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1.
Ann Surg ; 267(3): 443-450, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28426476

RESUMO

OBJECTIVE: The aim of this study was to evaluate the efficacy of intrasphincteric injections of autologous myoblasts (AMs) in fecal incontinence (FI) in a controlled study. SUMMARY OF BACKGROUND DATA: Adult stem cell therapy is expected to definitively cure FI by regenerating damaged sphincter. Preclinical data and results of open-label trials suggest that myoblast therapy may represent a noninvasive treatment option. METHODS: We conducted a phase 2 randomized, double-blind, placebo-controlled study of intrasphincteric injections of AM in 24 patients. The study compared outcome after AM (n = 12) or placebo (n = 12) injection using Cleveland Clinic Incontinence (CCI), score at 6 and 12 months. Patients in the placebo group were eligible to receive frozen AM after 1 year. RESULTS: At 6 months, the median CCI score significantly decreased from baseline in both the AM (9 vs 15, P = 0.02) and placebo (10 vs 15, P = 0.01) groups. Hence, no significant difference was found between the 2 groups (primary endpoint) at 6 months. At 12 months, the median CCI score continued to ameliorate in the AM group (6.5 vs 15, P = 0.006), while effect was lost in the placebo group (14 vs 15, P = 0.35). Consequently, there was a higher response rate at 12 months in the treated than the placebo arm (58% vs 8%, P = 0.03). After delayed frozen AM injection in the placebo group, the response rate was 60% (6/10) at 12 months. CONCLUSIONS: Intrasphincteric AM injections in FI patients have shown tolerance, safety, and clinical benefit at 12 months despite a transient placebo effect at 6 months.

2.
J Exp Med ; 213(11): 2413-2435, 2016 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-27647349

RESUMO

Combined immunodeficiency (CID) refers to inborn errors of human T cells that also affect B cells because of the T cell deficit or an additional B cell-intrinsic deficit. In this study, we report six patients from three unrelated families with biallelic loss-of-function mutations in RLTPR, the mouse orthologue of which is essential for CD28 signaling. The patients have cutaneous and pulmonary allergy, as well as a variety of bacterial and fungal infectious diseases, including invasive tuberculosis and mucocutaneous candidiasis. Proportions of circulating regulatory T cells and memory CD4+ T cells are reduced. Their CD4+ T cells do not respond to CD28 stimulation. Their CD4+ T cells exhibit a "Th2" cell bias ex vivo and when cultured in vitro, contrasting with the paucity of "Th1," "Th17," and T follicular helper cells. The patients also display few memory B cells and poor antibody responses. This B cell phenotype does not result solely from the T cell deficiency, as the patients' B cells fail to activate NF-κB upon B cell receptor (BCR) stimulation. Human RLTPR deficiency is a CID affecting at least the CD28-responsive pathway in T cells and the BCR-responsive pathway in B cells.


Assuntos
Alelos , Linfócitos B/imunologia , Proteínas dos Microfilamentos/genética , Mutação/genética , Linfócitos T/imunologia , Adolescente , Adulto , Sequência de Bases , Antígenos CD28/metabolismo , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/genética , Proliferação de Células/genética , Sobrevivência Celular/genética , Criança , Pré-Escolar , Dimerização , Feminino , Células HEK293 , Humanos , Memória Imunológica , Imunofenotipagem , Leucócitos/patologia , Masculino , NF-kappa B/metabolismo , Linhagem , Fenótipo , Receptores de Antígenos de Linfócitos B , Transdução de Sinais , Células Th17/imunologia , Células Th2/imunologia , Adulto Jovem
3.
PLoS One ; 10(11): e0133702, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26539981

RESUMO

OBJECTIVE: Anti-synthetase syndrome (anti-SS) is frequently associated with myositis and interstitial lung disease (ILD). We evaluated prospectively, in a multicenter, open-label, phase II study, the efficacy of rituximab on muscle and lung outcomes. METHODS: Patients were enrolled if they were refractory to conventional treatments (prednisone and at least 2 immunosuppressants). They received 1 g of rituximab at D0, D15, and M6. The primary endpoint was muscular improvement based on manual muscular testing (MMT10, Kendall score in 10 muscles) at M12. Secondary endpoints were normalization of creatine kinase (CK) level, ILD improvement based on forced vital capacity and/or diffuse capacity for carbon monoxide, and number and/or doses of associated immunosuppressants. RESULTS: Twelve patients were enrolled, and 10 completed the study. Only 2 patients presented an improvement of at least 4 points on at least two muscle groups (primary end-point). Overall, seven patients had an increase of at least 4 points on MMT10. CK level decreased from 399 IU/L (range, 48-11,718) to 74.5 IU/L (range, 40-47,857). Corticosteroid doses decreased from 52.5 mg/d (range, 10-70) to 9 mg/d (range, 7-65) and six patients had a decrease in the burden of their associated immunosuppressants. At baseline, all 10 patients presented with ILD. At M12, improvement of ILD was observed in 5 out of the 10 patients, stabilization in 4, and worsening in 1. CONCLUSIONS: This pilot study of rituximab treatment in patients with refractory anti-SS provided data on evolution of muscular and pulmonary parameters. Rituximab should now be evaluated in a larger, controlled study for this homogenous group of patients. TRIAL REGISTRATION: Clinicaltrials.gov NCT00774462.


Assuntos
Autoanticorpos/imunologia , Fatores Imunológicos/uso terapêutico , Miosite/tratamento farmacológico , Rituximab/uso terapêutico , Adulto , Creatina Quinase/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Capacidade Vital , Adulto Jovem
4.
Cell Transplant ; 23(12): 1475-87, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25565635

RESUMO

Genetic alterations have recently been described as emerging during the culture of embryonic stem cells or induced pluripotent stem cells, raising concerns about their safety in future clinical use. Myoblasts are adult stem cells with important therapeutic potential that have been used in clinical trials for almost 20 years, but their genome integrity has not yet been established. Here we produced 10 human myoblast preparations and investigated their genomic stability. At the third passage, half of the preparations had a normal karyotype and half showed one to four alterations/30 metaphases. Chromosome 2 trisomy was found in 1-2/30 metaphases and/or 2/100 nuclei by FISH in 3/10 samples, and there was no other recurrent anomaly. When prolonging cultures, these erratic abnormalities were never associated with a growth advantage. Cellular senescence was manifested in all samples by growth arrest before passage 15. Expression of TERT was always negative. Molecular analysis of individual p53 transcripts did not reveal tumorigenic mutations. CGH array (10 samples) and exome sequencing (one sample) failed to detect copy number variations or accumulation of mutations, respectively. Myoblasts did not grow either in soft agar or in vivo after injection in immunodeficient mice. Hence, occasional genomic abnormalities may occur during myoblast culture but are not associated with risk of transformation.


Assuntos
Transformação Celular Neoplásica , Instabilidade Cromossômica , Mioblastos/metabolismo , Mioblastos/patologia , Animais , Carcinogênese , Proliferação de Células , Células Cultivadas , Senescência Celular , Hibridização Genômica Comparativa , Feminino , Dosagem de Genes , Humanos , Imunofenotipagem , Cariotipagem , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Fenótipo
5.
Sci Transl Med ; 5(175): 175ra30, 2013 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-23467561

RESUMO

Pemphigus is a severe blistering condition of the skin and mucosa caused by autoantibodies directed against desmogleins, which are a type of keratinocyte adhesion protein. B cell depletion by rituximab has short-term efficacy against pemphigus. We aimed to assess the long-term course of pemphigus patients after B cell depletion and to understand the immunological mechanisms that mediate long-lasting remissions. We evaluated the clinical course of 22 pemphigus patients treated with rituximab after a 79-month median follow-up and compared the anti-desmoglein B cell response and B and T lymphocyte subpopulations and repertoire between patients who achieved complete remission (CR) and those who had incomplete remission (IR). Thirteen patients (59%) experienced CR during the study, including 10 patients off treatment and 3 patients with prednisone doses <10 mg/day; 9 patients had IR. A marked increase was observed in the ratio of CD19(+)CD27(-) naïve B cells to CD19(+)CD27(+) memory B cells. Indeed, patients in CR had a fourfold higher number of transitional B cells and interleukin-10-secreting regulatory B cells than those in IR. Furthermore, CR was associated with modification of the initial B cell repertoire and the disappearance of desmoglein-specific circulating immunoglobulin G-positive (IgG(+)) B lymphocytes, whereas a skewed B cell repertoire was observed in patients in IR. Thus, a blockage of B cell maturation, a prolonged repopulation with naïve B cells, and a delayed reappearance of memory B cells, which resulted in the disappearance of circulating desmoglein-specific IgG(+) B lymphocytes, contribute to the long-lasting effectiveness of rituximab for treating pemphigus.


Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Linfócitos B/imunologia , Desmogleínas/imunologia , Pênfigo/tratamento farmacológico , Humanos , Imunofenotipagem , Pênfigo/imunologia , Pênfigo/fisiopatologia , Rituximab
6.
Rheumatology (Oxford) ; 50(10): 1814-22, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21791546

RESUMO

OBJECTIVE: To analyse the therapeutic effects of etanercept (ETA) or adalimumab (ADA) on the numbers and phenotypes of CD4+CD25hi Tregs in RA patients. METHODS: RA patients received ADA (n = 28) or ETA (n = 20) and stable-dose MTX or LEF. Therapeutic responses were assessed with the 28-joint DAS (DAS-28) criteria after 12 weeks of treatment. Treg numbers and phenotypes, determined by flow cytometry using different gating strategies, were compared between responders and non-responders before and after 6 and 12 weeks of treatment. RESULTS: The percentages of good, moderate and non-responders among patients given ADA or ETA, respectively, were 46.5, 35.7 and 17.8% or 30, 20 and 50%, with respective mean (s.d.) pre-treatment CD4+CD25hi Treg percentages of 5.5 (0.04)% or 4.95 (0.02)%. Overall, for patients with active RA given ADA or ETA, neither TNF-α-blocking agent had an effect on Tregs percentage and absolute number. Moreover, CD4+CD25hi Treg counts remained unaffected in RA responders to ADA or ETA, compared with RA non-responders. Furthermore, the CD4+CD25hiCD45RA+, CD4+CD25hiCD45RO+ and CD4+CD25hiCD62L+ cell populations were unchanged by TNF-α-blocking agents. CONCLUSION: Neither ADA nor ETA modified the percentages or absolute numbers of circulating CD4+CD25hi Tregs and their phenotypes after being administered for 6 and 12 weeks to RA patients. TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00234234.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Imunoglobulina G/uso terapêutico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Linfócitos T Reguladores/efeitos dos fármacos , Adalimumab , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Artrite Reumatoide/imunologia , Artrite Reumatoide/fisiopatologia , Contagem de Células , Etanercepte , Feminino , Nível de Saúde , Humanos , Injeções Subcutâneas , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Masculino , Pessoa de Meia-Idade , Fenótipo , Índice de Gravidade de Doença , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Adulto Jovem
7.
Sci Transl Med ; 2(46): 46ra62, 2010 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-20739682

RESUMO

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, drug-induced reaction that involves both the skin and the viscera. Evidence for reactivation of herpes family viruses has been seen in some DRESS patients. To understand the immunological components of DRESS and their relationship to viral reactivation, we prospectively assessed 40 patients exhibiting DRESS in response to carbamazepine, allopurinol, or sulfamethoxazole. Peripheral blood T lymphocytes from the patients were evaluated for phenotype, cytokine secretion, and repertoire of CD4+ and CD8+ and for viral reactivation. We found Epstein-Barr virus (EBV), human herpes virus 6 (HHV-6), or HHV-7 reactivation in 76% of the patients. In all patients, circulating CD8+ T lymphocytes were activated, exhibited increased cutaneous homing markers, and secreted large amounts of tumor necrosis factor-alpha and interferon-gamma. The production of these cytokines was particularly high in patients with the most severe visceral involvement. In addition, expanded populations of CD8+ T lymphocytes sharing the same T cell receptor repertoire were detected in the blood, skin, liver, and lungs of patients. Nearly half of these expanded blood CD8+ T lymphocytes specifically recognized one of several EBV epitopes. Finally, we found that the culprit drugs triggered the production of EBV in patients' EBV-transformed B lymphocytes. Thus, cutaneous and visceral symptoms of DRESS are mediated by activated CD8+ T lymphocytes, which are largely directed against herpes viruses such as EBV.


Assuntos
Eosinofilia/induzido quimicamente , Linfócitos T/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Epitopos/imunologia , Feminino , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 6/imunologia , Herpesvirus Humano 7/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
8.
J Clin Immunol ; 30(5): 746-55, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20437084

RESUMO

BACKGROUND: Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by recurrent infections and defective immunoglobulin production. METHODS: The DEFI French national prospective study investigated peripheral T-cell and B-cell compartments in 313 CVID patients grouped according to their clinical phenotype, using flow cytometry. RESULTS: In patients developing infection only (IO), the main B-cell or T-cell abnormalities were a defect in switched memory B cells and a decrease in naive CD4(+) T cells associated with an increase in CD4(+)CD95(+) cells. These abnormalities were more pronounced in patients developing lymphoproliferation (LP), autoimmune cytopenia (AC), or chronic enteropathy (CE). Moreover, LP and AC patients presented an increase in CD21(low) B cells and CD4(+)HLA-DR(+) T cells and a decrease in regulatory T cells. CONCLUSION: In these large series of CVID patients, the major abnormalities of the B-cell and T-cell compartments, although a hallmark of CVID, were only observed in half of the IO patients and were more frequent and severe in patients with additional lymphoproliferative, autoimmune, and digestive complications.


Assuntos
Linfócitos B/imunologia , Imunodeficiência de Variável Comum/imunologia , Infecção/imunologia , Subpopulações de Linfócitos/imunologia , Linfócitos T/imunologia , Adulto , Idoso , Linfócitos B/metabolismo , Linfócitos B/patologia , Antígenos CD4/biossíntese , Separação Celular , Imunodeficiência de Variável Comum/complicações , Imunodeficiência de Variável Comum/patologia , Imunodeficiência de Variável Comum/fisiopatologia , Progressão da Doença , Feminino , Citometria de Fluxo , França , Humanos , Switching de Imunoglobulina/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos , Imunofenotipagem , Infecção/etiologia , Infecção/patologia , Infecção/fisiopatologia , Subpopulações de Linfócitos/metabolismo , Linfopenia , Masculino , Pessoa de Meia-Idade , Enteropatias Perdedoras de Proteínas , Linfócitos T/metabolismo , Linfócitos T/patologia , Receptor fas/biossíntese
9.
Biol Blood Marrow Transplant ; 16(3): 430-4, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19883775

RESUMO

Peripheral blood stem cell transplantation (PBSCT) is an alternative to bone marrow transplantation (BMT). Although CD4(+)CD25(+)CD127(lo) regulatory T cells (Tregs) have been shown to play important roles in the control of T cell reactivity, the Treg contents of both graft types have not been analyzed comparatively to date. We report herein that Treg frequencies are significantly reduced in PBSC compared to BM transplants. Furthermore, most Tregs from PBSC transplants are CD62L(lo), a phenotype reported to have poor suppressor activity. Both granulocyte-colony stimulating factor (G-CSF) administration and leukapheresis were found to contribute to the loss of CD62L(+) Tregs. Although higher T cell numbers are infused in PBSCT than in BMT, it is possible that the reduced Treg content of PBSC transplants may represent 1 factor contributing to the higher risk of GVHD reported after PBSCT.


Assuntos
Transplante de Medula Óssea , Transplante de Células-Tronco de Sangue Periférico , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/transplante , Apoptose/imunologia , Medula Óssea/efeitos dos fármacos , Fatores de Transcrição Forkhead/análise , Doença Enxerto-Hospedeiro/imunologia , Fator Estimulador de Colônias de Granulócitos/farmacologia , Humanos , Imunofenotipagem , Subunidade alfa de Receptor de Interleucina-7/análise , Selectina L/análise , Leucaférese , Antígenos Comuns de Leucócito/análise , Contagem de Linfócitos , Fatores de Risco , Subpopulações de Linfócitos T/química , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/transplante , Linfócitos T Reguladores/química , Linfócitos T Reguladores/imunologia , Doadores de Tecidos
10.
J Immunol ; 183(10): 6207-16, 2009 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-19841185

RESUMO

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by pathogenic autoantibodies directed against nuclear Ags and immune complex deposits in damaged organs. Environmental factors have been thought to play a role in the onset of the disease. The recognition of these factors is mediated by TLRs, in particular TLR2 and TLR4 which bind pathogen-associated molecular patterns of Gram(+) and Gram(-) bacteria, respectively. We attempted to determine the role of these TLRs in SLE by creating TLR2- or TLR4-deficient C57BL/6(lpr/lpr) mice. These mice developed a less severe disease and fewer immunological alterations. Indeed, in C57BL/6(lpr/lpr)-TLR2 or -TLR4-deficient mice, glomerular IgG deposits and mesangial cell proliferation were dramatically decreased and antinuclear, anti-dsDNA, and anti-cardiolipin autoantibody titers were significantly reduced. However, the response against nucleosome remained unaffected, indicating a role of TLR2 and TLR4 in the production of Abs directed against only certain categories of SLE-related autoantigens. Analysis of B cell phenotype showed a significant reduction of marginal zone B cells, particularly in C57BL/6(lpr/lpr)-TLR4-deficient mice, suggesting an important role of TLR4 in the sustained activation of these cells likely involved in autoantibody production. Interestingly, the lack of TLR4 also affected the production of cytokines involved in the development of lupus disease.


Assuntos
Autoanticorpos/biossíntese , Subpopulações de Linfócitos B/imunologia , Glomerulonefrite/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Receptor 2 Toll-Like/imunologia , Receptor 4 Toll-Like/imunologia , Animais , Anticorpos Antinucleares/biossíntese , Anticorpos Antinucleares/sangue , Autoanticorpos/sangue , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Subpopulações de Linfócitos B/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Glomerulonefrite/genética , Glomerulonefrite/metabolismo , Glomerulonefrite/patologia , Imunoglobulina G/sangue , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/metabolismo , Lúpus Eritematoso Sistêmico/patologia , Camundongos , Camundongos Endogâmicos MRL lpr , Camundongos Knockout , Camundongos Mutantes , Mutação/genética , Mutação/imunologia , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
11.
J Invest Dermatol ; 128(12): 2859-69, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18563177

RESUMO

Pemphigus are B-cell-mediated autoimmune diseases affecting skin and mucous membranes. They are characterized by the production of pathogenic autoantibodies directed against desmogleins (Dsg). In this prospective study, we treated 21 pemphigus patients with rituximab and analyzed immunological modifications induced by anti-CD20 immunotherapy. The total depletion of peripheral B cells led to a significant decrease of total serum IgM but not IgG levels. The B-cell depletion was followed by a progressive re-emergence of naive blood B lymphocytes, with one-third of them expressing a transitional CD19+CD38(high)CD24(high) phenotype. In most patients, clinical response to rituximab was closely related to the evolution of anti-Dsg autoantibodies that decreased in patients who achieved complete remission, whereas they remained unchanged or reincreased in relapsing patients. In contrast, serum antimicrobial IgG remained stable after rituximab treatment. B-cell repertoire analysis of three patients using immunoscope showed distortions of VH-IgM and VH-IgG immunoscope profiles before treatment, particularly clonal and oligoclonal expansions in some VH families, which were not found after B-cell reconstitution, following anti-CD20 immunotherapy. The depletion of autoreactive B cells leading to the elimination of anti-Dsg autoantibodies in most remitted patients and the restoration of a diverse B-cell repertoire by naive B lymphocytes may provide an explanation for the long-lasting efficacy of rituximab in pemphigus patients.


Assuntos
Linfócitos B/imunologia , Imunoterapia/métodos , Pênfigo/imunologia , ADP-Ribosil Ciclase 1/biossíntese , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Murinos , Formação de Anticorpos , Antígenos CD19/biossíntese , Antígenos CD20/química , Antígeno CD24/biossíntese , Citometria de Fluxo , Humanos , Imunoglobulina G/química , Imunoglobulina M/química , Fenótipo , Polissacarídeos/química , Rituximab
12.
Clin Immunol ; 127(1): 14-25, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18191619

RESUMO

Transitional B cells have been recently identified in human peripheral blood. However, their precise role in human B cell differentiation has not been established. Therefore, besides characterizing them further in the blood of healthy adults and children and cord blood, we used the immune reconstitution after hematopoietic stem cell transplantation (HSCT) model to define their role in human B cell development. Human transitional B cells are reliably identified as CD19(+) CD24(high) CD38(high) lymphocytes and represent approximately 4% of B cells in healthy adult peripheral blood. In contrast, they are abundant in cord blood (near 50% of B cells) and their percentage progressively decreases during infancy. Similarly, after HSCT, all B cells first appearing in peripheral blood are transitional B cells; afterwards, the transitional B cell percentage progressively decreases while the mature naïve B cell proportion rises. Our results now formally demonstrate that transitional B cells are necessary developmental intermediates for human mature B cell generation.


Assuntos
Subpopulações de Linfócitos B/citologia , Linfócitos B/citologia , Diferenciação Celular/imunologia , Transplante de Células-Tronco Hematopoéticas , Células Precursoras de Linfócitos B/citologia , Adulto , Antígenos CD/biossíntese , Subpopulações de Linfócitos B/imunologia , Linfócitos B/imunologia , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Células Precursoras de Linfócitos B/imunologia
13.
N Engl J Med ; 357(6): 545-52, 2007 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-17687130

RESUMO

BACKGROUND: The combination of multiple cycles of rituximab and intravenous immune globulins has been reported to be effective in patients with severe pemphigus. The aim of this study was to assess the efficacy of a single cycle of rituximab in severe types of pemphigus. METHODS: We studied 21 patients with pemphigus whose disease had not responded to an 8-week course of 1.5 mg of prednisone per kilogram of body weight per day (corticosteroid-refractory disease), who had had at least two relapses despite doses of prednisone higher than 20 mg per day (corticosteroid-dependent disease), or who had severe contraindications to corticosteroids. The patients were treated with four weekly infusions of 375 mg of rituximab per square meter of body-surface area. The primary end point was complete remission 3 months after the end of rituximab treatment; complete remission was defined as epithelialization of all skin and mucosal lesions. RESULTS: Eighteen of 21 patients (86%; 95% confidence interval, 64 to 97%) had a complete remission at 3 months. The disease relapsed in nine patients after a mean of 18.9+/-7.9 months. After a median follow-up of 34 months, 18 patients (86%) were free of disease, including 8 who were not receiving corticosteroids; the mean prednisone dose decreased from 94.0+/-10.2 to 12.0+/-7.5 mg per day (P=0.04) in patients with corticosteroid-refractory disease and from 29.1+/-12.4 to 10.9+/-16.5 mg per day (P=0.007) in patients with corticosteroid-dependent disease. Pyelonephritis developed in one patient 12 months after rituximab treatment, and one patient died of septicemia 18 months after rituximab treatment. These patients had a profound decrease in the number of circulating B lymphocytes but normal serum levels of IgG. CONCLUSIONS: A single cycle of rituximab is an effective treatment for pemphigus. Because of its potentially severe side effects, its use should be limited to the most severe types of the disease. (ClinicalTrials.gov number, NCT00213512 [ClinicalTrials.gov].).


Assuntos
Anticorpos Monoclonais/administração & dosagem , Fatores Imunológicos/administração & dosagem , Pênfigo/tratamento farmacológico , Idoso , Anti-Inflamatórios/administração & dosagem , Anticorpos/sangue , Anticorpos Monoclonais Murinos , Linfócitos B , Desmogleínas/imunologia , Esquema de Medicação , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Isotipos de Imunoglobulinas/sangue , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Pênfigo/imunologia , Prednisona/administração & dosagem , Indução de Remissão , Rituximab
14.
World J Gastroenterol ; 13(16): 2333-8, 2007 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-17511033

RESUMO

AIM: To quantify the intraepithelial lymphocytes (IELs) and to document the membrane expression of CD4, CD8, TCRgamma delta and adhesion and/or activation-associated molecules (CD103, CD28, CD44, CD69, HLA-DR, CD95/Fas) in the duodenal mucosa of patients with functional dyspepsia (FD) in order to provide arguments for an immunological process in FD. METHODS: Twenty-six FD patients according to Rome II criteria (20 were H pylori negative) were studied and compared to 12 healthy adults. IELs were isolated from five duodenal biopsy samples, then quantified by microscopy and flow cytometry while the membrane phenotypes were determined by cytofluorometry. RESULTS: Duodenal histological examination was normal. In H pylori negative patients, the number of IELs was not different from that in healthy controls. Median percentage expression of CD4, CD8, or TCRgamma delta and CD103, CD44, CD28, CD69 on CD3+ IELs, among the adhesion/activation associated molecules tested, was not different from that in healthy controls. In contrast, the median percentage expression of CD95/Fas [22 (9-65) vs 45 (19-88), P=0.03] and HLA-DR expressing CD3+ IELs [4 (0-30) vs 13 (4-42), P=0.04] was significantly lower in the H pylori negative FD group than in healthy controls, respectively. The number of IELs was significantly greater in H pylori positive FD patients than in healthy controls [median ratio for 100 enterocytes 27.5 (6.7-62.5) vs 10.8 (3-33.3), P=0.02] due to a higher number of CD8+ CD3+ IELs. CONCLUSION: In H pylori negative FD patients, the phenotypic characterization of IELs suggests that we cannot exclude a role of IELs in FD.


Assuntos
Duodeno/imunologia , Dispepsia/imunologia , Mucosa Intestinal/patologia , Linfócitos T/metabolismo , Adolescente , Adulto , Idoso , Biópsia , Complexo CD3/metabolismo , Antígenos CD8/metabolismo , Estudos de Casos e Controles , Moléculas de Adesão Celular/metabolismo , Contagem de Células , Membrana Celular/imunologia , Duodeno/metabolismo , Duodeno/patologia , Dispepsia/metabolismo , Feminino , Humanos , Mucosa Intestinal/metabolismo , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Prospectivos
15.
J Thorac Cardiovasc Surg ; 133(3): 791-7, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17320586

RESUMO

OBJECTIVE: The humoral pathway is suggested as playing a key role in transplant arteriosclerosis. The humoral immunity is demonstrated in the present study to induce direct vascular lesion. METHODS: Ten abdominal aortic grafts were performed on 4 groups of rats: Brown Norway (BN) isografts, BN to Lewis (LEW) allografts, and two BN to nude (RNU) grafted groups with and without any humoral transfer. The humoral sera were obtained by skin grafts performed in BN to LEW combination. Lewis anti-BN alloantisera was transferred in nude recipients through intraperitoneal injections. The aortic wall was histologically studied with morphometric analysis on the 21st day. Two additional BN to RNU aortic graft groups were evaluated by immunohistochemistry on days 3 (10 rats) and 10 (10 rats). RESULTS: In the absence of the humoral transfer, the BN aortic wall implanted in RNU remained intact. The humoral transfer induced a marked intimal proliferation (63 +/- 4 vs 4 +/- 1.1 microm; P < .001) and an adventitial cell infiltration (5.1 +/- 0.7 vs 2.8 +/- 0.6 x 10(3) c/mm2, P < .001). The medial thickness and the medial cell density were not modified. On day 3, the remaining endothelial cells were covered by immunoglobulin G deposits. On day 10 the endothelial cells disappeared completely and intimal proliferation occurred. In an additional cardiac graft group, transplant coronary arteriopathy was evidenced in 7 of the 9 nude recipients that had undergone the humoral transfer. CONCLUSION: The transplant arterial occlusive lesion is demonstrated here (1) to be induced by humoral antidonor immunity and (2) to be linked to an adventitial or perivascular inflammation.


Assuntos
Formação de Anticorpos , Aorta Abdominal/transplante , Arteriosclerose/imunologia , Transplante de Coração/imunologia , Antígenos de Histocompatibilidade/imunologia , Análise de Variância , Animais , Aorta Abdominal/patologia , Arteriosclerose/etiologia , Modelos Animais de Doenças , Rejeição de Enxerto , Sobrevivência de Enxerto , Transplante de Coração/efeitos adversos , Transplante de Coração/métodos , Imuno-Histoquímica , Masculino , Probabilidade , Distribuição Aleatória , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos Lew , Ratos Nus , Fatores de Risco , Especificidade da Espécie , Imunologia de Transplantes , Transplante Homólogo
16.
Med Sci (Paris) ; 22(12): 1075-80, 2006 Dec.
Artigo em Francês | MEDLINE | ID: mdl-17156729

RESUMO

B lymphocytes represent an important arm of the immune system. Besides their main function of providing antibodies protecting against pathogens, they also exert some regulatory functions, in particular for secondary lymphoid tissue differentiation. Human B cells can be divided in various subsets representing different maturation stages and different pathways of humoral immune responses. Naïve IgMlow IgDhigh CD27- B cells can participate in T-cell dependent immune responses leading to germinal center formation in follicles of secondary lymphoid organs. Interactions with follicular helper T cells, a recently identified CD185+ T cell population providing help to follicular B cell, involve costimulatory molecules including CD40, CD27, CD278 and SAP-recruiting receptors. B cell interaction with follicular helper T cells represents a critical step controlling the generation of plama cells that ultimately produce high affinity, somatically mutated, class-switched antibodies or of their memory B cell counterpart (identified as CD27+ Ig switched or IgMonly B cells). IgMhigh IgDlow CD27+ B cells are a puzzling population apparently specialized in T-independent responses to bacterial capsular polysaccharides. The extra-follicular, probably antigen-independent, differentiation pathway of these cells, allowing pre-immune repertoire diversification by somatic hypermutation, is not yet characterized. However, circulating IgMhigh IgDlow CD27+ B cells are similar to splenic marginal zone B cells. In addition to these subsets, minor populations can also be identified in peripheral blood, such as transitional B cells and plasma blasts. All together, deciphering human B cell heterogeneity provides tools for investigations of humoral immunodeficiencies and auto-immune diseases, that will in return shed more light on B cell biology.


Assuntos
Linfócitos B/imunologia , Antígenos CD/imunologia , Subpopulações de Linfócitos B/imunologia , Diferenciação Celular , Humanos , Switching de Imunoglobulina/imunologia , Ativação Linfocitária , Modelos Imunológicos , Fenótipo
17.
Ann Med Interne (Paris) ; 153(8): 503-12, 2002 Dec.
Artigo em Francês | MEDLINE | ID: mdl-12610424

RESUMO

Systemic lupus erythematosus is a non-organ-specific autoimmune disease characterized biologically by B lymphocyte hyperactivity and the production of autoantibodies directed against various cellular components, in particular nuclear antigens. Different strains of mice spontaneously develop a lupus-like disease and constitute a guidelight for human SLE. Both polyclonal B cell stimulation and clonal expansion induced by self-antigens participate in B cell hyperactivity observed in human and mouse SLE. B cells are hyperactive to various stimuli, in particular those delivered by T cells through surface molecules or cytokines. The consequences are an increased production of immunoglobulins and the development of autoantibodies thought to induce the major part of tissue lesions. B cells also participate in the pathological process as antigen-presenting and cytokine-secreting cells. An intrinsic defect of B cells is suspected to be responsible for B cell anomalies as illustrated by certain spontaneous murine models of SLE (motheaten mice) and by lupus-like syndromes observed in mice rendered deficient for genes controlling the B-cell receptor (BCR) signaling pathway. Genome wide scan analysis of various lupus strains allowed to identify several loci predisposing to lupus among which certain are associated with B cell hyperactivity suggesting that the intrinsic defect is inherited.


Assuntos
Linfócitos B/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Animais , Anticorpos Antinucleares/imunologia , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Humanos , Imunidade Celular , Lúpus Eritematoso Sistêmico/genética , Camundongos , Modelos Animais , Receptores de Antígenos de Linfócitos B/imunologia , Linfócitos T/imunologia
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