in response to the second vaccine dose. Persisting antibody titers were similar for both HIV-positive and non-infected controls, six months after immunization. CONCLUSION: One dose of MF59-adjuvanted vaccine was sufficient to provide adequate levels of seroprotection against A/H1N1 influenza disease in HIV-positive children. However, a two-dose vaccination schedule may be optimal for this population.
Assuntos
Infecções por HIV/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/administração & dosagem , Adjuvantes Imunológicos/administração & dosagem , Adolescente , Adulto , Anticorpos Antivirais/sangue , Criança , Pré-Escolar , Relação Dose-Resposta Imunológica , Feminino , Infecções por HIV/complicações , Humanos , Esquemas de Imunização , Vacinas contra Influenza/efeitos adversos , Vacinas contra Influenza/imunologia , Influenza Humana/complicações , Influenza Humana/imunologia , Influenza Humana/prevenção & controle , Masculino , Polissorbatos/administração & dosagem , Estudos Prospectivos , Segurança , Esqualeno/administração & dosagem , Adulto JovemRESUMO
The PEDVAC study is the first trial designed to analyze safety and immunogenicity of a therapeutic vaccination with a multiclade multigene HIV DNA vaccine (HIVIS) in infected children. Twenty HIV-1 vertically infected children (6-16 years of age), on stable antiretroviral treatment for at least 6 months with HIV-1 RNA<50 copies/ml and stable CD4 counts (> 400 cells/mm³ or 25%) over 12 months of follow-up, were recruited into the study. Enrolled patients have been randomized into two arms: a control group of 10 children who continued previous antiretroviral treatment (HAART) (arm A) and a group of 10 children immunized intramuscularly with the HIVIS DNA vaccine in addition to previous HAART (arm B). Immunizations took place at week 0, 4, 12 and the boosting dose is planned at week 36. The 10 children in the vaccine group have received the first 3 priming doses of the HIVIS vaccine. Safety data showed good tolerance to the vaccination schedule. Mild cutaneous self-limeted reactions consisted of local irritation, usually itching or erythema +/- swelling at the injection site, were reported. No severe systemic adverse events have been observed. No vaccinated children had a decrease of CD4 T-cell counts from baseline. None experienced virological failure. Analysis of cellular immune responses was scheduled at week 0, 4, 12, 16, 20, 40, 60, 72 and 96 by standard lymphoproliferation assay, intracellular cytokine staining and cell-ELISA, a miniaturized assay to measure antigen-induced IFNγ secretion. Evaluation of these results is in progress and will provide key information on the status and changes of antigen specific immunity during HIV DNA immunization.
Assuntos
Vacinas contra a AIDS/administração & dosagem , Infecções por HIV/terapia , HIV-1/patogenicidade , Vacinas de DNA/administração & dosagem , Vacinas contra a AIDS/efeitos adversos , Vacinas contra a AIDS/imunologia , Adolescente , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Criança , Avaliação de Medicamentos , Feminino , Seguimentos , Infecções por HIV/imunologia , HIV-1/imunologia , Humanos , Imunidade Celular , Imunidade Humoral , Injeções Intramusculares , Interferon gama/imunologia , Masculino , Vacinação , Vacinas de DNA/efeitos adversos , Vacinas de DNA/imunologia , Carga ViralRESUMO
BACKGROUND: Nuclear factor-kappaB (NF-kappaB) is a key transcription factor that regulates both innate and adaptive immunity as well as ectodermal development. Mutations in the coding region of the IkappaB kinase gamma/NF-kappaB essential modifier (NEMO) gene cause X-linked ectodermal dysplasia with immunodeficiency. OBJECTIVE: To determine the genetic cause of recurrent sinopulmonary infections and dysgammaglobulinemia in a patient with a normal NEMO coding sequence and his affected brother. METHODS: TNF-alpha and IFN-alpha production in response to Toll-like receptor (TLR) stimulation was analyzed by ELISA, NEMO mRNA levels were measured by quantitative PCR, and NEMO protein expression was measured by Western blotting. NF-kappaB activation was assessed by nuclear translocation of p65 and luciferase reporter gene assays. RESULTS: TLR-induced TNF-alpha and IFN-alpha production by PBMCs was impaired in the patient and his brother. Sequencing of the patient's NEMO gene revealed a novel mutation in the 5' untranslated region, which was also present in the brother, resulting in abnormally spliced transcripts and a 4-fold reduction in mRNA levels. NEMO protein levels in EBV transformed B cells and fibroblasts from the index patient were 8-fold lower than normal controls. NF-kappaB p65 nuclear translocation in the patient's EBV B cells after TLR7 ligation was defective. NF-kappaB-dependent luciferase gene expression in IL-1-stimulated fibroblasts from the patient was impaired. CONCLUSION: This is the first description of immune deficiency resulting from low expression of a normal NEMO protein.
Assuntos
Regiões 5' não Traduzidas/genética , Quinase I-kappa B/genética , Síndromes de Imunodeficiência/etiologia , Mutação , Criança , Citocinas/biossíntese , Humanos , Quinase I-kappa B/análise , Proteínas I-kappa B/metabolismo , Síndromes de Imunodeficiência/genética , Interleucina-1beta/farmacologia , Masculino , Inibidor de NF-kappaB alfa , NF-kappa B/metabolismo , Fosforilação , Sítios de Splice de RNA , RNA Mensageiro/análise , Receptores Toll-Like/fisiologiaRESUMO
The treatment of choice for severe combined immunodeficiency is bone marrow transplantation from an HLA-identical donor sibling without conditioning. However, this may result in low donor stem cell chimerism, leading to reduced long-term immune reconstitution. We compared engraftment, metabolic, and T-cell and B-cell immune reconstitution of HLA-identical sibling bone marrow transplantation performed in 2 severe combined immunodeficiency infants with adenosine deaminase deficiency from the same family treated with or without a reduced intensity conditioning regimen (busulfan/fludarabine). Only the patient who received conditioning showed a stable mixed chimerism in all lineages, including bone marrow myeloid and B cells. The use of conditioning resulted in higher thymus-derived naïve T cells and T-cell receptor excision circles, normalization of the T-cell repertoire, and faster and complete B-cell and metabolic reconstitution. These results suggest the utility of exploring the use of reduced intensity conditioning in bone marrow transplantation from HLA-identical donor in severe combined immunodeficiency to improve long-term immune reconstitution.
Assuntos
Transplante de Medula Óssea/métodos , Imunodeficiência Combinada Severa/terapia , Condicionamento Pré-Transplante/métodos , Adenosina Desaminase/deficiência , Agamaglobulinemia/terapia , Linfócitos B/citologia , Transplante de Medula Óssea/imunologia , Sobrevivência de Enxerto , Humanos , Lactente , Irmãos , Linfócitos T/citologia , Transplante IsogênicoRESUMO
Antiviral T-cell immune responses appear to be crucial to control HIV replication. Infants treated before the third month of life with highly active antiretroviral treatment (HAART) did not develop a persistent HIV-specific immune response. We evaluated how delayed initiation of HAART after 3 months of age influences the development of HIV-1-specific T-cell responses during long-term follow-up in 9 HIV-1 vertically infected infants. These data suggest that a longer antigenic stimulation, due to a larger window for therapeutic intervention with HAART, is associated with the establishment of a persistent specific HIV immune response resulting in a long-term viral control of vertically infected infants.
Assuntos
Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1/imunologia , Transmissão Vertical de Doenças Infecciosas , Linfócitos T/imunologia , Sequência de Aminoácidos , Esquema de Medicação , Infecções por HIV/virologia , Humanos , Lactente , Ativação Linfocitária , Dados de Sequência Molecular , Peptídeos/química , Resultado do Tratamento , Produtos do Gene gag do Vírus da Imunodeficiência Humana/química , Produtos do Gene nef do Vírus da Imunodeficiência Humana/química , Produtos do Gene tat do Vírus da Imunodeficiência Humana/químicaRESUMO
OBJECTIVE: To assess the virological, immunological and metabolic effects of switching from an efficacious first-line protease inhibitor (PI)-based HAART to a simplified triple nucleoside reverse transcriptase inhibitor (NRTI) regimen in children vertically infected with HIV. DESIGN: Prospective, open-label, before-after study of 20 vertically infected children with at least 12 consecutive months of undetectable viral load under a PI-based HAART and no previous history of NRTI treatment. METHODS: At study entry, HAART was shifted to a triple-NRTI combination. RESULTS: The children were aged 2 to 18 years (median, 7.9) and were followed for 96 weeks. All were receiving a PI-based regimen for an average duration of 4 years before enrollment. At study entry, 12 patients (60%) switched to abacavir, 5 (25%) to lamivudine; 2 (10%) to zidovudine and 2 to didanosine (10%). All but one patient maintained plasma HIV RNA < 50 copies/ml during the entire follow-up. No immunological failure was observed at week 96. A trend of normalization (P < 0.001) of T cell receptor Vbeta families of the CD8 cell subset was detected in 19/20 (95%), with an increased HIV-specific CD8 T cell response (P < 0.01) in 17/20 (85%). Dyslipidaemia significantly improved during the follow up (P < 0.001). No new cases of lipodystrophy were detected. CONCLUSIONS: Switching to triple-NRTI regimens in selected HIV-infected children with an extremely low likelihood of harbouring nucleoside-associated mutations maintains viral suppression and immunological function, improving metabolic abnormalities and the effort to take medication for up to 96 weeks.
Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , HIV-1 , Inibidores da Transcriptase Reversa/uso terapêutico , Adolescente , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Terapia Antirretroviral de Alta Atividade/métodos , Linfócitos T CD8-Positivos/imunologia , Criança , Pré-Escolar , Colesterol/sangue , Métodos Epidemiológicos , Feminino , Infecções por HIV/imunologia , Infecções por HIV/transmissão , Infecções por HIV/virologia , Inibidores da Protease de HIV/efeitos adversos , Humanos , Transmissão Vertical de Doenças Infecciosas , Masculino , Cooperação do Paciente , Estudos Prospectivos , Receptores de Antígenos de Linfócitos T alfa-beta/análise , Inibidores da Transcriptase Reversa/efeitos adversos , Resultado do Tratamento , Triglicerídeos/sangueRESUMO
To evaluate the effects of switching from successful long-term protease inhibitor (PI)-based HAART to a three nucleoside reverse transcriptase inhibitor PI-sparing regimen, viral load quantification, HIV-specific lymphoproliferative assay and T-cell receptor (TCR) spectratyping were performed during 96 weeks of simplification follow-up in 19 HIV-infected children. Our data showed that simplification of therapeutic strategies acts positively on immune competence in HIV paediatric patients. Our children maintained viral suppression, increased lymphoproliferative responses and normalized TCRBV repertoire on the CD8 subset.
Assuntos
Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Adolescente , Antígenos Virais/imunologia , Linfócitos T CD8-Positivos/imunologia , Criança , Pré-Escolar , Infecções por HIV/imunologia , Inibidores da Protease de HIV/imunologia , Humanos , Estudos Prospectivos , Receptores de Antígenos de Linfócitos T/imunologia , Inibidores da Transcriptase Reversa/imunologia , Linfócitos T/imunologia , Resultado do Tratamento , Carga ViralRESUMO
Umbilical cord blood transplantation has been successfully employed for treatment of many immune and hematologic disorders. The aim of this study was to evaluate the quality of immune reconstitution after umbilical cord blood transplantation in 6 leukemia children. T-cell receptor Vbeta third complementary region spectratyping was used for monitoring the contribution of the thymic pathway in patients' immune reconstitution. Absolute numbers of lymphocyte subsets (T, B, and natural killer), and lymphoproliferative in vitro response to mitogens, recovered within 12 months after transplantation. Furthermore, an overall diversification of T-cell receptor complexity in the repopulating T cells, with a polyclonal Gaussian profiles in most (74%) of total families was observed. Noteworthy, we showed a wider and more rapid reconstitution of T-cell receptor CD4+ T cell families compared with T-cell receptor CD8+ T ones still exhibiting some perturbations at 24 months. These data show that umbilical cord blood transplantation allows immune reconstitution already within 12 months with generation of newly diversified CD4+ T lymphocyte subsets.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Leucemia/terapia , Subpopulações de Linfócitos/imunologia , Adolescente , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células/efeitos dos fármacos , Criança , Pré-Escolar , Seguimentos , Teste de Histocompatibilidade , Humanos , Sistema Imunitário , Técnicas In Vitro , Lactente , Leucemia/imunologia , Contagem de Linfócitos , Subpopulações de Linfócitos/efeitos dos fármacos , Mitógenos/farmacologia , Transplante Homólogo , Resultado do TratamentoRESUMO
DiGeorge syndrome (DGS) is a congenital disorder characterized by typical facial features, hypoparatyroidism, conotruncal cardiac defects and thymic hypoplasia. Although there are some reports addressing lymphocytes counts and function in DGS children over time, few data have been reported on the T-cell receptor V beta (TCRBV) repertoire in relation to disease progression. The aim of this study was to evaluate the degree and nature of immunodeficiency and to investigate a possible correlation to clinical findings. We used third complementary region (CDR3) size spectratyping as a tool for monitoring T-cell repertoire diversity in 7 DGS's children. The rate of thymic output, the phenotype and function of peripheral T-cells and the humoral immunity were also investigated. At baseline a profound alteration of the TCR repertoire was noted, mainly in the CD8+ T-cells, in DGS patients when compared to a control group. Furthermore, analysis of thymic output showed a significant decrease in TCR rearrangement excision circles (TRECs) levels in the patient group. Immunoglobulin abnormalities were also detected. The observed TCR repertoire alterations, although not statistically significant, may suggest an increased susceptibility to infections. A parallel increase in the TCR repertoire diversity and clinical improvement occurred during the follow-up. Our results confirm that the extent of immunodeficiency is highly variable and could improve through childhood, and indicate that TCR repertoire may be a useful marker to clinically monitor thymic function in this primary immunodeficiency.
Assuntos
Formação de Anticorpos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Síndrome de DiGeorge/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Criança , Pré-Escolar , Regiões Determinantes de Complementaridade , Feminino , Rearranjo Gênico , Genes de Imunoglobulinas , Humanos , Lactente , Masculino , Fenótipo , Timo/fisiologiaRESUMO
A mutation of the stromal cell-derived factor 1 gene (SDF-1 3'A) was shown to protect adults exposed to human immunodeficiency virus type 1 (HIV-1) from infection and to affect HIV disease progression in adults. The presence of this mutation in HIV-1-infected Kenyan children did not predict mother-to-child virus transmission. The SDF-1 3'A polymorphism was studied in 256 HIV-1-infected, 118 HIV-1-exposed but uninfected, and 170 unexposed and uninfected children of Italian origin, and the frequency of SDF-1 3'A heterozygosity and homozygosity in each of the 3 groups was similar. Of the 256 HIV-1-infected children, 194 were regularly followed up and were assigned to groups according to disease progression. The frequency of the SDF-1 3'A allele was substantially lower among children with long-term nonprogression than among children with rapid (P =.0329) or delayed (P =.0375) progression. We show that the presence of the SDF-1 3'A gene correlates with accelerated disease progression in HIV-1-infected children born to seropositive mothers but does not protect against mother-to-child HIV-1 transmission.