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3.
Cells ; 8(1)2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30646564

RESUMO

Adverse outcomes following virus-associated disease in patients receiving allogeneic haematopoietic stem cell transplantation (HSCT) have encouraged strategies to control viral reactivation in immunosuppressed patients. However, despite timely treatment with antiviral medication, some viral infections remain refractory to treatment, which hampers outcomes after HSCT, and are responsible for a high proportion of transplant-related morbidity and mortality. Adoptive transfer of donor-derived lymphocytes aims to improve cellular immunity and to prevent or treat viral diseases after HSCT. Early reports described the feasibility of transferring nonspecific lymphocytes from donors, which led to the development of cell therapy approaches based on virus-specific T cells, allowing a targeted treatment of infections, while limiting adverse events such as graft versus host disease (GvHD). Both expansion and direct selection techniques have yielded comparable results in terms of efficacy (around 70⁻80%), but efficacy is difficult to predict for individual cases. Generating bespoke products for each donor⁻recipient pair can be expensive, and there remains the major obstacle of generating products from seronegative or poorly responsive donors. More recent studies have focused on the feasibility of collecting and infusing partially matched third-party virus-specific T cells, reporting response rates of 60⁻70%. Future development of this approach will involve the broadening of applicability to multiple viruses, the optimization and cost-control of manufacturing, larger multicentred efficacy trials, and finally the creation of cell banks that can provide prompt access to virus-specific cellular product. The aim of this review is to summarise present knowledge on adoptive T cell manufacturing, efficacy and potential future developments.


Assuntos
Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunoterapia Adotiva/métodos , Linfócitos T/transplante , Viroses/terapia , Adulto , Criança , Doação Dirigida de Tecido , Doença Enxerto-Hospedeiro/etiologia , Humanos , Viroses/etiologia
4.
Haematologica ; 104(5): 1074-1082, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30514805

RESUMO

Platelet destruction in immune thrombocytopenia is caused by autoreactive antibody and T-cell responses, most commonly directed against platelet glycoprotein IIb/IIIa. Loss of self-tolerance in the disease is also associated with deficient activity of regulatory T cells. Having previously mapped seven major epitopes on platelet glycoprotein IIIa that are recognized by helper T cells from patients with immune thrombocytopenia, the aim was to test whether peptide therapy with any of these sequences, alone or in combination, could inhibit responses to the antigen in humanized mice expressing HLA-DR15. None of the individual peptides, delivered by a putative tolerogenic regimen, consistently suppressed the antibody response to subsequent immunization with human platelet glycoprotein IIb/IIIa. However, the combination of glycoprotein IIIa peptides aa6-20 and aa711-725, which contain the predominant helper epitopes in patients and elicited the strongest trends to suppress when used individually, did abrogate this response. The peptide combination also blunted, but did not reverse, the ongoing antibody response when given after immunization. Suppression of antibody was associated with reduced splenocyte T-cell responsiveness to the antigen, and with the induction of a regulatory T-cell population that is more responsive to the peptides than to purified platelet glycoprotein IIb/IIIa. Overall, these data demonstrate that combinations of peptides containing helper epitopes, such as platelet glycoprotein IIIa aa6-20 and aa711-725, can promote in vivo suppression of responses to the major antigen implicated in immune thrombocytopenia. The approach offers a promising therapeutic option to boost T-cell regulation, which should be taken forward to clinical trials.

5.
Cell Immunol ; 332: 58-76, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30077333

RESUMO

Macrophages are key in orchestrating immune responses to micro-environmental stimuli, sensed by a complex set of surface receptors. The human cell line THP-1 has a monocytic phenotype, including the ability to differentiate into macrophages, providing a tractable, standardised surrogate for human monocyte-derived macrophages. Here we assessed the expression of 49 surface markers including Fc, complement, C-type lectin and scavenger receptors; TIMs; Siglecs; and co-stimulatory molecules by flow cytometry on both THP-1 monocytes and macrophages and following macrophage activation with seven standard conditioning/polarizing stimuli. Of the 34 surface markers detected on macrophages, 18 altered expression levels on activation. From these, expression of 9 surface markers were consistently altered by all conditioning regimens, while 9 were specific to individual polarizing stimuli. This study provides a resource for the study of macrophages and highlights that macrophage polarization states share much in common and the differences do not easily fit a simple classification system.


Assuntos
Diferenciação Celular/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Células THP-1/imunologia , Biomarcadores/sangue , Linhagem Celular , Proteínas do Sistema Complemento/imunologia , Humanos , Lectinas Tipo C/imunologia , Ativação de Macrófagos/imunologia
6.
Oncotarget ; 9(29): 20377-20385, 2018 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-29755658

RESUMO

The heritability of classical Hodgkin lymphoma (cHL) has yet to be fully deciphered. We report a family with five members diagnosed with nodular sclerosis cHL. Genetic analysis of the family provided evidence of linkage at chromosomes 2q35-37, 3p14-22 and 21q22, with logarithm of odds score >2. We excluded the possibility of common genetic variation influencing cHL risk at regions of linkage, by analysing GWAS data from 2,201 cHL cases and 12,460 controls. Whole exome sequencing of affected family members identified the shared missense mutations p.(Arg76Gln) in FAM107A and p.(Thr220Ala) in SLC26A6 at 3p21 as being predicted to impact on protein function. FAM107A expression was shown to be low or absent in lymphoblastoid cell lines and SLC26A6 expression lower in lymphoblastoid cell lines derived from p.(Thr220Ala) mutation carriers. Expression of FAM107A and SLC26A6 was low or absent in Hodgkin Reed-Sternberg (HRS) cell lines and in HRS cells in Hodgkin lymphoma tissue. No sequence variants were detected in KLHDC8B, a gene previously suggested as a cause of familial cHL linked to 3p21. Our findings provide evidence for candidate gene susceptibility to familial cHL.

7.
Pediatr Transplant ; 22(2)2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29388302

RESUMO

EBV-CTL immunotherapy targets EBV antigens expressed by tumor cells in PTLD. Data on outcome of EBV-CTL in pSOT patients are limited. The aim of the study is to describe our experience with allogeneic, third-party EBV-CTL for the treatment of PTLD in pSOT patients in a single tertiary center. Retrospective review was performed of all pSOT patients who received EBV-CTL for PTLD. PTLD was diagnosed using World Health Organization histologic criteria. EBV-CTLs were derived from human leukocyte antigen-typed, EBV-seropositive third-party donors, and cryopreserved and maintained by an accredited national blood transfusion service. Ten patients received EBV-CTL for histologically proven PTLD from 1999 to 2016 following liver (n=5), combined intestinal/liver (n=4), and liver/kidney (n=1) transplantation. PTLD occurred at median age of 40 months (range: 12-144) and median post-transplant interval of 8 months (range: 2-107). Seven had monomorphic, two had polymorphic, and one had Hodgkin-type PTLD. All were of B-cell origin and EBV-positive on histology. EBV-CTL achieved an overall remission rate of 80% (8 of 10). Transient adverse effects included fever, tachycardia, and vomiting. None developed graft-versus-host disease or opportunistic infections. EBV-CTL is an effective treatment for PTLD in pSOT patients, with good remission rate and minimal toxicity.


Assuntos
Herpesvirus Humano 4/imunologia , Imunoterapia/métodos , Transtornos Linfoproliferativos/terapia , Transplante de Órgãos , Complicações Pós-Operatórias/terapia , Linfócitos T Citotóxicos/transplante , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Transtornos Linfoproliferativos/etiologia , Masculino , Complicações Pós-Operatórias/imunologia , Complicações Pós-Operatórias/virologia , Estudos Retrospectivos , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/virologia , Resultado do Tratamento
8.
Cancer Res ; 78(1): 75-87, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29122767

RESUMO

Protein tyrosine phosphatase PTP1B is a critical regulator of signaling pathways controlling metabolic homeostasis, cell proliferation, and immunity. In this study, we report that global or myeloid-specific deficiency of PTP1B in mice decreases lifespan. We demonstrate that myeloid-specific deficiency of PTP1B is sufficient to promote the development of acute myeloid leukemia. LysM-PTP1B-/- mice lacking PTP1B in the innate myeloid cell lineage displayed a dysregulation of bone marrow cells with a rapid decline in population at midlife and a concomitant increase in peripheral blood blast cells. This phenotype manifested further with extramedullary tumors, hepatic macrophage infiltration, and metabolic reprogramming, suggesting increased hepatic lipid metabolism prior to overt tumor development. Mechanistic investigations revealed an increase in anti-inflammatory M2 macrophage responses in liver and spleen, as associated with increased expression of arginase I and the cytokines IL10 and IL4. We also documented STAT3 hypersphosphorylation and signaling along with JAK-dependent upregulation of antiapoptotic proteins Bcl2 and BclXL. Our results establish a tumor suppressor role for PTP1B in the myeloid lineage cells, with evidence that its genetic inactivation in mice is sufficient to drive acute myeloid leukemia.Significance: This study defines a tumor suppressor function for the protein tyrosine phosphatase PTP1B in myeloid lineage cells, with evidence that its genetic inactivation in mice is sufficient to drive acute myeloid leukemia. Cancer Res; 78(1); 75-87. ©2017 AACR.


Assuntos
Leucemia Mieloide Aguda/etiologia , Fígado/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Baço/patologia , Animais , Citocinas/genética , Feminino , Leucemia Mieloide Aguda/genética , Fígado/enzimologia , Longevidade/genética , Macrófagos/enzimologia , Macrófagos/patologia , Masculino , Camundongos Knockout , Células Mieloides/enzimologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Pirazóis/farmacologia , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT5/metabolismo , Baço/enzimologia , Proteína bcl-X/metabolismo
9.
Immunology ; 149(4): 413-422, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27502559

RESUMO

Although eosinophils are inflammatory cells, there is increasing attention on their immunomodulatory roles. For example, murine eosinophils can present antigen to CD4+ T helper (Th) cells, but it remains unclear whether human eosinophils also have this ability. This study determined whether human eosinophils present a range of antigens, including allergens, to activate Th cells, and characterized their expression of MHC class II and co-stimulatory molecules required for effective presentation. Human peripheral blood eosinophils purified from non-allergic donors were pulsed with the antigens house dust mite extract (HDM), Timothy Grass extract (TG) or Mycobacterium tuberculosis purified protein derivative (PPD), before co-culture with autologous CD4+ Th cells. Proliferative and cytokine responses were measured, with eosinophil expression of HLA-DR/DP/DQ and the co-stimulatory molecules CD40, CD80 and CD86 determined by flow cytometry. Eosinophils pulsed with HDM, TG or PPD drove Th cell proliferation, with the response strength dependent on antigen concentration. The cytokine responses varied with donor and antigen, and were not biased towards any particular Th subset, often including combinations of pro- and anti-inflammatory cytokines. Eosinophils up-regulated surface expression of HLA-DR/DP/DQ, CD80, CD86 and CD40 in culture, increases that were sustained over 5 days when incubated with antigens, including HDM, or the major allergens it contains, Der p I or Der p II. Human eosinophils can, therefore, act as effective antigen-presenting cells to stimulate varied Th cell responses against a panel of antigens including HDM, TG or PPD, an ability that may help to determine the development of allergic disease.


Assuntos
Eosinófilos/metabolismo , Mycobacterium tuberculosis/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Apresentação do Antígeno , Antígenos de Dermatophagoides/imunologia , Antígenos de Dermatophagoides/metabolismo , Antígenos de Plantas/imunologia , Antígenos de Plantas/metabolismo , Proteínas de Artrópodes/imunologia , Proteínas de Artrópodes/metabolismo , Células Cultivadas , Técnicas de Cocultura , Cisteína Endopeptidases/imunologia , Cisteína Endopeptidases/metabolismo , Citocinas/metabolismo , Eosinófilos/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Ativação Linfocitária , Phleum , Pyroglyphidae , Tuberculina/imunologia , Tuberculina/metabolismo
10.
J Leukoc Biol ; 100(4): 737-746, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27129285

RESUMO

Inhibitory receptors of the human leukocyte immunoglobulin-like receptor family are constitutively expressed on all myeloid cell types and regulate their functional activity. We demonstrate that ligation of the human leukocyte antigen class I-specific receptor LILRB1, during the differentiation of monocytes to dendritic cells in vitro, results in increased expression of the nuclear factor κB inhibitor protein ABIN1 (also known as TNIP1). Similarly increased expression of ABIN1/TNIP1 was observed in the "immunosuppressive" monocyte populations of patients with non-Hodgkin lymphoma ex vivo. Reducing expression of ABIN1/TNIP1 using small interfering ribonucleic acid allows dendritic cells and immunosuppressive monocytes to respond to stimulation by allowing nuclear factor κB translocation to the nucleus (P < 0.001), increasing cell surface expression of antigen presentation and costimulatory molecules (P < 0.01), increasing phagocytic capacity (P < 0.001), secreting proinflammatory cytokines (P < 0.01), and an increasing ability to stimulate T cell responses (P < 0.05). Our study, therefore, identifies an important functional role for ABIN1/TNIP1 in mediating the effects of LILRB1 ligation-induced inhibitory effects on immune responses. Our findings suggest that inhibiting the LILRB1-ABIN1/TNIP1 pathway in antigen-presenting cells could be a therapeutic approach to stimulate antitumor immune responses. Conversely, stimulation of the pathway may also ameliorate autoimmune diseases in which TNIP1 is a susceptibility gene.


Assuntos
Antígenos CD/fisiologia , Proteínas de Ligação a DNA/biossíntese , Células Dendríticas/citologia , Monócitos/citologia , Mielopoese/fisiologia , NF-kappa B/metabolismo , Receptores Imunológicos/fisiologia , Apresentação do Antígeno , Núcleo Celular/metabolismo , Células Cultivadas , Citocinas/metabolismo , Proteínas de Ligação a DNA/genética , Células Dendríticas/imunologia , Regulação da Expressão Gênica/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Interleucina-4/farmacologia , Receptor B1 de Leucócitos Semelhante a Imunoglobulina , Linfoma não Hodgkin/sangue , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Fagocitose , Transporte Proteico , Interferência de RNA , RNA Interferente Pequeno/genética , Proteínas Recombinantes/farmacologia , Linfócitos T/imunologia
11.
J Allergy Clin Immunol ; 137(5): 1498-1505.e1, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26920464

RESUMO

BACKGROUND: Viral infections are a leading fatal complication for patients with primary immunodeficiencies (PIDs) who require hematopoietic stem cell transplantation (HSCT). Use of virus-specific T lymphocytes (VSTs) has been successful for the treatment and prevention of viral infections after HSCT for malignant and nonmalignant conditions. Here we describe the clinical use of VSTs in patients with PIDs at 4 centers. OBJECTIVE: We sought to evaluate the safety and efficacy of VSTs for treatment of viral infections in patients with PIDs. METHODS: Patients with PIDs who have received VST therapy on previous or current protocols were reviewed in aggregate. Clinical information, including transplantation details, viral infections, and use of antiviral and immunosuppressive pharmacotherapy, were evaluated. Data regarding VST production, infusions, and adverse reactions were compared. RESULTS: Thirty-six patients with 12 classes of PID diagnoses received 37 VST products before or after HSCT. Twenty-six (72%) patients had received a diagnosis of infection with cytomegalovirus, EBV, adenovirus, BK virus, and/or human herpesvirus 6. Two patients were treated before HSCT because of EBV-associated lymphoproliferative disease. Partial or complete responses against targeted viruses occurred in 81% of patients overall. Time to response varied from 2 weeks to 3 months (median, 28 days). Overall survival at 6 months after therapy was 80%. Four patients had graft-versus-host disease in the 45 days after VST infusion, which in most cases was therapy responsive. CONCLUSION: VSTs derived from either stem cell donors or third-party donors are likely safe and effective for the treatment of viral infections in patients with PIDs.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência/terapia , Imunoterapia Adotiva , Linfócitos T/transplante , Viroses/terapia , Adolescente , Adulto , Criança , Pré-Escolar , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/virologia , Humanos , Síndromes de Imunodeficiência/virologia , Lactente , Carga Viral , Viroses/virologia , Adulto Jovem
12.
Arthritis Res Ther ; 17: 274, 2015 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-26416719

RESUMO

INTRODUCTION: Infection with Epstein-Barr virus (EBV) has been suggested to contribute to the pathogenesis of autoimmune diseases, including rheumatoid arthritis (RA). We sought to determine whether prior infection with the virus occurs more frequently in patients with RA compared to controls. METHODS: We performed a systematic review and meta-analyses of studies that reported the prevalence of anti-EBV antibodies in the sera of cases with RA and controls by searching Medline and Embase databases from 1946 to 2014, with no language restriction. Mantel-Haenszel odds ratios for the detection of anti-EBV antibodies were calculated, and meta-analyses conducted. Quality assessments were performed using a modified version of the Newcastle-Ottawa scale. RESULTS: Twenty-three studies were included. Quality assessment found most studies reported acceptable selection criteria but poor descriptions of how cases and controls were recruited. When all studies were included, there was a statistically significant higher seroprevalence of anti-VCA IgG in patients with RA compared to controls with an odds ratio (OR) of 1.61 (95 % confidence interval (CI) 1.05-2.46, p = 0.03), which is a similar-sized summary OR to that reported for systemic lupus erythematosus (SLE). However, when studies were restricted to those reporting more plausible levels of exposure to EBV in the control groups, no significant association was apparent, OR 1.47 (95 % CI 0.88-2.46, p = 0.14). Using anti-EBNA 1 or anti-EA IgG as markers of previous infection also did not yield significant associations (OR 1.05, 95 % CI 0.68-1.61, p = 0.82; OR 2.2, 95 % CI 0.86-5.65, p = 0.10 respectively). CONCLUSIONS: Overall, these findings do not demonstrate an association between EBV seroprevalence and RA and therefore do not support the hypothesis that prior infection with EBV predisposes to the development of RA. This contrasts with meta-analyses that indicate EBV infection is associated with multiple sclerosis and SLE.


Assuntos
Anticorpos Antivirais/imunologia , Artrite Reumatoide/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/imunologia , Artrite Reumatoide/virologia , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/fisiologia , Humanos , Imunoglobulina G/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/virologia , Esclerose Múltipla/imunologia , Esclerose Múltipla/virologia , Razão de Chances , Estudos Soroepidemiológicos
13.
Br J Haematol ; 167(3): 402-10, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25066775

RESUMO

Epstein-Barr virus (EBV) is associated with several malignancies, including post-transplant lymphoproliferative disorder (PTLD). Conventional treatments for PTLD are often successful, but risk organ rejection and cause significant side effects. EBV-specific cytotoxic T lymphocytes (CTLs) generated in vitro from peripheral blood lymphocytes provide an alternative treatment modality with few side effects, but autologous CTLs are difficult to use in clinical practice. Here we report the establishment and operation of a bank of EBV-specific CTLs derived from 25 blood donors with human leucocyte antigen (HLA) types found at high frequency in European populations. Since licensure, there have been enquiries about 37 patients, who shared a median of three class I and two class II HLA types with these donors. Cells have been infused into ten patients with lymphoproliferative disease, eight of whom achieved complete remission. Neither patient with refractory disease was matched for HLA class II. Both cases of EBV-associated non-haematopoietic sarcoma receiving cells failed to achieve complete remission. Thirteen patients died before any cells could be issued, emphasizing that the bank should be contacted before patients become pre-terminal. Thus, this third party donor-derived EBV-specific CTL cell bank can supply most patients with appropriately matched cells and most recipients have good outcomes.


Assuntos
Infecções por Vírus Epstein-Barr/terapia , Herpesvirus Humano 4/imunologia , Imunoterapia Adotiva , Transtornos Linfoproliferativos/terapia , Linfócitos T Citotóxicos/imunologia , Bancos de Tecidos/organização & administração , Adolescente , Aloenxertos , Neoplasias do Sistema Nervoso Central/terapia , Neoplasias do Sistema Nervoso Central/virologia , Pré-Escolar , Infecções por Vírus Epstein-Barr/imunologia , Feminino , Antígenos HLA/análise , Teste de Histocompatibilidade , Humanos , Lactente , Leiomiossarcoma/terapia , Leiomiossarcoma/virologia , Licenciamento , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/virologia , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/virologia , Masculino , Pessoa de Meia-Idade , Nova Zelândia , Complicações Pós-Operatórias/imunologia , Complicações Pós-Operatórias/terapia , Complicações Pós-Operatórias/virologia , Indução de Remissão , Sarcoma/terapia , Sarcoma/virologia , Especificidade do Receptor de Antígeno de Linfócitos T , Linfócitos T Citotóxicos/transplante , Bancos de Tecidos/normas , Resultado do Tratamento , Adulto Jovem
14.
Arthritis Res Ther ; 16(1): R3, 2014 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-24387619

RESUMO

INTRODUCTION: Infection with Epstein-Barr virus (EBV) has been suggested to contribute to the pathogenesis of systemic lupus erythematosus (SLE). We sought to determine whether prior infection with the virus occurs more frequently in patients with SLE compared to matched controls. METHODS: We performed a systematic review and meta-analyses of studies that reported the prevalence of anti-EBV antibodies in the sera from cases of SLE and controls by searching Medline and Embase databases from 1966 to 2012, with no language restriction. Mantel-Haenszel odds ratios (OR) for the detection of anti-EBV antibodies were calculated, and meta-analyses conducted. Quality assessments were performed using a modified version of the Newcastle-Ottawa scale. RESULTS: Twenty-five case-control studies were included. Quality assessment found most studies reported acceptable selection criteria but poor description of how cases and controls were recruited. There was a statistically significant higher seroprevalence of anti-viral capsid antigen (VCA) IgG (OR 2.08; 95% confidence interval (CI) 1.15 - 3.76, p = 0.007) but not anti-EBV-nuclear antigen1 (EBNA1) (OR 1.45; 95% CI 0.7 to 2.98, p = 0.32) in cases compared to controls. The meta-analyses for anti-early antigen (EA) /D IgG and anti-VCA IgA also showed significantly high ORs (4.5; 95% CI 3.00 to 11.06, p < 0.00001 and 5.05 (95% CI 1.95 - 13.13), p = 0.0009 respectively). However, funnel plot examination suggested publication bias. CONCLUSIONS: Overall, our findings support the hypothesis that infection with EBV predisposes to the development of SLE. However, publication bias cannot be excluded and the methodological conduct of studies could be improved, with regard to recruitment, matching and reporting of blinded laboratory analyses.


Assuntos
Infecções por Vírus Epstein-Barr/epidemiologia , Lúpus Eritematoso Sistêmico/virologia , Anticorpos Antivirais/sangue , Humanos , Prevalência , Estudos Soroepidemiológicos
15.
Haematologica ; 99(3): 588-96, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24441145

RESUMO

The offspring from pregnancies of women who have developed anti-D blood group antibodies are at risk of hemolytic disease of the newborn. We have previously mapped four peptides containing immunodominant T-helper cell epitopes from the RhD protein and the purpose of the work was to develop these into a product for suppression of established anti-D responses. A panel of each of the four immunodominant RhD peptides was synthesized with modifications to improve manufacturability and solubility, and screened for retention of recognition by human T-helper cells. A selected version of each sequence was combined in a mixture (RhDPmix), which was tested for suppressive ability in a humanized murine model of established immune responses to RhD protein. After HLA-DR15 transgenic mice had been immunized with RhD protein, a single dose of RhDPmix, given either intranasally (P=0.008, Mann-Whitney rank sum test) or subcutaneously (P=0.043), rapidly and significantly suppressed the ongoing antibody response. This was accompanied by reduced T-helper cell responsiveness, although this change was less marked for subcutaneous RhDPmix delivery, and by the recruitment of cells with a regulatory T-cell phenotype. The results support human trials of RhDPmix peptide immunotherapy in women with established antibody responses to the RhD blood group.


Assuntos
Formação de Anticorpos/genética , Formação de Anticorpos/imunologia , Antígenos de Histocompatibilidade/genética , Fragmentos de Peptídeos/imunologia , Sistema do Grupo Sanguíneo Rh-Hr/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Adulto , Animais , Feminino , Humanos , Epitopos Imunodominantes/administração & dosagem , Epitopos Imunodominantes/imunologia , Imunoterapia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Fragmentos de Peptídeos/administração & dosagem , Sistema do Grupo Sanguíneo Rh-Hr/química , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Adulto Jovem
16.
Eur J Immunol ; 44(4): 1069-83, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24435677

RESUMO

Candida albicans remains the fungus most frequently associated with nosocomial bloodstream infection. In disseminated candidiasis, the role of Foxp3(+) regulatory T (Treg) cells remains largely unexplored. Our aims were to characterize Foxp3(+) Treg-cell activation in a murine intravenous challenge model of disseminated C. albicans infection, and determine the contribution to disease. Flow cytometric analyses demonstrated that C. albicans infection drove in vivo expansion of a splenic CD4(+) Foxp3(+) population that correlated positively with fungal burden. Depletion from Foxp3(hCD2) reporter mice in vivo confirmed that Foxp3(+) cells exacerbated fungal burden and inflammatory renal disease. The CD4(+) Foxp3(+) population expanded further after in vitro stimulation with C. albicans antigens (Ags), and included at least three cell types. These arose from proliferation of the natural Treg-cell subset, together with conversion of Foxp3(-) cells to the induced Treg-cell form, and to a cell type sharing effector Th17-cell characteristics, expressing ROR-γt, and secreting IL-17A. The expanded Foxp3(+) T cells inhibited Th1 and Th2 responses, but enhanced Th17-cell responses to C. albicans Ags in vitro, and in vivo depletion confirmed their ability to enhance the Th17-cell response. These data lead to a model for disseminated candidiasis whereby expansion of Foxp3(+) T cells promotes Th17-cell responses that drive pathology.


Assuntos
Candida albicans/imunologia , Candidíase/imunologia , Proliferação de Células , Fatores de Transcrição Forkhead/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Candida albicans/fisiologia , Candidíase/microbiologia , Células Cultivadas , Citocinas/imunologia , Citocinas/metabolismo , Citometria de Fluxo , Fatores de Transcrição Forkhead/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Nefropatias/imunologia , Nefropatias/virologia , Camundongos , Camundongos Endogâmicos C57BL , Baço/imunologia , Baço/virologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/microbiologia , Células Th17/metabolismo , Células Th17/microbiologia
17.
Ann Hum Genet ; 77(6): 465-71, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23937567

RESUMO

Angiotensin-I converting enzyme (ACE) occupies a pivotal role in cardiovascular homeostasis. Major loci for plasma ACE have been identified at ACE on Chromosome 17 and at ABO on Chromosome 9. We sought to characterise the genetic architecture of plasma ACE at finer resolution in two populations. We carried out a GWAS in 1810 individuals of Japanese ethnicity; this identified signals at ACE and ABO that together accounted for nearly half of the population variability of the trait. We conducted measured haplotype analysis at the ABO locus in 1425 members of 248 British families using haplotypes of three SNPs, which together tagged the alleles responsible for the principal blood group antigens A1, A2, B and O. Type O alleles were associated with intermediate plasma ACE activity compared to Type A1 alleles (in whom plasma ACE activity was ∼36% lower) and Type B alleles (in whom plasma ACE activity was ∼36% higher). We demonstrated heterogeneity among A alleles: A2 alleles were associated with plasma ACE activity that was very similar to the O alleles. Variation at ACE accounted for 35% of the trait variance, and variation at ABO accounted for 15%. A further 10% could be ascribed to polygenic effects.


Assuntos
Sistema do Grupo Sanguíneo ABO/genética , Alelos , Heterogeneidade Genética , Peptidil Dipeptidase A/sangue , Peptidil Dipeptidase A/genética , Locos de Características Quantitativas , Ativação Enzimática , Grupo com Ancestrais do Continente Europeu/genética , Frequência do Gene , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos , Humanos , Japão , Fenótipo , Polimorfismo de Nucleotídeo Único
18.
Case Rep Hematol ; 2013: 718480, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23653870

RESUMO

Refractory anemia with ring sideroblasts associated with marked thrombocytosis (RARS-T) is a hematological malignancy that combines features of both a myeloproliferative and myelodysplastic disorder. There have been recent reports of the successful treatment of anemia in 2 patients with RARS-T with lenalidomide. Here we report the successful treatment of massive splenomegaly in a patient with a long history of RARS-T resulting in complete resolution of splenomegaly, but with prolonged severe cytopenias. We also report the acquisition of the t(3;12)(q26;p13) translocation previously described in cases of myelodysplasia and the potential for transformation to myelofibrosis.

19.
PLoS One ; 8(4): e61110, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23585874

RESUMO

BACKGROUND: A role for Epstein Barr virus (EBV) in multiple sclerosis (MS) has been postulated. Previous systematic reviews found higher prevalences of anti-EBV antibodies in MS patients compared to controls, but many studies have since been published, and there is a need to apply more rigorous systematic review methods. METHODOLOGY/PRINCIPAL FINDINGS: We examined the link between EBV and MS by conducting a systematic review and meta-analysis of case-control and cohort studies that examined the prevalence of anti-EBV antibodies in the serum of cases and controls. We searched Medline and Embase databases from 1960 to 2012, with no language restriction. The Mantel-Haenszel odds ratios (OR) for anti-EBV antibodies sero-positivity were calculated, and meta-analysis conducted. Quality assessment was performed using a modified version of the Newcastle Ottawa scale. Thirty-nine studies were included. Quality assessment found most studies reported acceptable selection and comparability of cases and controls. However the majority had poor reporting of ascertainment of exposure. Most studies found a higher sero-prevalence of anti-EBNA IgG and anti-VCA IgG in cases compared to controls. The results for anti-EA IgG were mixed with only half the studies finding a higher sero-prevalence in cases. The meta-analysis showed a significant OR for sero-positivity to anti-EBNA IgG and anti-VCA IgG in MS cases (4.5 [95% confidence interval (CI) 3.3 to 6.6, p<0.00001] and 4.5 [95% CI 2.8 to 7.2, p<0.00001] respectively). However, funnel plot examination suggested publication bias for the reporting of the anti-EBNA IgG. No significant difference in the OR for sero-positivity to anti-EA IgG was found (1.4 [95% CI 0.9 to 2.1, p = 0.09]). CONCLUSION/SIGNIFICANCE: These findings support previous systematic reviews, however publication bias cannot be excluded. The methodological conduct of studies could be improved, particularly with regard to reporting and conduct of laboratory analyses.


Assuntos
Anticorpos Antivirais/sangue , Infecções por Vírus Epstein-Barr/sangue , Antígenos Nucleares do Vírus Epstein-Barr/sangue , Herpesvirus Humano 4/imunologia , Imunoglobulina G/sangue , Esclerose Múltipla/sangue , Adolescente , Adulto , Criança , Pré-Escolar , Bases de Dados Bibliográficas , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Humanos , Masculino , Esclerose Múltipla/complicações , Esclerose Múltipla/imunologia , Esclerose Múltipla/virologia , Razão de Chances , Viés de Publicação
20.
Eur J Immunol ; 43(5): 1274-85, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23400950

RESUMO

CTLA-4 is a crucial immune regulator that mediates both negative costimulation signals to T cells, and regulatory T (Treg)-cell extrinsic control of effector responses. Here we present evidence supporting a novel mechanism for this extrinsic suppression, executed by the alternatively spliced soluble CTLA-4 isoform (sCTLA-4). Analyses of human T cells in vitro show that sCTLA-4 secretion can be increased during responses, and has potent inhibitory properties, since isoform-specific blockade of its activity significantly increased Ag-driven proliferation and cytokine (IFN-γ, IL-17) secretion. Treg cells were demonstrated to be a prominent source of sCTLA-4, which contributed to suppression in vitro when their numbers were limiting. The soluble isoform was also produced by, and inhibited, murine T cells responding to Ag in vitro, and blockade of its activity in vivo protected against metastatic spread of melanoma in mice. We conclude that sCTLA-4 is an important immune regulator, responsible for at least some of the inhibitory effects previously ascribed to the membrane-bound isoform. These results suggest that the immune system exploits the different CTLA-4 isoforms for either intrinsic or extrinsic regulation of T-cell activity.


Assuntos
Anticorpos Neutralizantes/farmacologia , Antígeno CTLA-4/imunologia , Melanoma Experimental/tratamento farmacológico , Metástase Neoplásica/prevenção & controle , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/imunologia , Animais , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/genética , Células Cultivadas , Feminino , Humanos , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-17/biossíntese , Interleucina-17/imunologia , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos BALB C , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Solubilidade , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo
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