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2.
Br Dent J ; 222(12): 931-935, 2017 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-28642521

RESUMO

Background The UK sports drinks market has a turnover in excess of £200 million. Adolescents consume 15.6% of total energy as free sugars, much higher than the recommended 5%. Sugar sweetened beverages, including sports drinks, account for 30% of total free sugar intake for those aged 11-18 years.Objective To investigate children's knowledge and attitudes surrounding sports drinks.Method One hundred and eighty-three self-complete questionnaires were distributed to four schools in South Wales. Children aged 12-14 were recruited to take part. Questions focussed on knowledge of who sports drinks are aimed at; the role of sports drinks in physical activity; and the possible detrimental effects to oral health. Recognition of brand logo and sports ambassadors and the relationship of knowledge to respondents' consumption of sports drinks were assessed.Results There was an 87% (160) response rate and 89.4% (143) claimed to drink sports drinks. 45.9% thought that sports drinks were aimed at everyone; approximately a third (50) viewed teenagers as the target group. Over two thirds recognised the brand logos, yet less than a third could identify brand ambassadors. About half were aware that dental erosion may result from consumption and approximately two thirds knew that they were linked to dental caries and energy provision. Despite this the majority claimed to drink them. As previously reported most of those drinking sports drinks did so because of the taste.Conclusion Whilst most of the respondents had some understanding of the detrimental effects on health the majority of them were drinking them regularly despite this knowledge. Work is therefore needed at a macro level, with soft drink manufacturers, to consider marketing and reformulation of products for adolescent consumers who appear to enjoy them.


Assuntos
Bebidas Energéticas , Conhecimentos, Atitudes e Prática em Saúde , Adolescente , Criança , Bebidas Energéticas/efeitos adversos , Feminino , Rotulagem de Alimentos , Humanos , Masculino , Inquéritos e Questionários , País de Gales
3.
Br Dent J ; 222(8): 613-620, 2017 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-28428570

RESUMO

Background The expansion of the novelty sweets market in the UK has major potential public health implications in children and young adults as they may cause dental erosion.Objective To investigate the erosive potential of the novelty sweets in term of their physiochemical properties and amount of enamel loss.Subjects and methods The pH of a variety of novelty sweets was tested in vitro using a pH meter and the neutralisable acidity was assessed by titrating the sweets against 0.1M NaOH. The viscosity of the novelty sweets was measured using a rotational viscometer. The wettability of enamel by each sweet was measured using dynamic contact angle analyser. Enamel loss was assessed using contact profilometry.Results The pH ranged from 1.8-3.2, the neutralisable acidity ranged from 9-201 ml of 0.1 NaOH. The viscosity of the novelty sweets that come in liquid form ranged from 2-594 mPa s. The surface enamel erosion ranged from 1.95-15.77 µm and from 2.5-17.6 µm with and without immersing in saliva for 1 hour before immersing in acidic solution respectively. The amount of subsurface enamel loss was ranged from 0.75 to 2.3 µm following ultrasonication at 0 min of acidic attack and from 0.23 to 0.85 µm at 60 minutes of acidic attack while immersed in saliva. The contact angle between enamel surface and four sweet was less than the angle formed between the orange juice and the enamel which caused more wettability of enamel.Conclusion The pH is lower than the critical value for enamel erosion (5.5), high neutralisable acidity and high sugar content strongly suggest that these sweets may cause significant amount of dental erosion clinically. In addition, the degree of wettability of enamel by solution is an important factor to consider in determining the enamel loss caused by acidic solution. Immediate tooth brushing would cause further enamel loss as a result of the mechanical removal of softened enamel. However, it has been suggested that postponing brushing after erosive attack should be reconsidered.


Assuntos
Doces/efeitos adversos , Erosão Dentária/etiologia , Doces/análise , Inglaterra , Humanos , Concentração de Íons de Hidrogênio , Viscosidade , Molhabilidade
4.
Am J Transplant ; 17(11): 2810-2819, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28444847

RESUMO

Building on studies showing that ischemia-reperfusion-(I/R)-injury is complement dependent, we tested links among complement activation, transplantation-associated I/R injury, and murine cardiac allograft rejection. We transplanted BALB/c hearts subjected to 8-h cold ischemic storage (CIS) into cytotoxic T-lymphocyte associated protein 4 (CTLA4)Ig-treated wild-type (WT) or c3-/- B6 recipients. Whereas allografts subjected to 8-h CIS rejected in WT recipients with a median survival time (MST) of 37 days, identically treated hearts survived >60 days in c3-/- mice (p < 0.05, n = 4-6/group). Mechanistic studies showed recipient C3 deficiency prevented induction of intragraft and serum chemokines/cytokines and blunted the priming, expansion, and graft infiltration of interferon-γ-producing, donor-reactive T cells. MST of hearts subjected to 8-h CIS was >60 days in mannose binding lectin (mbl1-/- mbl2-/- ) recipients and 42 days in factor B (cfb-/- ) recipients (n = 4-6/group, p < 0.05, mbl1-/- mbl2-/- vs. cfb-/- ), implicating the MBL (not alternative) pathway. To pharmacologically target MBL-initiated complement activation, we transplanted BALB/c hearts subjected to 8-h CIS into CTLA4Ig-treated WT B6 recipients with or without C1 inhibitor (C1-INH). Remarkably, peritransplantation administration of C1-INH prolonged graft survival (MST >60 days, p < 0.05 vs. controls, n = 6) and prevented CI-induced increases in donor-reactive, IFNγ-producing spleen cells (p < 0.05). These new findings link donor I/R injury to T cell-mediated rejection through MBL-initiated, complement activation and support testing C1-INH administration to prevent CTLA4Ig-resistant rejection of deceased donor allografts in human transplant patients.


Assuntos
Abatacepte/farmacologia , Antígeno CTLA-4/imunologia , Proteínas do Sistema Complemento/imunologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/imunologia , Transplante de Coração/efeitos adversos , Linfócitos T/imunologia , Aloenxertos , Animais , Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto/efeitos dos fármacos , Imunossupressores/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Doadores de Tecidos
5.
Br Dent J ; 220(11): 575-9, 2016 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-27283564

RESUMO

Background Reducing sugar consumption is a primary focus of current global public health policy. Achieving 5% of total energy from free sugars will be difficult acknowledging the concentration of free sugars in sugar sweetened beverages, confectionery and as hidden sugars in many savoury items. The expansion of the novelty sweet market in the UK has significant implications for children and young adults as they contribute to dental caries, dental erosion and obesity.Objective To identify the most available types of novelty sweets within the high school fringe in Cardiff, UK and to assess their price range and where and how they were displayed in shops.Subjects and methods Shops within a ten minute walking distance around five purposively selected high schools in the Cardiff aea representing different levels of deprivation were visited. Shops in Cardiff city centre and three supermarkets were also visited to identify the most commonly available novelty sweets.Results The ten most popular novelty sweets identified in these scoping visits were (in descending order): Brain Licker, Push Pop, Juicy Drop, Lickedy Lips, Big Baby Pop, Vimto candy spray, Toxic Waste, Tango candy spray, Brain Blasterz Bitz and Mega Mouth candy spray. Novelty sweets were located on low shelves which were accessible to all age-groups in 73% (14 out of 19) of the shops. Novelty sweets were displayed in the checkout area in 37% (seven out of 19) shops. The price of the top ten novelty sweets ranged from 39p to £1.Conclusion A wide range of acidic and sugary novelty sweets were easily accessible and priced within pocket money range. Those personnel involved in delivering dental and wider health education or health promotion need to be aware of recent developments in children's confectionery. The potential effects of these novelty sweets on both general and dental health require further investigation.


Assuntos
Bebidas , Doces , Cárie Dentária , Saúde Bucal , Instituições Acadêmicas , Adolescente , Comércio , Alimentos , Humanos , País de Gales
6.
Br Dent J ; 220(12): 639-43, 2016 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-27338907

RESUMO

Background Sports drinks intended to improve performance and hydrate athletes taking part in endurance sport are being marketed to children, for whom these products are not intended. Popularity among children has grown exponentially. Worryingly they consume them socially, as well as during physical activity. Sports drinks are high in sugar and are acidic. Product marketing ignores the potential harmful effects of dental caries and erosion.Objective To investigate the use of sports drinks by children.Method One hundred and eighty-three self-complete questionnaires were distributed to four schools in South Wales. Children in high school years 8 and 9 (aged 12-14) were recruited to take part. Questions focused on use of sports drinks, type consumed, frequency of and reason for consumption and where drinks were purchased.Results One hundred and sixty children responded (87% response rate): 89.4% (143) claimed to drink sports drinks, half drinking them at least twice a week. Lucozade Sport(™) was the most popular brand. The main reason for consuming the drinks was attributed to the 'nice taste' (90%, 129/143). Most respondents purchased the drinks from local shops (80.4%, 115) or supermarkets (54.5%, 78). More boys claimed to drink sports drinks during physical activity (77.9% versus 48.6% girls, P <0.001). Whereas more girls claimed to drink them socially (51.4% versus 48.5% boys, NS).Conclusion A high proportion of children consumed sports drinks regularly and outside of sporting activity. Dental health professionals should be aware of the popularity of sports drinks with children when giving health education advice or designing health promotion initiatives.


Assuntos
Bebidas , Cárie Dentária , Adolescente , Criança , Comportamento de Ingestão de Líquido , Feminino , Alimentos , Humanos , Masculino , Esportes , Inquéritos e Questionários
7.
Am J Transplant ; 16(7): 1949-50, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26792650
8.
Mucosal Immunol ; 9(1): 137-45, 2016 01.
Artigo em Inglês | MEDLINE | ID: mdl-26013006

RESUMO

Foxp3-expressing regulatory T cells (Tregs) are central regulators of immune homeostasis and tolerance. As it has been suggested that proper Treg function is compromised under inflammatory conditions, seeking for a pathway that enhances or stabilizes Treg function is a subject of considerable interest. We report that interleukin (IL)-27, an IL-12 family cytokine known to have both pro- and anti-inflammatory roles in T cells, plays a pivotal role in enhancing Treg function to control T cell-induced colitis, a model for inflammatory bowel disease (IBD) in humans. Unlike wild-type (WT) Tregs capable of inhibiting colitogenic T-cell expansion and inflammatory cytokine expression, IL-27R-deficient Tregs were unable to downregulate inflammatory T-cell responses. Tregs stimulated with IL-27 expressed substantially improved suppressive function in vitro and in vivo. IL-27 stimulation of Tregs induced expression of Lag3, a surface molecule implicated in negatively regulating immune responses. Lag3 expression in Tregs was critical to mediate Treg function in suppressing colitogenic responses. Human Tregs also displayed enhanced suppressive function and Lag3 expression following IL-27 stimulation. Collectively, these results highlight a novel function for the IL-27/Lag3 axis in modulating Treg regulation of inflammatory responses in the intestine.


Assuntos
Antígenos CD/imunologia , Colite/imunologia , Fatores de Transcrição Forkhead/imunologia , Interleucinas/imunologia , Receptores de Interleucina/imunologia , Linfócitos T Reguladores/imunologia , Animais , Antígenos CD/genética , Proliferação de Células , Colite/genética , Colite/patologia , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica , Humanos , Interleucinas/genética , Interleucinas/farmacologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Cultura Primária de Células , Receptores de Interleucina/deficiência , Receptores de Interleucina/genética , Transdução de Sinais , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/patologia , Proteína do Gene 3 de Ativação de Linfócitos
10.
Am J Transplant ; 15(12): 3166-73, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26226830

RESUMO

Previous studies suggest that quantifying donor-reactive memory T cells prior to kidney transplantation by interferon gamma enzyme-linked immunosorbent spot assay (IFNγELISPOT) can assist in assessing risk of posttransplant allograft injury. Herein, we report an analysis of IFNγELISPOT results from the multicenter, Clinical Trials in Organ Transplantation-01 observational study of primary kidney transplant recipients treated with heterogeneous immunosuppression. Within the subset of 176 subjects with available IFNγELISPOT results, pretransplant IFNγELISPOT positivity surprisingly did not correlate with either the incidence of acute rejection (AR) or estimated glomerular filtration rate (eGFR) at 6- or 12-month. These unanticipated results prompted us to examine potential effect modifiers, including the use of T cell-depleting, rabbit anti-thymocyte globulin (ATG). Within the no-ATG subset, IFNγELISPOT(neg) subjects had higher 6- and 12-month eGFRs than IFNγELISPOT(pos) subjects, independent of biopsy-proven AR, peak PRA, human leukocyte antigen mismatches, African-American race, donor source, and recipient age or gender. In contrast, IFNγELISPOT status did not correlate with posttransplant eGFR in subjects given ATG. Our data confirm an association between pretransplant IFNγELISPOT positivity and lower posttransplant eGFR, but only in patients who do not receive ATG induction. Controlled studies are needed to test the hypothesis that ATG induction is preferentially beneficial to transplant candidates with high frequencies of donor-reactive memory T cells.


Assuntos
Biomarcadores/análise , Ensaio de Imunoadsorção Enzimática/métodos , Rejeição de Enxerto/diagnóstico , Interferon gama/análise , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Complicações Pós-Operatórias , Adulto , Animais , Soro Antilinfocitário/imunologia , Criança , Feminino , Seguimentos , Taxa de Filtração Glomerular , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto , Humanos , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Coelhos , Fatores de Risco , Doadores de Tecidos
11.
Am J Transplant ; 15(5): 1192-204, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25731734

RESUMO

We have reported that B6.CCR5(-/-) mice reject renal allografts with high serum donor-specific antibody (DSA) titers and marked C4d deposition in grafts, features consistent with antibody-mediated rejection (AMR). B6.huCD20/CCR5(-/-) mice, where human CD20 expression is restricted to B cells, rejected A/J renal allografts by day 26 posttransplant with DSA first detected in serum on day 5 posttransplant and increased thereafter. Recipient treatment with anti-huCD20 mAb prior to the transplant and weekly up to 7 weeks posttransplant promoted long-term allograft survival (>100 days) with low DSA titers. To investigate the effect of B cell depletion at the time serum DSA was first detected, recipients were treated with anti-huCD20 mAb on days 5, 8, and 12 posttransplant. This regimen significantly reduced DSA titers and graft inflammation on day 15 posttransplant and prolonged allograft survival >60 days. However, DSA returned to the titers observed in control treated recipients by day 30 posttransplant and histological analyses on day 60 posttransplant indicated severe interstitial fibrosis. These results indicate that anti-huCD20 mAb had the greatest effect as a prophylactic treatment and that the distinct kinetics of DSA responses accounts for acute renal allograft failure versus the development of fibrosis.


Assuntos
Anticorpos/imunologia , Antígenos CD20/química , Rejeição de Enxerto/prevenção & controle , Transplante de Rim , Insuficiência Renal/imunologia , Insuficiência Renal/cirurgia , Aloenxertos , Animais , Formação de Anticorpos/imunologia , Creatinina/sangue , Modelos Animais de Doenças , Fibrose/fisiopatologia , Citometria de Fluxo , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia de Fluorescência , Receptores CCR5/genética , Fatores de Tempo , Transplante Homólogo
12.
Am J Transplant ; 15(2): 333-45, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25582188

RESUMO

Acute and chronic rejection impact distinct compartments of cardiac allografts. Intramyocardial mononuclear cell infiltrates define acute rejection, whereas chronic rejection affects large arteries. Hearts transplanted from male to female C57BL/6 mice undergo acute rejection with interstitial infiltrates at 2 weeks that resolve by 6 weeks when large arteries develop arteriopathy. These processes are dependent on T cells because no infiltrates developed in T cell-deficient mice and transfer of CD4 T cells restored T cell as well as macrophage infiltrates and ultimately neointima formation. Markers of inflammatory macrophages were up-regulated in the interstitium acutely and decreased as markers of wound healing macrophages increased chronically. Programmed cell death protein, a negative costimulator, and its ligand PDL1 were up-regulated in the interstitium during resolution of acute rejection. Blocking PDL1:PD1 interactions in the acute phase increased interstitial T cell infiltrates. Toll-like receptor (TLR) 4 and its endogenous ligand hyaluronan were increased in arteries with neointimal expansion. Injection of hyaluronan fragments increased intragraft production of chemokines. Our data indicate that negative costimulatory pathways are critical for the resolution of acute interstitial infiltrates. In the arterial compartment recognition of endogenous ligands including hyaluronan by the innate TLRs may support the progression of arteriopathy.


Assuntos
Rejeição de Enxerto/fisiopatologia , Transplante de Coração , Miocárdio/metabolismo , Miocárdio/patologia , Transdução de Sinais/fisiologia , Animais , Antígeno B7-H1/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Quimiocina CCL2/metabolismo , Quimiocina CXCL9/metabolismo , Feminino , Ácido Hialurônico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Receptor 4 Toll-Like/metabolismo
13.
Br Dent J ; 217(10): E20, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25415038

RESUMO

OBJECTIVE: Children's magazines are popular in the United Kingdom, but their content is poorly regulated. Consequently, food and beverages high in fat, salt and sugar (HFSS), detrimental to oral and wider health, make unrestricted appearances. The study aim was to assess the amount of HFSS food and drink children are exposed to while reading magazines; with particular focus on foods containing free sugars due to their known cariogenic properties, and foods with low pH due to their erosive potential. DESIGN: Eleven of the most popular UK children's magazines were selected and purchased at four separate time points in 2012. These 44 magazines were examined using content analysis; any references to food/beverages (in advertisements, free gifts, editorial and general content) were recorded. RESULTS: Of the 508 food references observed, 73.6% (374/508) were for foods detrimental to oral health owing to their high sugar and/or acid content. 5.9% (30/508) were considered 'unhealthy' due to their fat or salt content. 20.5% of references were for 'healthy' foods (104/508). The most common food categories referenced were baked goods (181/508) and sweets (86/508). Over a third (36.4%, 16/44) of magazines came with free sweets. In terms of positioning, the food/drink references were predominantly found in the general content of the magazines, including the editorial spreads. Direct advertisements for food/drink only accounted for 9.6% (36/374) of the total number of references counted. CONCLUSION: Food references within children's magazines are biased towards unhealthy foods especially those detrimental to oral health; these permeate throughout the general and editorial content and are not restricted to direct advertisements. Magazine editors, journalists and illustrators are responsible for the editorial and general content of magazines. Without regulation, subliminal placement of advertisements within editorial and general content leads to 'advertorials' which are known to confuse children and parents alike. This study concludes that regulation may therefore need to cover more than just the direct advertisements. Dental professionals need to be aware of current trends in children's media when giving health education advice or designing health promotion initiatives.


Assuntos
Alimentos , Saúde Bucal , Publicações Periódicas como Assunto , Publicidade/estatística & dados numéricos , Bebidas/estatística & dados numéricos , Criança , Dieta Cariogênica/estatística & dados numéricos , Carboidratos da Dieta , Alimentos/estatística & dados numéricos , Humanos , Publicações Periódicas como Assunto/estatística & dados numéricos , Reino Unido
14.
Am J Transplant ; 14(8): 1753-64, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25040187

RESUMO

The pathogenic role of macrophages in antibody-mediated rejection (AMR) remains unclear. Monocyte chemoattractant protein-1 (MCP-1/CCL2) is a potent chemotactic factor for monocytes and macrophages. The current studies used a murine model of AMR to investigate the role of graft-derived CCL2 in AMR and how macrophages may participate in antibody-mediated allograft injury. B6.CCR5−/−/CD8−/− recipients rejected MHC-mismatched WT A/J allografts with high donor-reactive antibody titers and diffuse C4d deposition in the large vessels and myocardial capillaries, features consistent with AMR. In contrast, A/J.CCL2−/− allografts induced low donor-reactive antibody titers and C4d deposition at Day 7 posttransplant. Decreased donor-reactive CD4 T cells producing interferon gamma were induced in response to A/J.CCL2−/− versus WT allografts. Consequently, A/J.CCL2−/− allograft survival was modestly but significantly longer than A/J allografts. Macrophages purified from WT allografts expressed high levels of IL-1ß and IL-12p40 and this expression and the numbers of classically activated macrophages were markedly reduced in CCL2-deficient allografts on Day 7. The results indicate that allograft-derived CCL2 plays an important role in directing classically activated macrophages into allografts during AMR and that macrophages are important contributors to the inflammatory environment mediating graft tissue injury in this pathology, suggesting CCL2 as a therapeutic target for AMR.


Assuntos
Anticorpos/sangue , Quimiocina CCL2/metabolismo , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Transplante de Coração , Animais , Linfócitos T CD4-Positivos/citologia , Proliferação de Células , Sobrevivência Celular , Quimiocina CCL2/genética , Quimiotaxia , Citocinas/metabolismo , Citometria de Fluxo , Sobrevivência de Enxerto , Interferon gama/metabolismo , Macrófagos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/citologia , Fatores de Tempo , Transplante Homólogo
15.
Am J Transplant ; 14(6): 1277-89, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24842641

RESUMO

The presence of CD28(-) memory CD8 T cells in the peripheral blood of renal transplant patients is a risk factor for graft rejection and resistance to CTLA-4Ig induction therapy. In vitro analyses have indicated poor alloantigen-induced CD28(-) memory CD8 T cell proliferation, raising questions about mechanisms mediating their clonal expansion in kidney grafts to mediate injury. Candidate proliferative cytokines were tested for synergy with alloantigen in stimulating CD28(-) memory CD8 T cell proliferation. Addition of IL-15, but not IL-2 or IL-7, to co-cultures of CD28(-) or CD28(+) memory CD8 T cells and allogeneic B cells rescued proliferation of the CD28(-) and enhanced CD28(+) memory T cell proliferation. Proliferating CD28(-) memory CD8 T cells produced high amounts of interferon gamma and tumor necrosis factor alpha and expressed higher levels of the cytolytic marker CD107a than CD28(+) memory CD8 T cells. CTLA-4Ig inhibited alloantigen-induced proliferation of CD28(+) memory CD8 T cell proliferation but had no effect on alloantigen plus IL-15-induced proliferation of either CD28(-) or CD28(+) memory CD8 T cells. These results indicate the ability of IL-15, a cytokine produced by renal epithelial during inflammation, to provoke CD28(-) memory CD8 T cell proliferation and to confer memory CD8 T cell resistance to CTLA-4Ig-mediated costimulation blockade.


Assuntos
Antígenos CD28/imunologia , Linfócitos T CD8-Positivos/citologia , Antígeno CTLA-4/imunologia , Memória Imunológica , Interleucina-15/fisiologia , Ativação Linfocitária , Linfócitos T CD8-Positivos/imunologia , Humanos , Teste de Cultura Mista de Linfócitos
16.
Am J Transplant ; 14(3): 568-79, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24502272

RESUMO

Differences in levels of environmentally induced memory T cells that cross-react with donor MHC molecules are postulated to account for the efficacy of allograft tolerance-inducing strategies in rodents versus their failure in nonhuman primates and human transplant patients. Strategies to study the impact of donor-reactive memory T cells on allografts in rodents have relied on the pretransplant induction of memory T cells cross-reactive with donor allogeneic MHC molecules through recipient viral infection, priming directly with donor antigen or adoptive transfer of donor antigen primed memory T cells. Each approach accelerates allograft rejection and confers resistance to tolerance induction, but also biases the T cell repertoire to strong donor reactivity. The ability of endogenous memory T cells within unprimed mice to directly reject an allograft is unknown. Here, we show a direct association between increased duration of cold ischemic allograft storage and numbers and enhanced functions of early graft infiltrating endogenous CD8 memory T cells. These T cells directly mediate rejection of allografts subjected to prolonged ischemia and this rejection is resistant to costimulatory blockade. These findings recapitulate the clinically significant impact of endogenous memory T cells with donor reactivity in a mouse transplant model in the absence of prior recipient priming.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Rejeição de Enxerto/imunologia , Transplante de Coração/efeitos adversos , Memória Imunológica/imunologia , Transferência Adotiva , Aloenxertos , Animais , Anticorpos Monoclonais/farmacologia , Western Blotting , Isquemia Fria , Citocinas/genética , Citocinas/metabolismo , Citometria de Fluxo , Humanos , Técnicas Imunoenzimáticas , Antígeno-1 Associado à Função Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
17.
Am J Transplant ; 14(2): 284-94, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24410909

RESUMO

We utilized mouse models to elucidate the immunologic mechanisms of functional graft loss during mixed antibody-mediated rejection of renal allografts (mixed AMR), in which humoral and cellular responses to the graft occur concomitantly. Although the majority of T cells in the graft at the time of rejection were CD8 T cells with only a minor population of CD4 T cells, depletion of CD4 but not CD8 cells prevented acute graft loss during mixed AMR. CD4 depletion eliminated antidonor alloantibodies and conferred protection from destruction of renal allografts. ELISPOT revealed that CD4 T effectors responded to donor alloantigens by both the direct and indirect pathways of allorecognition. In transfer studies, CD4 T effectors primed to donor alloantigens were highly effective at promoting acute graft dysfunction, and exhibited the attributes of effector T cells. Laser capture microdissection and confirmatory immunostaining studies revealed that CD4 T cells infiltrating the graft produced effector molecules with graft destructive potential. Bioluminescent imaging confirmed that CD4 T effectors traffic to the graft site in immune replete hosts. These data document that host CD4 T cells can promote acute dysfunction of renal allografts by directly mediating graft injury in addition to facilitating antidonor alloantibody responses.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Rejeição de Enxerto/etiologia , Isoanticorpos/imunologia , Isoantígenos/imunologia , Nefropatias/imunologia , Transplante de Rim/efeitos adversos , Animais , Citometria de Fluxo , Nefropatias/complicações , Nefropatias/cirurgia , Microdissecção e Captura a Laser , Depleção Linfocítica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , Camundongos Transgênicos , Transplante Homólogo
18.
Am J Transplant ; 13(10): 2634-44, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23968332

RESUMO

Noninvasive biomarkers are needed to assess immune risk and ultimately guide therapeutic decision-making following kidney transplantation. A requisite step toward these goals is validation of markers that diagnose and/or predict relevant transplant endpoints. The Clinical Trials in Organ Transplantation-01 protocol is a multicenter observational study of biomarkers in 280 adult and pediatric first kidney transplant recipients. We compared and validated urinary mRNAs and proteins as biomarkers to diagnose biopsy-proven acute rejection (AR) and stratify patients into groups based on risk for developing AR or progressive renal dysfunction. Among markers tested for diagnosing AR, urinary CXCL9 mRNA (odds ratio [OR] 2.77, positive predictive value [PPV] 61.5%, negative predictive value [NPV] 83%) and CXCL9 protein (OR 3.40, PPV 67.6%, NPV 92%) were the most robust. Low urinary CXCL9 protein in 6-month posttransplant urines obtained from stable allograft recipients classified individuals least likely to develop future AR or a decrement in estimated glomerular filtration rate between 6 and 24 months (92.5-99.3% NPV). Our results support using urinary CXCL9 for clinical decision-making following kidney transplantation. In the context of acute dysfunction, low values can rule out infectious/immunological causes of injury. Absent urinary CXCL9 at 6 months posttransplant defines a subgroup at low risk for incipient immune injury.


Assuntos
Injúria Renal Aguda/urina , Biomarcadores/urina , Quimiocina CXCL9/urina , Rejeição de Enxerto/urina , Transplante de Rim , Injúria Renal Aguda/cirurgia , Adulto , Biomarcadores/sangue , Quimiocina CXCL9/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Seguimentos , Taxa de Filtração Glomerular , Rejeição de Enxerto/etiologia , Humanos , Testes de Função Renal , Masculino , Prognóstico , Estudos Prospectivos , Fatores de Risco
19.
Am J Transplant ; 13(9): 2293-307, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23914930

RESUMO

Endogenous memory CD8 T cells infiltrate MHC-mismatched cardiac allografts within 12-24 h posttransplant in mice and are activated to proliferate and produce IFN-γ. To more accurately assess the graft injury directly imposed by these endogenous memory CD8 T cells, we took advantage of the ability of anti-LFA-1 mAb given to allograft recipients on days 3 and 4 posttransplant to inhibit the generation of primary effector T cells. When compared to grafts from IgG-treated recipients on day 7 posttransplant, allografts from anti-LFA-1 mAb-treated recipients had increased numbers of CD8 T cells but these grafts had marked decreases in expression levels of mRNA encoding effector mediators associated with graft injury and decreases in donor-reactive CD8 T cells producing IFN-γ. Despite this decreased activity within the allograft, CD8 T cells in allografts from recipients treated with anti-LFA-1 mAb continued to proliferate up to day 7 posttransplant and did not upregulate expression of the exhaustion marker LAG-3 but did have decreased expression of ICOS. These results indicate that endogenous memory CD8 T cells infiltrate and proliferate in cardiac allografts in mice but do not express sufficient levels of functions to mediate overt graft injury and acute rejection.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Transplante de Coração , Imunologia de Transplantes , Aloenxertos , Animais , Anticorpos Monoclonais/farmacologia , Antígenos CD/biossíntese , Linfócitos T CD4-Positivos/imunologia , Ligante de CD40/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Proteína Coestimuladora de Linfócitos T Induzíveis/biossíntese , Ativação Linfocitária , Camundongos , Proteína do Gene 3 de Ativação de Linfócitos
20.
Am J Transplant ; 13(9): 2268-79, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23834725

RESUMO

Lymphopenia is induced by lymphoablative therapies and chronic viral infections. We assessed the impact of lymphopenia on cardiac allograft survival in recipients conditioned with peritransplant costimulatory blockade (CB) to promote long-term graft acceptance. After vascularized MHC-mismatched heterotopic heart grafts were stably accepted through CB, lymphopenia was induced on day 60 posttransplant by 6.5 Gy irradiation or by administration of anti-CD4 plus anti-CD8 mAb. Long-term surviving allografts were gradually rejected after lymphodepletion (MST = 74 ± 5 days postirradiation). Histological analyses indicated signs of severe rejection in allografts following lymphodepletion, including mononuclear cell infiltration and obliterative vasculopathy. Lymphodepletion of CB conditioned recipients induced increases in CD44(high) effector/memory T cells in lymphatic organs and strong recovery of donor-reactive T cell responses, indicating lymphopenia-induced proliferation (LIP) and donor alloimmune responses occurring in the host. T regulatory (CD4(+) Foxp(3+)) cell and B cell numbers as well as donor-specific antibody titers also increased during allograft rejection in CB conditioned recipients given lymphodepletion. These observations suggest that allograft rejection following partial lymphocyte depletion is mediated by LIP of donor-reactive memory T cells. As lymphopenia may cause unexpected rejection of stable allografts, adequate strategies must be developed to control T cell proliferation and differentiation during lymphopenia.


Assuntos
Rejeição de Enxerto/imunologia , Transplante de Coração , Linfopenia/imunologia , Tolerância Periférica/imunologia , Tolerância ao Transplante/efeitos dos fármacos , Transferência Adotiva , Aloenxertos , Animais , Feminino , Linfopenia/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Linfócitos T , Irradiação Corporal Total
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