RESUMO
Relapse of acute myeloblastic leukemia (AML) after first allogenic hematopoietic stem-cell transplantation (allo-HSCT) is a fatal complication. Sixty-five children transplanted for AML were included in a prospective national study from June 2005 to July 2008 to explore the feasibility of preemptive immune modulation based on the monitoring of blood chimerism. Relapse occurred in 23 patients (35%). The median time between the last complete chimerism and relapse was 13.5 days (2-138). Prompt discontinuation of cyclosporin and the administration of donor lymphocyte infusions (DLIs) based on chimerism monitoring failed as a preemptive tool, either for detecting relapse or certifying long-term remission.
Assuntos
Ciclosporina/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Imunomodulação , Leucemia Mieloide Aguda , Transfusão de Linfócitos , Doadores de Tecidos , Quimeras de Transplante/sangue , Aloenxertos , Criança , Ciclosporina/efeitos adversos , Feminino , Humanos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/prevenção & controle , Masculino , Estudos Prospectivos , RecidivaRESUMO
Relapse after transplantation is a major cause of treatment failure in paediatric acute lymphoblastic leukaemia (ALL). Here, we report the findings of a prospective national study designed to investigate the feasibility of immune intervention in children in first or subsequent remission following myeloablative conditioning. This study included 133 children who received a transplant for ALL between 2005 and 2008. Minimal Residual Disease (MRD) based on T cell receptor/immunoglobulin gene rearrangements was measured on days -30, 30, 90 and 150 post-transplantation. Ciclosporin treatment was rapidly discontinued and donor lymphocyte infusions (DLI) were programmed for patients with a pre- or post-transplant MRD status ≥10(-3) . Only nine patients received DLI. Pre- and post-transplant MRD status, and the duration of ciclosporin were independently associated with 5-year overall survival (OS), which was 62·07% for the whole cohort. OS was substantially higher in patients cleared of MRD than in those with persistent MRD (52·3% vs. 14·3%, respectively). Only pre-transplant MRD status (Hazard Ratio 2·57, P = 0·04) and duration of ciclosporin treatment (P < 0·001) were independently associated with relapse. The kinetics of chimerism were not useful for predicting relapse, whereas MRD monitoring up to 90 d post-transplantation was a valuable prognostic tool to guide therapeutic intervention.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Quimeras de Transplante , Transferência Adotiva , Criança , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Linfócitos , Masculino , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prognóstico , Modelos de Riscos Proporcionais , Doadores de Tecidos , Resultado do TratamentoRESUMO
Multiple sclerosis is a common disease with proven heritability, but, despite large-scale attempts, no underlying risk genes have been identified. Traditional linkage scans have so far identified only one risk haplotype for multiple sclerosis (at HLA on chromosome 6), which explains only a fraction of the increased risk to siblings. Association scans such as admixture mapping have much more power, in principle, to find the weak factors that must explain most of the disease risk. We describe here the first high-powered admixture scan, focusing on 605 African American cases and 1,043 African American controls, and report a locus on chromosome 1 that is significantly associated with multiple sclerosis.
Assuntos
Cromossomos Humanos Par 1/genética , Predisposição Genética para Doença , Esclerose Múltipla/genética , Negro ou Afro-Americano/genética , Mapeamento Cromossômico/métodos , Genoma Humano , Humanos , Esclerose Múltipla/etnologiaRESUMO
In this study, we explored the potential of human naive CD4(+) T cells to acquire regulatory properties upon stimulation. We demonstrated that, in vitro, pre-activated naive CD4(+)CD25(-)CD45RA(+) T cells could become anergic and suppressive CD4(+)CD25(+) T cells upon lower intensity TCR stimulation. These CD4(+)CD25(+) T cells generated in vitro potently suppress the proliferation of allogenic CD4(+)CD25(-) T cells independently of cytokines and in a contact-dependent manner. Our data indicate that expression of Foxp3 is not necessary to induce the suppressive T cell activity. We demonstrate that these CD4(+)CD25(+) T cells are unresponsive upon re-stimulation and that their suppressive activity is transient. However, we showed that the anergy and the suppressive function could be reversed by increasing the stimulus and their level of activation. We concluded from our data that these anergy and suppressive activities are related to a fine tuning of TCR activation threshold.
Assuntos
Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Antígenos CD/metabolismo , Antígenos CD40/imunologia , Antígeno CTLA-4 , Divisão Celular/imunologia , Células Cultivadas , Anergia Clonal , Regulação para Baixo , Fatores de Transcrição Forkhead/imunologia , Humanos , Subunidade alfa de Receptor de Interleucina-2/imunologia , Antígenos Comuns de Leucócito/imunologia , Ativação Linfocitária , Linfócitos T Reguladores/metabolismoRESUMO
The TNF family member TRAIL is emerging as a promising cytotoxic molecule for antitumor therapy. However, its mechanism of action and the possible modulation of its effect by the microenvironment in follicular lymphomas (FL) remain unknown. We show here that TRAIL is cytotoxic only against FL B cells and not against normal B cells, and that DR4 is the main receptor involved in the initiation of the apoptotic cascade. However, the engagement of CD40 by its ligand, mainly expressed on a specific germinal center CD4(+) T cell subpopulation, counteracts TRAIL-induced apoptosis in FL B cells. CD40 induces a rapid RNA and protein up-regulation of c-FLIP and Bcl-x(L). The induction of these antiapoptotic molecules as well as the inhibition of TRAIL-induced apoptosis by CD40 is partially abolished when NF-kappaB activity is inhibited by a selective inhibitor, BAY 117085. Thus, the antiapoptotic signaling of CD40, which interferes with TRAIL-induced apoptosis in FL B cells, involves NF-kappaB-mediated induction of c-FLIP and Bcl-x(L) which can respectively interfere with caspase 8 activation or mitochondrial-mediated apoptosis. These findings suggest that a cotreatment with TRAIL and an inhibitor of NF-kappaB signaling or a blocking anti-CD40 Ab could be of great interest in FL therapy.
Assuntos
Apoptose/imunologia , Linfócitos B/imunologia , Antígenos CD40/imunologia , Ligante de CD40/metabolismo , Linfoma Folicular/imunologia , NF-kappa B/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Apoptose/efeitos dos fármacos , Linfócitos B/metabolismo , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/imunologia , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Ligante de CD40/imunologia , Caspase 8/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Humanos , Linfoma Folicular/metabolismo , Linfoma Folicular/patologia , NF-kappa B/efeitos dos fármacos , NF-kappa B/imunologia , Nitrilas/farmacologia , Tonsila Palatina/imunologia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF , Receptores do Fator de Necrose Tumoral/imunologia , Receptores do Fator de Necrose Tumoral/metabolismo , Proteínas Recombinantes/metabolismo , Transdução de Sinais , Sulfonas/farmacologia , Regulação para Cima , Proteína bcl-X/imunologia , Proteína bcl-X/metabolismoRESUMO
Acute graft-versus-host disease (aGVHD), mediated by CD4(+) and CD8(+) effector T cells, is a life-threatening complication in hematopoietic stem cell transplantation. CD4(+)CD25(hi) regulatory T cells (T(reg)) have been shown to modulate tolerance to aGVHD in murine models. Based on these observations, we examined their role in the prevention of aGVHD in patients who underwent transplantation with peripheral blood-mobilized hematopoietic stem cells after administration of granulocyte colony-stimulating factor. The effects of the G-CSF on the phenotype, frequency, and function of CD4(+)CD25(hi) T cells were analyzed in grafts and after transplantation to determine whether these cells were regulatory T cells. CD4(+)CD25(hi) T cells could be detected at the same frequency before and after granulocyte colony-stimulating factor administration in the donors' peripheral blood. The isolation of these cells from the grafts or from the recipients' peripheral blood after transplantation revealed that they were suppressive to the same extent as T(reg) isolated from healthy volunteers. Their number and frequency were estimated in the grafts and the results indicated that protection against aGVHD was not dependent on the T(reg) amount transferred to the recipients. Similarly there was no correlation between the number of circulating CD4(+)CD25(hi) T cells in the recipients' peripheral blood during the early period after transplantation and the outcome of aGVHD.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Fator Estimulador de Colônias de Granulócitos/farmacologia , Transplante de Células-Tronco Hematopoéticas , Transferência Adotiva , Adulto , Linfócitos T CD4-Positivos/efeitos dos fármacos , Contagem de Células , Feminino , Doença Enxerto-Hospedeiro/imunologia , Fator Estimulador de Colônias de Granulócitos/imunologia , Mobilização de Células-Tronco Hematopoéticas , Humanos , Imunofenotipagem , Subunidade alfa de Receptor de Interleucina-2/imunologia , Masculino , Pessoa de Meia-Idade , Imunologia de Transplantes , Resultado do TratamentoRESUMO
Platelet additive solutions (PAS) have been developed since the years 1980. However, decisive improvements have been made in the last five years, leading nowadays to several PAS available for transfusion practice. Few compounds are present in PAS, with the intention of controlling platelet metabolic alterations and activation that occur during storage: acetate, which is a substrate for the tricarboxylic acid cycle, enables to maintain oxidative metabolism, is present in all PAS; a buffer effect is required to prevent the progressive pH fall during storage, and is obtained either with sodium phosphate or gluconate; platelet activation is controlled by citrate, and in the latest PAS, by magnesium and potassium. It is important to note that whatever the PAS used, it is mandatory to maintain a final concentration of 20-40% of plasma, mainly in order to ensure glucose availability. The use of PAS leads to a more rationalized blood processing, as it provides an additional volume of plasma available for plasma fractionation, it contributes to standardization of blood components, and it is part of at least one pathogen reduction process. The expected benefit for patient is the reduction of adverse reactions related to plasma. There is already evidence that the incidence of allergic adverse reactions is reduced. In the case of other less frequent adverse reactions such as transfusion related acute lung injury (TRALI) or haemolytic reaction due to minor ABO incompatibility, only a long-term follow-up through haemovigilance organization will be informative.
Assuntos
Transfusão de Plaquetas/métodos , Soluções , Acetatos/sangue , Glicemia/metabolismo , Preservação de Sangue/métodos , Citratos/sangue , Humanos , Magnésio/sangue , Fosfatos/sangue , Transfusão de Plaquetas/efeitos adversos , Potássio/sangue , Conservantes Farmacêuticos , Resultado do TratamentoRESUMO
By combining all the data available from the Genetic Analysis of Multiple sclerosis in EuropeanS (GAMES) project, we have been able to identify 17 microsatellite markers showing consistent evidence for apparent association. As might be expected five of these markers map within the Major Histocompatibility Complex (MHC) and are in LD with HLA-DRB1. Individual genotyping of the 12 non-MHC markers confirmed association for three of them--D11S1986, D19S552 and D20S894. Association mapping across the candidate genes implicated by these markers in 937 UK trio families revealed modestly associated haplotypes in JAG1 (p=0.019) on chromosome 20p12.2 and POU2AF1 (p=0.003) on chromosome 11q23.1.
Assuntos
Proteínas de Ligação ao Cálcio/genética , Predisposição Genética para Doença , Testes Genéticos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Desequilíbrio de Ligação/genética , Proteínas de Membrana/genética , Esclerose Múltipla/genética , Transativadores/genética , Europa (Continente)/epidemiologia , Feminino , Genótipo , Humanos , Proteína Jagged-1 , Masculino , Repetições de Microssatélites , Esclerose Múltipla/epidemiologia , Proteínas Serrate-JaggedRESUMO
Immature dendritic cells (DCs) derived from CD34+ progenitor cells or peripheral monocytes, are used as in vitro sensitization models in many chemical allergen treatment studies. During the sensitization, DCs follow maturation process and gain the capacity to migrate to lymph nodes where they stimulate T cells. Chemokine receptor allows DCs to migrate along chemotactic gradients. In this work, we used immature DCs from peripheral monocytes to evaluate the influence of allergens on chemokine receptor and surface-marker expression. We tested the sensitizers dinitrochlorobenzene, Bandrowski's base, and coumarin, as well as the tolerogen dichloronitrobenzene, the irritant sodium dodecyl sulfate and the solvent dimethyl sulfoxide. All skin sensitizers up-regulated the co-stimulatory molecule CD86 and increased the CD83+ cell population. No expression of the chemokine receptors CCR2, CCR3, CCR6, or CXCR5 was observed on DCs exposed to the tested chemicals. The strong allergen dinitrochlorobenzene slightly increased CCR7 expression on DCs but down-regulated CCR1 surface expression. CCR1 down-regulation was not mediated by a classical maturation pathway, as it was unaffected by the corticosteroid dexamethasone.
Assuntos
Alérgenos/farmacologia , Células Dendríticas/efeitos dos fármacos , Irritantes/farmacologia , Receptores de Quimiocinas/metabolismo , Antígenos CD/imunologia , Antígeno B7-1/imunologia , Antígeno B7-2 , Cumarínicos/farmacologia , Células Dendríticas/imunologia , Dimetil Sulfóxido/farmacologia , Dinitroclorobenzeno/farmacologia , Humanos , Imunoglobulinas/imunologia , Técnicas In Vitro , Leucócitos Mononucleares/citologia , Glicoproteínas de Membrana/imunologia , Fenilenodiaminas/farmacologia , Dodecilsulfato de Sódio/farmacologia , Antígeno CD83RESUMO
We report the results of a genome-wide screen for linkage disequilibrium (LD) in multiple sclerosis (MS) performed on 200 cases, 200 controls and 200 case-parent trios from France employing pooled DNA methodology. A total of 3510 microsatellite markers supplied through the GAMES collaborative were analysed and ranked according to their evidence for association. The most promising 117 markers were then followed up in a two-step validation process. In the first step, additional PCR of the DNA pools was performed in order to refine the ranking order. In the second step, markers were genotyped in individual cases and parents from the trio families. Seven markers showing nominally significant allele frequency differences between affected and unaffected emerged-D6S265, D12S1064, TNFa, D7S1824, D14S1426, D14S605 and D21S2051. These potential associations will require confirmation in further studies.
Assuntos
Testes Genéticos/métodos , Esclerose Múltipla/genética , Alelos , Estudos de Casos e Controles , França/epidemiologia , Frequência do Gene , Testes Genéticos/estatística & dados numéricos , Genoma Humano , Genótipo , Humanos , Cooperação Internacional , Desequilíbrio de Ligação , Repetições de Microssatélites , Esclerose Múltipla/epidemiologia , Estudos ProspectivosRESUMO
The breakdown of tolerance to autologous bacterial flora has been implicated as a major factor contributing to the initiation and perpetuation of chronic inflammation in inflammatory bowel diseases (IBD). To test whether bacterial DNA is at the origin of inflammation in IBD, we have examined the response of lamina propria (LPMC) or peripheral mononuclear cells (PBMC) and purified T cells from IBD patients and control patients to stimulations with a set of oligodeoxynucleotides (ODNs) characterized by the presence or absence of cytosine-guanosine dinucleotides (CpG) and/or 3' poly-guanosine (poly-G) extension. Furthermore we have evaluated the costimulatory activities of these ODNs on T cells activated via CD2 or CD3 pathway. We demonstrated that CpG ODNs induce higher proliferation of LPMC from inflammatory intestinal mucosa compared to healthy mucosa. We confirmed that CpG ODNs do not directly costimulate peripheral blood T cells activated by CD3 pathway. Finally, we revealed that CpG or non-CpG ODNs with 3' poly-G extension inhibit completely CD2 activation of purified PB or LP T-cells whereas only CpG ODNs without poly-G extension enhance proliferation and IFN-gamma production of PB T cells stimulated by CD2 pathway only in presence of NK and NK T cells. Our data suggest that NK T cells may be the primary target of ODNs and play a crucial role in indirect T-cell activation by ODN.
Assuntos
Mucosa Intestinal/imunologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária/imunologia , Oligodesoxirribonucleotídeos/imunologia , Linfócitos T/imunologia , Antígenos CD2/imunologia , Complexo CD3/imunologia , Ilhas de CpG/imunologia , Humanos , Doenças Inflamatórias Intestinais/imunologia , Interferon gama/imunologia , Poli G/imunologiaRESUMO
OBJECTIVES: Three recently identified NOD2/CARD15 mutations have been described associated with an increased susceptibility Crohn's disease (CD). Our aim was to examine the potential association of these NOD2 mutations with CD and different subsets of CD phenotypes in our population. METHODS: Two hundred and five well-defined CD patients from north-western France and 95 ethnically matched healthy controls were genotyped for mutations R702W, G908R and Leu1007insC by DNA sequencing. Allele and genotype frequencies of NOD2 variants were examined in the whole series of CD and in different subgroups of CD phenotypes defined by the clinical characteristics of the Vienna classification (age at diagnosis, location and behaviour) or by histological features (granuloma). RESULTS: Carriers of at least one NOD2/CARD15 variant were significantly more frequent in CD than in controls (38.0% versus 20.0%, P < 0.002), and the R702W allele was the most significant contributor to this NOD2 association with CD. Homozygotes and compound heterozygotes combined had a higher risk of CD (odds ratio = 12.0, P < 0.0026) than simple heterozygotes for any variant (odds ratio = 2.2, P < 0.013) compared with subjects with no variant. Univariate analysis revealed that carriage of at least one NOD2 mutation was significantly associated with ileal involvement (P < 0.03), and stricturing evolution (P < 0.0015). Granuloma was associated with an excess of the R702W allele (16.1% versus 8.0%, Pc < 0.035), and was correlated with a young age at diagnosis, whatever the NOD2/CARD15 genotype. Multivariate analysis demonstrated that carriage of NOD2/CARD15 mutants, especially R702W, was primarily and independently associated both with stricturing evolution of CD and the presence of granuloma. CONCLUSIONS: In our population, all NOD2/CARD15 mutant genotypes, especially compound heterozygosity, were found to increase the risk of CD, but R702W was the sole allele showing a significant association with CD. In addition, we confirm the positive and independent association of the R702W mutation with stricturing behaviour and describe a second one with the presence of granuloma.
Assuntos
Proteínas de Transporte/genética , Doença de Crohn/genética , Peptídeos e Proteínas de Sinalização Intracelular , Polimorfismo Genético/genética , Adolescente , Adulto , Idoso , Análise de Variância , Criança , Feminino , Frequência do Gene , Predisposição Genética para Doença/genética , Granuloma/genética , Heterozigoto , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Proteína Adaptadora de Sinalização NOD2RESUMO
It has been demonstrated that T cells with regulatory properties are present within the peripheral blood CD4(+)CD25(+) T cell compartment. Here, we describe an original method to purify human CD4(+)CD25(+)CD152(+) T lymphocytes as living cells by forcing the exportation of CTLA-4 molecules stored in intracellular vesicules at the cell surface. By doing so, we demonstrate that CD4(+)CD25(+) T cells contain a smaller and more homogeneous population enriched in cells with in vitro regulatory activity. Moreover, we show that this enrichment in regulatory T cells is associated with an increased expression of Foxp3 and that CD4(+)CD25(+)CD152(+) T lymphocytes display a much stronger suppressive activity in controlling in vitro proliferation of alloantigen-specific T cells than CD4(+)CD25(+)CD152(-) T lymphocytes purified in parallel. Lastly, by purifying such cells expressing CTLA-4, we demonstrate that indeed CTLA-4 is involved in CD4(+)CD25(+)CD152(+) T cell regulatory activity, while suppressive cytokines are not.
Assuntos
Antígenos de Diferenciação/metabolismo , Linfócitos T CD4-Positivos/imunologia , Antígenos CD , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Antígeno CTLA-4 , Citocinas/metabolismo , Humanos , Ionomicina/farmacologia , Ionóforos/farmacologia , Receptores de Interleucina-2/imunologiaRESUMO
We carried out a multicenter performance evaluation of three new DNA-based human leukocyte antigen (HLA) typing assays: INNO-LiPA HLA-A Update, INNO-LiPA HLA-B Update, and INNO-LiPA HLA-DQB1 Update. After optimization, the accuracy rates were all 100%, and the final observed resolutions were 99.4, 92.4, and 85.6%, respectively. These rapid and easy-to-perform assays yielded results fully concordant with other DNA-based tissue typing tests.
Assuntos
Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-DQ/genética , Teste de Histocompatibilidade/métodos , Frequência do Gene , Cadeias beta de HLA-DQ , HumanosRESUMO
The frequent alteration of human leucocyte antigen (HLA) class I molecule expression observed in non-Hodgkin's lymphomas (NHL), similarly to solid tumours, has been reported to favour tumoral escape from the immune system. In order to identify the underlying mechanisms, we analysed 15 HLA defective NHL including partial (n = 10) and total class I (n = 5) loss, as well as HLA class II defects (n = 5). The HLA defect concerned HLA-A and -B antigens in 14 of 15 cases. In the cases with partial defect, the use of specific allelic monoclonal antibodies detected a defect of both alleles of A or B loci in six of seven tested cases. Allelic reverse transcription polymerase chain reaction (RT-PCR) demonstrated defects in six of nine cases, including four alterations of both A and B mRNA alleles. Real-time quantitative RT-PCR (RQ-PCR) did not detect the HLA-DR transcript in the two negative HLA-DR lymphomas, contrasting with the presence of CMH II transactivator (CIITA) transcript. Loss of heterozygosity (LOH) was detected in nine of 14 cases through variable pattern of nine microsatellites markers of the HLA locus. Taken together, these findings demonstrate the complexity and the variability of the mechanisms underlying HLA protein deficiencies with a high frequency of LOH. The diversity of these mechanisms indicates the importance of positive selection of HLA altered clones in the development of these NHL cases.
Assuntos
Antígenos HLA/genética , Perda de Heterozigosidade , Linfoma não Hodgkin/genética , Citometria de Fluxo , Expressão Gênica , Genótipo , Antígenos HLA-DR/genética , Antígenos HLA-DR/metabolismo , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Repetições de Microssatélites , RNA Mensageiro/genética , RNA Neoplásico/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Evasão Tumoral/genéticaRESUMO
We have developed a real-time quantitative polymerase chain reaction (PCR) assay using TaqMan technology (Applied Biosystems, Foster City, CA) for monitoring donor cell engraftment in allogenic hematopoietic stem cell transplant recipients. For this purpose, we selected 19 specific sequence polymorphisms belonging to 11 human biallelic loci located on 9 different chromosomes. Using a set of specially designed primers and fluorogenic probes, we evaluated the 19 markers' informativity on a panel of 126 DNA samples from 63 recipient/donor pairs. In more than 90% of these pairs, discrimination between recipient and donor genetic profile was possible. By using serial dilutions of mixed DNAs, we evaluated the linearity and sensitivity of the method. A linear correlation with r higher than 0.98 and a sensitivity of 0.1% proved reproducible. Fluorescent-based PCR of short tandem repeats (STR-PCR) and real-time PCR chimerism assay were compared with a panel of artificial cell mixtures. The main advantage of the real-time PCR method over STR-PCR chimerism assays is the absence of PCR competition and plateau biases, and results evidenced greater sensitivity and linearity with the real-time PCR method. Furthermore, different samples can be tested in the same PCR run with a final result in fewer than 48 hours. Finally, we prospectively analyzed patients who received allografts and present 4 different clinical situations that illustrate the informativity level of our method. In conclusion, this new assay provides an accurate quantitative assessment of mixed chimerism that can be useful in guiding early implementation of additional treatments in hematopoietic stem cell transplantation.
Assuntos
Transplante de Medula Óssea , Sobrevivência de Enxerto/genética , Reação em Cadeia da Polimerase/métodos , Quimeras de Transplante/genética , Adolescente , Adulto , Transplante de Medula Óssea/normas , Sondas de DNA , Feminino , Marcadores Genéticos , Hematopoese/genética , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase/normas , Sensibilidade e EspecificidadeRESUMO
Multiple sclerosis is a chronic inflammatory disease of the central nervous system with a genetic component. Until now, the more consistent association with the disease is found with the major histocompatibility complex, especially HLA-DRB1*1501-DQB1*0602 haplotype. In this report, we demonstrate the interaction of Cytotoxic T Lymphocyte-associated antigen 4 (CTLA-4 [CD152]) gene with DRB1*15 haplotype in multiple sclerosis genetic susceptibility. Our data were obtained from two European independent family-based studies including 610 multiple sclerosis family trios. Ann Neurol 2003;54:119-122
Assuntos
Antígenos de Diferenciação/genética , Antígenos HLA-DR/genética , Imunoconjugados , Esclerose Múltipla/genética , Abatacepte , Antígenos CD , Antígeno CTLA-4 , Estudos de Coortes , Primers do DNA/genética , Predisposição Genética para Doença , Subtipos Sorológicos de HLA-DR , Humanos , Immunoblotting , Reação em Cadeia da Polimerase , Polimorfismo Genético/genética , Regiões Promotoras Genéticas/genéticaRESUMO
Multiple sclerosis (MS) is a demyelinating autoimmune disease with a strong yet complex genetic component. To date only the HLA-DR locus, and specifically the HLA-DR15 allele, has been identified and confirmed as influencing the risk of developing MS. Genomic screens on several datasets have been performed and have identified several chromosomal regions with interesting results, but none have yet been confirmed. We tested seven of the most-promising regions (on chromosomes 1p, 2p, 3p, 3q, 5q, 19q, and Xp) identified from several genomic screens in a dataset of 98 multiplex MS families from the United States and 90 multiplex MS families from France. The results did not confirm linkage to 2p, 3q, 5q, or Xp in the overall dataset, or in subsets defined by geographic origin or HLA-DR15 status. Regions on 1p34, 3p14, and 19q13 produced lod scores >0.90 in at least one subset of the data, suggesting that these regions should be examined in more detail.