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1.
Artigo em Inglês | MEDLINE | ID: mdl-33093763

RESUMO

Background: Serum Amyloid A (SAA) is an acute phase protein and we analyzed its concentrations in lung transplantated patients (LTX). Methods: 26 LTX patients (58.6 ± 11 years) and 11 healthy controls (55 ± 11.3 years). Three groups of LTX patients: acute rejection (AR, 7) bronchiolitis obliterans syndrome (BOS, 3), acute infection (INF, 9) and stable patients (NEG, 7). Results: In LTX patients SAA concentrations were significantly increased, particularly in AR and INF. In LTX-AR patients were observed a correlation between SAA levels and peripheral CD4+ lymphocyte percentage (r=0.9, p<0.01) and a reverse correlation with FVC percentages (r -0.94, p=0.01). Conclusions: SAA may represent a potential biomarker of LTX acute complications, with a prognostic value in AR. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (1): 2-7).


Assuntos
Bronquiolite Obliterante/sangue , Rejeição de Enxerto/sangue , Transplante de Pulmão/efeitos adversos , Infecções Oportunistas/sangue , Proteína Amiloide A Sérica/metabolismo , Doença Aguda , Adulto , Idoso , Biomarcadores/sangue , Bronquiolite Obliterante/diagnóstico , Bronquiolite Obliterante/imunologia , Estudos de Casos e Controles , Feminino , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/imunologia , Humanos , Hospedeiro Imunocomprometido , Masculino , Pessoa de Meia-Idade , Infecções Oportunistas/diagnóstico , Infecções Oportunistas/imunologia , Resultado do Tratamento
3.
Transplantation ; 104(8): e224-e235, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32732828

RESUMO

BACKGROUND: Lack of support for self-management may contribute to adverse health outcomes. eHealth has the potential to support self-management, but evidence in solid organ transplantation remains unclear. This review aims to evaluate the benefits and harms of eHealth interventions to support self-management in solid organ transplant recipients. METHODS: We searched Cochrane Central Register of Controlled Trials, MEDLINE, and Embase databases for randomized trials of eHealth interventions in solid organ transplant recipients. We calculated the risk ratios or standardized mean difference of outcomes, and summary estimates were determined using random-effects models. The Cochrane risk of bias tool and Grading of Recommendations, Assessment, Development, and Evaluations were used to assess trial quality. RESULTS: Twenty-one trials from 6 countries involving 2114 participants were included. Compared with standard care, eHealth interventions improved medication adherence (risk ratio, 1.34; CI, 1.12-2.56; I = 75%) and self-monitoring behavior (risk ratio, 2.58; CI, 1.56-4.27; I = 0%) up to 12 mo posttransplant. The treatment effects were largely consistent across different subgroups except for intervention functionality and mode of delivery. The effects on other outcomes were uncertain. Nine trials reported harms. The overall risk of bias was considered high or unclear, and the quality of evidence was low to very low for all outcomes. CONCLUSIONS: eHealth interventions may improve medication adherence and self-monitoring behavior in the short term, but high-quality intervention studies are needed to determine whether eHealth will improve long-term patient-relevant outcomes.


Assuntos
Rejeição de Enxerto/prevenção & controle , Transplante de Órgãos/efeitos adversos , Autogestão/métodos , Telemedicina/métodos , Transplantados , Rejeição de Enxerto/imunologia , Humanos , Imunossupressores/uso terapêutico , Adesão à Medicação/estatística & dados numéricos , Educação de Pacientes como Assunto/métodos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Sistemas de Alerta , Resultado do Tratamento
4.
Transplantation ; 104(8): 1537-1541, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32732829

RESUMO

This historical retrospective explores the study of the freemartin condition and its impact on the discovery of immunologic tolerance and the field of transplant surgery-from the ancient Romans, to early modern anatomists Valsalva, Scarpa, and Hunter, to contemporary immunologists Owen, Medawar, and Billingham, and to legendary transplant surgeon Joseph Murray. The legacy of freemartin cattle in the understanding of acquired tolerance and transplant immunology represents generations of scientific inquiry guided by careful observation and occasional serendipity, and the present-day immunologists and surgeons exploring immune transplant tolerance owe much to the history of the freemartin, several millennia in the making.


Assuntos
Rejeição de Enxerto/imunologia , Infertilidade Feminina/veterinária , Transplante de Órgãos/história , Transplante de Tecidos/história , Tolerância ao Transplante , Animais , Pesquisa Biomédica/história , Bovinos/imunologia , Feminino , Rejeição de Enxerto/prevenção & controle , História do Século XVII , História do Século XVIII , História do Século XIX , História do Século XX , História do Século XXI , História Antiga , Humanos , Infertilidade Feminina/imunologia , Transplante de Órgãos/efeitos adversos , Transplante de Tecidos/efeitos adversos
5.
Transplantation ; 104(8): 1560-1565, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32732832

RESUMO

The 25th Annual Congress of the International Liver Transplantation Society was held in Toronto, Canada, from May 15 to 18, 2019. Surgeons, hepatologists, anesthesiologists, critical care intensivists, radiologists, pathologists, and research scientists from all over the world came together with the common aim of improving care and outcomes for liver transplant recipients and living donors. Some of the featured topics at this year's conference included multidisciplinary perioperative care in liver transplantation, worldwide approaches to organ allocation, donor steatosis, and updates in pediatrics, immunology, and radiology. This report presents excerpts and highlights from invited lectures and select abstracts, reviewed and compiled by the Vanguard Committee of International Liver Transplantation Society. This will hopefully contribute to further advances in clinical practice and research in liver transplantation.


Assuntos
Congressos como Assunto , Seleção do Doador/organização & administração , Transplante de Fígado , Assistência Perioperatória/métodos , Sociedades Médicas/organização & administração , Adulto , Fatores Etários , Canadá , Criança , Cuidados Críticos/métodos , Cuidados Críticos/organização & administração , Seleção do Doador/métodos , Doença Hepática Terminal/cirurgia , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Hepatectomia/efeitos adversos , Humanos , Imunossupressão/efeitos adversos , Imunossupressão/métodos , Cooperação Internacional , Doadores Vivos , Preservação de Órgãos/instrumentação , Preservação de Órgãos/métodos , Segurança do Paciente , Seleção de Pacientes , Perfusão/instrumentação , Perfusão/métodos , Melhoria de Qualidade , Alocação de Recursos/organização & administração , Resultado do Tratamento
6.
Transplantation ; 104(8): 1566-1573, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32732833

RESUMO

BACKGROUND: Xenogeneic organ transplantation has been proposed as a potential approach to fundamentally solve organ shortage problem. Xenogeneic immune responses across species is one of the major obstacles for clinic application of xeno-organ transplantation. The generation of glycoprotein galactosyltransferase α 1, 3 (GGTA1) knockout pigs has greatly contributed to the reduction of hyperacute xenograft rejection. However, severe xenograft rejection can still be induced by xenoimmune responses to the porcine major histocompatibility complex antigens swine leukocyte antigen class I and class II. METHODS: We simultaneously depleted GGTA1, ß2-microglobulin (ß2M), and major histocompatibility complex class II transactivator (CIITA) genes using clustered regularly interspaced short palindromic repeats and CRISPR-associated proteins technology in Bamma pig fibroblast cells, which were further used to generate GGTA1ß2MCIITA triple knockout (GBC-3KO) pigs by nuclear transfer. RESULTS: The genotype of GBC-3KO pigs was confirmed by polymerase chain reaction and Sanger sequencing, and the loss of expression of α-1,3-galactose, SLA-I, and SLA-II was demonstrated by flow cytometric analysis using fluorescent-conjugated lectin from bandeiraea simplicifolia, anti-ß2-microglobulin, and swine leukocyte antigen class II DR antibodies. Furthermore, mixed lymphocyte reaction assay revealed that peripheral blood mononuclear cells from GBC-3KO pigs were significantly less effective than (WT) pig peripheral blood mononuclear cells in inducing human CD3CD4 and CD3CD8 T-cell activation and proliferation. In addition, GBC-3KO pig skin grafts showed a significantly prolonged survival in immunocompetent C57BL/6 mice, when compared with wild-type pig skin grafts. CONCLUSIONS: Taken together, these results demonstrate that elimination of GGTA1, ß2M, and CIITA genes in pigs can effectively alleviate xenogeneic immune responses and prolong pig organ survival in xenogenesis. We believe that this work will facilitate future research in xenotransplantation.


Assuntos
Rejeição de Enxerto/prevenção & controle , Xenoenxertos/imunologia , Transplante de Órgãos/métodos , Transplante Heterólogo/métodos , Aloenxertos/provisão & distribução , Animais , Animais Geneticamente Modificados/imunologia , Sistemas CRISPR-Cas/genética , Modelos Animais de Doenças , Feminino , Galactosiltransferases/genética , Galactosiltransferases/imunologia , Técnicas de Inativação de Genes/métodos , Genes MHC da Classe II/genética , Genes MHC da Classe II/imunologia , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/genética , Sobrevivência de Enxerto/imunologia , Xenoenxertos/transplante , Humanos , Masculino , Camundongos , Transplante de Órgãos/efeitos adversos , Suínos/genética , Suínos/imunologia , Transplante Heterólogo/efeitos adversos , Microglobulina beta-2/genética , Microglobulina beta-2/imunologia
7.
Transplantation ; 104(8): 1580-1590, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32732835

RESUMO

BACKGROUND: Although short-term outcomes for liver transplantation have improved, patient and graft survival are limited by infection, cancer, and other complications of immunosuppression. Rapid induction of tolerance after liver transplantation would decrease these complications, improving survival and quality of life. Tolerance to kidneys, but not thoracic organs or islets, has been achieved in nonhuman primates and humans through the induction of transient donor chimerism. Since the liver is considered to be tolerogenic, we tested the hypothesis that the renal transplant transient chimerism protocol would induce liver tolerance. METHODS: Seven cynomolgus macaques received immune conditioning followed by simultaneous donor bone marrow and liver transplantation. The more extensive liver surgery required minor adaptations of the kidney protocol to decrease complications. All immunosuppression was discontinued on postoperative day (POD) 28. Peripheral blood chimerism, recipient immune reconstitution, liver function tests, and graft survival were determined. RESULTS: The level and duration of chimerism in liver recipients were comparable to those previously reported in renal transplant recipients. However, unlike in the kidney model, the liver was rejected soon after immunosuppression withdrawal. Rejection was associated with proliferation of recipient CD8 T effector cells in the periphery and liver, increased serum interleukin (IL)-6 and IL-2, but peripheral regulatory T cell (Treg) numbers did not increase. Antidonor antibody was also detected. CONCLUSIONS: These data show the transient chimerism protocol does not induce tolerance to livers, likely due to greater CD8 T cell responses than in the kidney model. Successful tolerance induction may depend on greater control or deletion of CD8 T cells in this model.


Assuntos
Transplante de Medula Óssea/efeitos adversos , Rejeição de Enxerto/prevenção & controle , Transplante de Fígado/efeitos adversos , Quimeras de Transplante/imunologia , Condicionamento Pré-Transplante/métodos , Aloenxertos/imunologia , Animais , Medula Óssea/imunologia , Transplante de Medula Óssea/métodos , Modelos Animais de Doenças , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Humanos , Fígado/imunologia , Transplante de Fígado/métodos , Macaca fascicularis , Linfócitos T Citotóxicos/imunologia , Tolerância ao Transplante , Transplante Homólogo/efeitos adversos
8.
Transplantation ; 104(8): 1591-1603, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32732836

RESUMO

BACKGROUND: Combined liver-kidney transplantation (CLKT) improves survival for liver transplant recipients with renal dysfunction; however, the tenuous perioperative hemodynamic and metabolic milieu in high-acuity CLKT recipients increases delayed graft function and kidney allograft failure. We sought to analyze whether delayed KT through pumping would improve kidney outcomes following CLKT. METHODS: A retrospective analysis (University of California Los Angeles [n = 145], Houston Methodist Hospital [n = 79]) was performed in all adults receiving CLKT at 2 high-volume transplant centers from February 2004 to January 2017, and recipients were analyzed for patient and allograft survival as well as renal outcomes following CLKT. RESULTS: A total of 63 patients (28.1%) underwent delayed implantation of pumped kidneys during CLKT (dCLKT) and 161 patients (71.9%) received early implantation of nonpumped kidneys during CLKT (eCLKT). Most recipients were high-acuity with median biologic model of end-stage liver disease (MELD) score of, 35 for dCLKT and 34 for eCLKT (P = ns). Pretransplant, dCLKT had longer intensive care unit stay, were more often intubated, and had greater vasopressor use. Despite this, dCLKT exhibited improved 1-, 3-, and 5-year patient and kidney survival (P = 0.02) and decreased length of stay (P = 0.001), kidney allograft failure (P = 0.012), and dialysis duration (P = 0.031). This reduced kidney allograft futility (death or continued need for hemodialysis within 3 mo posttransplant) for dCLKT (6.3%) compared with eCLKT (19.9%) (P = 0.013). CONCLUSIONS: Delayed implantation of pumped kidneys is associated with improved patient and renal allograft survival and decreased hospital length of stay despite longer kidney cold ischemia. These data should inform the ethical debate as to the futility of performing CLKT in high-acuity recipients.


Assuntos
Doença Hepática Terminal/cirurgia , Rejeição de Enxerto/epidemiologia , Transplante de Rim/efeitos adversos , Transplante de Fígado/efeitos adversos , Preservação de Órgãos/métodos , Idoso , Aloenxertos/imunologia , Aloenxertos/provisão & distribução , Isquemia Fria/instrumentação , Isquemia Fria/métodos , Isquemia Fria/estatística & dados numéricos , Doença Hepática Terminal/complicações , Estudos de Viabilidade , Feminino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/imunologia , Humanos , Rim/imunologia , Transplante de Rim/ética , Transplante de Rim/métodos , Transplante de Rim/estatística & dados numéricos , Transplante de Fígado/ética , Transplante de Fígado/métodos , Transplante de Fígado/estatística & dados numéricos , Masculino , Futilidade Médica/ética , Pessoa de Meia-Idade , Preservação de Órgãos/instrumentação , Preservação de Órgãos/estatística & dados numéricos , Perfusão/instrumentação , Perfusão/métodos , Perfusão/estatística & dados numéricos , Insuficiência Renal/etiologia , Insuficiência Renal/cirurgia , Estudos Retrospectivos , Fatores de Tempo , Tempo para o Tratamento/estatística & dados numéricos , Transplante Homólogo/efeitos adversos , Transplante Homólogo/ética , Transplante Homólogo/métodos , Resultado do Tratamento
9.
Transplantation ; 104(8): 1633-1643, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32732841

RESUMO

BACKGROUND: The cellular infiltrate in protocol liver biopsies (PB) following pediatric liver transplantation remains mostly uncharacterized, yet there is increasing concern about the role of inflammation and fibrosis in long-term liver allografts. We aimed to define cell types in PB and to analyze their relationship with donor-specific antibodies (DSA) and histological phenotype. METHODS: PB were performed at least 1 year after transplantation. We identified 4 phenotypes: normal, fibrosis, inflammation, inflammation with fibrosis. Cell types were counted after immunostaining for CD3, CD4, CD8, CD68, CD20, MUM1, and FoxP3. RESULTS: Forty-four patients underwent 1 PB between 2000 and 2015. Eleven percent (5/44) of PB displayed normal histology, 13.6% (6/44) fibrosis, 34.1% (15/44) inflammation, and 40.9% (18/44) inflammation and fibrosis. The main cell types in the portal tracts and lobules were CD3+ and CD68+ cells. Frequency of de novo DSA was 63% (27/44). The presence of CD8+ cells in the lobules was associated with fibrosis. Inflammation and fibrosis in PB were associated with the presence of circulating de novo DSA, number of de novo DSA, and C1q binding activity when compared to other phenotypes. CONCLUSIONS: T cells (CD3+) and macrophages (CD68+) were the most prevalent cell-types in PB. In the presence of inflammation, portal tracts were enriched in CD3+, CD20+ but displayed fewer CD68+. This coincided with the presence and number of de novo DSA. How these cellular and humoral actors interact is unclear, but peripheral DSA may be a marker of immune cellular activity in the seemingly quiescent allograft.


Assuntos
Doença Hepática Terminal/cirurgia , Rejeição de Enxerto/imunologia , Isoanticorpos/imunologia , Transplante de Fígado/efeitos adversos , Sistema Porta/imunologia , Adolescente , Adulto , Aloenxertos/irrigação sanguínea , Aloenxertos/imunologia , Aloenxertos/patologia , Biópsia , Criança , Pré-Escolar , Doença Hepática Terminal/diagnóstico , Doença Hepática Terminal/etiologia , Feminino , Fibrose , Seguimentos , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto/imunologia , Antígenos HLA/imunologia , Teste de Histocompatibilidade/estatística & dados numéricos , Humanos , Imunidade Celular , Lactente , Isoanticorpos/análise , Fígado/irrigação sanguínea , Fígado/imunologia , Fígado/patologia , Doadores Vivos/estatística & dados numéricos , Macrófagos/imunologia , Masculino , Sistema Porta/citologia , Índice de Gravidade de Doença , Linfócitos T/imunologia , Transplantados/estatística & dados numéricos , Transplante Homólogo/efeitos adversos , Adulto Jovem
10.
Transplantation ; 104(8): 1686-1694, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32732848

RESUMO

BACKGROUND: It is commonly believed that mTOR inhibitors (mTORi) should not be used in high-immunological risk kidney transplant recipients due to a perceived increased risk of rejection. However, almost all trials that examined the association of optimal-dose mTORi with calcineurin inhibitor (CNI) have excluded hypersensitized recipients from enrollment. METHODS: To shed light on this issue, we examined 71 consecutive patients with a baseline calculated panel reactive antibody (cPRA) ≥50% that underwent kidney transplantation from June 2013 to December 2016 in our unit. Immunosuppression was based on CNI (tacrolimus), steroids and alternatively mycophenolic acid (MPA; n = 38), or mTORi (either everolimus or sirolimus, n = 33, target trough levels 3-8 ng/mL). RESULTS: Demographic and immunological risk profiles were similar, and almost 90% of patients in both groups received induction with lymphocyte-depleting agents. Cox-regression analysis of rejection-free survival revealed better results for mTORi versus MPA in terms of biopsy-proven acute rejection (hazard ratio [confidence interval], 0.32 [0.11-0.90], P = 0.031 at univariable analysis and 0.34 [0.11-0.95], P = 0.040 at multivariable analysis). There were no differences in 1-year renal function, Banff chronicity score at 3- and 12-month protocol biopsy and development of de novo donor-specific antibodies. Tacrolimus trough levels along the first year were not different between groups (12-mo levels were 8.72 ± 2.93 and 7.85 ± 3.07 ng/mL for MPA and mTORi group respectively, P = 0.277). CONCLUSIONS: This single-center retrospective cohort analysis suggests that in hypersensitized kidney transplant recipients receiving tacrolimus-based immunosuppressive therapy similar clinical outcomes may be obtained using mTOR inhibitors compared to mycophenolate.


Assuntos
Dessensibilização Imunológica/métodos , Rejeição de Enxerto/prevenção & controle , Imunossupressores/administração & dosagem , Transplante de Rim/efeitos adversos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adulto , Idoso , Inibidores de Calcineurina/administração & dosagem , Inibidores de Calcineurina/efeitos adversos , Dessensibilização Imunológica/efeitos adversos , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Everolimo/administração & dosagem , Everolimo/efeitos adversos , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Rejeição de Enxerto/imunologia , Antígenos HLA/imunologia , Humanos , Imunossupressores/efeitos adversos , Isoanticorpos/imunologia , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/efeitos adversos , Estudos Retrospectivos , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Serina-Treonina Quinases TOR/imunologia , Tacrolimo/administração & dosagem , Tacrolimo/efeitos adversos , Resultado do Tratamento
11.
Transplantation ; 104(8): 1703-1711, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32732850

RESUMO

BACKGROUND: There are limited data on the outcome of transplant recipients with familial Mediterranean fever (FMF)-associated AA amyloidosis. The aim of the present study is to evaluate demographic, clinical, laboratory, and prognostic characteristics and outcome measures of these patients. METHODS: Eighty-one renal transplant recipients with FMF-associated AA amyloidosis (group 1) and propensity score-matched transplant recipients (group 2, n = 81) with nonamyloidosis etiologies were evaluated in this retrospective, multicenter study. Recurrence of AA amyloidosis was diagnosed in 21 patients (group 1a), and their features were compared with 21 propensity score-matched recipients with FMF amyloidosis with no laboratory signs of recurrence (group 1b). RESULTS: The risk of overall allograft loss was higher in group 1 compared with group 2 (25 [30.9%] versus 12 [14.8%]; P = 0.015 [hazard ratio, 2.083; 95% confidence interval, 1.126-3.856]). Patients in group 1 were characterized by an increased risk of mortality compared with group 2 (11 [13.6%] versus 0%; P = 0.001 [hazard ratio, 1.136; 95% confidence interval, 1.058-1.207]). Kaplan-Meier analysis revealed that 5- and 10-year patient survival rates in group 1 (92.5% and 70.4%) were significantly lower than in group 2 (100% and 100%; P = 0.026 and P = 0.023, respectively). Although not reaching significance, overall, 5- and 10-year graft survival rates (57.1%, 94.7%, and 53.8%, respectively) in group 1a were worse than in group 1b (76.2%, 95%, and 77.8%, respectively; P = 0.19, P = 0.95, and P = 0.27, respectively). CONCLUSIONS: AA amyloidosis is associated with higher risk of mortality after kidney transplantation. Inflammatory indicators should be monitored closely, and persistent high levels of acute-phase reactants should raise concerns about amyloid recurrence in allograft.


Assuntos
Amiloidose/cirurgia , Febre Familiar do Mediterrâneo/complicações , Rejeição de Enxerto/mortalidade , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Adulto , Aloenxertos/imunologia , Aloenxertos/patologia , Amiloidose/imunologia , Amiloidose/mortalidade , Amiloidose/patologia , Biópsia , Febre Familiar do Mediterrâneo/imunologia , Febre Familiar do Mediterrâneo/mortalidade , Febre Familiar do Mediterrâneo/cirurgia , Feminino , Seguimentos , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto/imunologia , Humanos , Estimativa de Kaplan-Meier , Rim/imunologia , Rim/patologia , Falência Renal Crônica/imunologia , Falência Renal Crônica/mortalidade , Falência Renal Crônica/patologia , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Proteína Amiloide A Sérica/imunologia , Proteína Amiloide A Sérica/metabolismo , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem
12.
Transplantation ; 104(8): 1726-1737, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32732853

RESUMO

BACKGROUND: De novo donor-specific antibodies (DSAs) are associated with antibody-mediated rejection (AMR) and allograft loss. Whether monitoring of de novo DSA (dnDSA) paired with systematic kidney biopsy should become routine remains to be established. METHODS: A retrospective multicentric study (9 French kidney transplant units of the Spiesser group) included patients without graft dysfunction biopsied because of the presence of dnDSA (One Lambda, mean fluorescence intensity [MFI], >1000). RESULTS: One hundred twenty-three patients (85 male/38 female; mean age, 49.5 ± 13.1 y old) were biopsied after the detection of a dnDSA, 65.3 months (median) after kidney transplantation. Graft function was stable within 3 months before biopsy (estimated glomerular filtration rate, 55.3 ± 18.9 mL/min/1.73 m). Fifty-one subclinical AMRs (sAMRs) (41.4%) were diagnosed, of which 32 (26%) active and 19 (15.5%) chronic active sAMR. Seventy-two biopsies revealed no AMR (58.5%). Predictive factors associated with the diagnosis of active sAMR were MFI of immunodominant DSA >4000, MFI of the sum of DSA >6300, age of the recipient <45 years old, and the absence of steroids at biopsy. The presence of proteinuria >200 mg/g was predictive of chronic active sAMR. The decrease of estimated glomerular filtration rate at 5 years post-biopsy was significantly higher in patients with acute sAMR (-25.2 ± 28.3 mL/min/1.73 m) and graft survival significantly lower. CONCLUSIONS: Performing a kidney graft biopsy for the occurrence of dnDSA without renal dysfunction leads to the diagnosis of a sAMR in over 40% of cases. Nevertheless, we did not observe any effect of standard treatment in acute sAMR.


Assuntos
Protocolos Clínicos , Rejeição de Enxerto/diagnóstico , Isoanticorpos/sangue , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Adulto , Aloenxertos , Biópsia , Feminino , Seguimentos , Rejeição de Enxerto/sangue , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/terapia , Sobrevivência de Enxerto/imunologia , Antígenos HLA/imunologia , Teste de Histocompatibilidade/normas , Humanos , Imunossupressores/uso terapêutico , Isoanticorpos/imunologia , Rim , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante Homólogo/efeitos adversos , Resultado do Tratamento
13.
Science ; 369(6503)2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32732394

RESUMO

The lymphoid system is intimately involved in immunological processes. The small lymphocyte that circulates through blood into lymphoid tissues, then through the lymph and back to the blood through the thoracic duct, is able to initiate immune responses after appropriate stimulation by antigen. However, the lymphocytes found in the thymus are deficient in this ability despite the fact that the thymus plays a central role in lymphocyte production and in ensuring the normal development of immunological faculty. During embryogenesis, lymphocytes are present in the thymus before they can be identified in the circulation and in other lymphoid tissues. They become "educated" in the thymus to recognize a great diversity of peptide antigens bound to the body's own marker antigen, the major histocompatibility complex, but they are purged if they strongly react against their own self-components. Lymphocytes differentiate to become various T cell subsets and then exit through the bloodstream to populate certain areas of the lymphoid system as peripheral T lymphocytes with distinct markers and immune functions.


Assuntos
Imunoterapia , Subpopulações de Linfócitos T/imunologia , Timo/imunologia , Animais , Linfócitos B/imunologia , Diferenciação Celular , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Humanos , Linfoma/imunologia , Linfoma/terapia , Camundongos , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/terapia , Transplante de Pele , Subpopulações de Linfócitos T/citologia , Timo/citologia
14.
PLoS One ; 15(8): e0234396, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32756556

RESUMO

INTRODUCTION: Early conversion to a CNI-free immunosuppression with SRL was associated with an improved 1- and 3- yr renal function as compared with a CsA-based regimen in the SMART-Trial. Mixed results were reported on the occurrence of donor specific antibodies under mTOR-Is. Here, we present long-term results of the SMART-Trial. METHODS AND MATERIALS: N = 71 from 6 centers (n = 38 SRL and n = 33 CsA) of the original SMART-Trial (ITT n = 140) were enrolled in this observational, non-interventional extension study to collect retrospectively and prospectively follow-up data for the interval since baseline. Primary objective was the development of dnDSA. Blood samples were collected on average 8.7 years after transplantation. RESULTS: Development of dnDSA was not different (SRL 5/38, 13.2% vs. CsA 9/33, 27.3%; P = 0.097). GFR remained improved under SRL with 64.37 ml/min/1.73m2 vs. 53.19 ml/min/1.73m2 (p = 0.044). Patient survival did not differ between groups at 10 years. There was a trend towards a reduced graft failure rate (11.6% SRL vs. 23.9% CsA, p = 0.064) and less tumors under SRL (2.6% SRL vs. 15.2% CsA, p = 0.09). CONCLUSIONS: An early conversion to SRL did not result in an increased incidence of dnDSA nor increased long-term risk for the recipient. Transplant function remains improved with benefits for the graft survival.


Assuntos
Inibidores de Calcineurina/administração & dosagem , Imunossupressão/métodos , Imunossupressores/administração & dosagem , Transplante de Rim , Sirolimo/administração & dosagem , Adulto , Especificidade de Anticorpos , Esquema de Medicação , Feminino , Seguimentos , Taxa de Filtração Glomerular , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Humanos , Estimativa de Kaplan-Meier , Transplante de Rim/efeitos adversos , Transplante de Rim/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Serina-Treonina Quinases TOR/antagonistas & inibidores , Fatores de Tempo , Doadores de Tecidos
15.
Emerg Top Life Sci ; 4(2): 207-227, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32691841

RESUMO

Human pregnancy, critical for our species survival, is inefficient and prone to complications such as infertility, spontaneous miscarriages and preeclampsia (PE). Immunological factors may be important as the embryo is 50% paternal and foreign to the mother. Mouse pregnancy models, and in particular the murine CBA/J x DBA/2 mating combination, has been widely used to investigate mechanisms causing and preventing partner-specific recurrent miscarriages (RM) and PE. Occult losses can represent T cell-mediated rejection, and antigen-specific regulatory T cells (Tregs) with classical αß T cell receptors (TcR) activated by semen antigens at the time of mating are protective. If there is no occult loss, an inadequate Treg response can also predispose to RM. In RM, proinflammatory cytokines from natural killer (NK)-type cells and macrophages of the innate immune system are responsible and cells with γδ TcR protect via release of TGF-ß-type molecules. Immunization of abortion-prone female CBA/J mice or administration of cell-associated or soluble CD200, an immune check point inhibitor, can prevent abortions by augmenting uterine decidual suppressor cell activity. Human studies suggest that is also true in couples with RM. Environmental activators of the innate immune system, such as bacterial LPS and stress, can cause abortions as well as occult losses. The endogenous level of Tregs and activation of Tregs specific for the male H-Y antigen may determine success rates and alter the male:female birth ratio. Intralipid alters LPS clearance, prevents abortions in the CBAxDBA/2 model, and is effective in increasing live birth rates in couples undergoing IVF treatment.


Assuntos
Aborto Habitual/imunologia , Modelos Animais de Doenças , Eclampsia/imunologia , Infertilidade/imunologia , Aborto Habitual/prevenção & controle , Aborto Habitual/terapia , Animais , Antígenos CD/metabolismo , Citocinas/metabolismo , Eclampsia/prevenção & controle , Eclampsia/terapia , Implantação do Embrião , Feminino , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Humanos , Infertilidade/prevenção & controle , Infertilidade/terapia , Células Matadoras Naturais/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos CBA , Camundongos Endogâmicos DBA , Gravidez , Complicações na Gravidez , Resultado da Gravidez , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Razão de Masculinidade , Linfócitos T Reguladores/metabolismo
16.
Nat Rev Nephrol ; 16(9): 509-524, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32641760

RESUMO

ATP and its ultimate degradation product adenosine are potent extracellular signalling molecules that elicit a variety of pathophysiological functions in the kidney through the activation of P2 and P1 purinergic receptors, respectively. Extracellular purines can modulate immune responses, balancing inflammatory processes and immunosuppression; indeed, alterations in extracellular nucleotide and adenosine signalling determine outcomes of inflammation and healing processes. The functional activities of ectonucleotidases such as CD39 and CD73, which hydrolyse pro-inflammatory ATP to generate immunosuppressive adenosine, are therefore pivotal in acute inflammation. Protracted inflammation may result in aberrant adenosinergic signalling, which serves to sustain inflammasome activation and worsen fibrotic reactions. Alterations in the expression of ectonucleotidases on various immune cells, such as regulatory T cells and macrophages, as well as components of the renal vasculature, control purinergic receptor-mediated effects on target tissues within the kidney. The role of CD39 as a rheostat that can have an impact on purinergic signalling in both acute and chronic inflammation is increasingly supported by the literature, as detailed in this Review. Better understanding of these purinergic processes and development of novel drugs targeting these pathways could lead to effective therapies for the management of acute and chronic kidney disease.


Assuntos
Trifosfato de Adenosina/imunologia , Adenosina/imunologia , Tolerância Imunológica/imunologia , Inflamação/imunologia , Nefropatias/imunologia , Receptores Purinérgicos P1/imunologia , Receptores Purinérgicos P2/imunologia , 5'-Nucleotidase/metabolismo , Lesão Renal Aguda/imunologia , Lesão Renal Aguda/metabolismo , Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Antígenos CD/metabolismo , Apirase/metabolismo , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/metabolismo , Nefropatias Diabéticas/imunologia , Nefropatias Diabéticas/metabolismo , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/metabolismo , Humanos , Nefropatias/metabolismo , Neoplasias Renais/imunologia , Neoplasias Renais/metabolismo , Transplante de Rim , Macrófagos/imunologia , Macrófagos/metabolismo , Doenças Renais Policísticas/imunologia , Doenças Renais Policísticas/metabolismo , Receptores Purinérgicos P1/metabolismo , Receptores Purinérgicos P2/metabolismo , Insuficiência Renal Crônica/imunologia , Insuficiência Renal Crônica/metabolismo , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
17.
Mol Immunol ; 125: 140-150, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32682148

RESUMO

Successful transplantation outcome is the final goal in most end stage and nonfunctional organs; however, despite using different therapeutic strategies, antibody-mediated rejection is still a big obstacle. B cells have a key role in transplant rejection by several functions, such as antibody production, antigen presenting, contribution in T cell activation, forming the germinal center, and tertiary lymphoid organs. Therefore, B cells modulation seems to be very crucial in transplant outcome. A double-edged sword function is considered for B cells during transplantation; On the one hand, antibody production against the transplanted organ induces antibody-mediated rejection. On the other hand, IL10 production by regulatory B (Breg) cells induces graft tolerance. Nowadays, several monoclonal antibodies (mAb) are available for B cell modulation that are routinely used in transplant recipients, among which rituximab (anti-CD20 mAb) act in eliminating B cells. However, there are some other monoclonal antibodies, such as epratuzumab and Inotuzumab ozogamicin (IO), which exert anti-CD22 activity, resulting in disruption of B cell functions and induction of tolerance in autoimmune disease or B cell malignancies; that notwithstanding, these mAbs have not yet been tried in transplantation. In this review, we focus on different methods for modulating the activity of B cells as well as induction of Breg cells, aiming to prevent the allograft rejection.


Assuntos
Anticorpos Monoclonais/farmacologia , Linfócitos B/efeitos dos fármacos , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Tolerância ao Transplante/efeitos dos fármacos , Tolerância ao Transplante/imunologia , Animais , Linfócitos B/imunologia , Humanos , Transplante Homólogo
18.
Scand J Immunol ; 92(5): e12923, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32593197

RESUMO

Antibody-mediated rejections (AMR) in the absence of circulating anti-HLA-DSA have highlighted the role of non-HLA antibodies, particularly those directed against endothelial cells. Of these, MICA (major histocompatibility complex class I chain-related molecule A) antibodies are the most notable and important because of their potential in promoting graft rejections. Limited studies have focused on the impact of MICA donor-specific antibodies (DSA) on graft outcome as compared to those that are not donor-specific (NDSA). We evaluated pre- and post-transplant sera at POD 7, 30, 90, 180 and the time of biopsy from 206 consecutive primary live donor renal transplant recipients for anti-MICA and anti-HLA antibodies using single antigen bead assay on a Luminex platform. Recipients who developed MICA antibodies and their donors were phenotyped for MICA alleles. For the purpose of antibody analysis, patients were categorized into three major groups: biopsy-proven AMR, acute cellular rejection (ACR) and those with no rejection episodes (NRE). During the mean follow-up period of 17.37 ± 6.88 months, 16 of the 206 recipients developed AMR, while ACR was observed in only 13 cases. A quarter (25%) of the AMR cases had anti-MICA antibodies as compared to 7.7% of those experiencing ACR and 6.2% of the NRE group. Allelic typing revealed that all MICA Ab +ve AMR cases were due to the presence of donor-specific antibodies. MICA-DSA even in the absence of HLA-DSA was significantly associated with AMR but not with ACR when compared with the NRE group (P = <.01).


Assuntos
Anticorpos/imunologia , Antígenos HLA/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Transplante de Rim/métodos , Doadores Vivos/estatística & dados numéricos , Adulto , Alelos , Anticorpos/sangue , Células Endoteliais/imunologia , Feminino , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Antígenos HLA/genética , Antígenos de Histocompatibilidade Classe I/genética , Teste de Histocompatibilidade , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Transplante Homólogo , Adulto Jovem
19.
Cell Immunol ; 354: 104131, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32563029

RESUMO

Non-HLA antibody responses following solid organ transplantation have become increasingly emphasised, with several large clinical series suggesting that such responses contribute to late graft failure. Many of the responses described recognise both recipient and donor moieties of the target antigen and thus represent auto-, rather than allo-immunity. Within this rapidly evolving field, many questions remain unanswered: what triggers the response; how innate and adaptive humoral autoimmunity integrate; and most pressingly, how autoimmunity contributes to graft damage and its relationship to other effector mechanisms of graft rejection. This review summarises recent clinical and experimental studies of humoral autoimmunity in transplant rejection, and considers some of the answers to these questions.


Assuntos
Autoanticorpos/imunologia , Autoimunidade , Rejeição de Enxerto/imunologia , Imunidade Humoral , Transplante de Órgãos , Imunidade Adaptativa , Animais , Autoantígenos/imunologia , Humanos , Imunidade Inata , Transplante Homólogo
20.
J Plast Reconstr Aesthet Surg ; 73(9): 1593-1603, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32475735

RESUMO

INTRODUCTION: Vascularised composite allotransplantation (VCA) permits like-for-like reconstruction following extensive soft tissue injuries. The initial management of extensive soft tissue injury can lead to the development of anti-HLA antibodies through injury-related factors, transfusion and cadaveric grafting. The role of antibody-mediated rejection, donor-specific antibody formation and graft rejection in the context of VCA remains unclear. This systematic review aimed to determine whether pre-transplant management strategies influence immunological outcome following VCA. METHODS: A systematic review of MEDLINE, EMBASE and CINAHL using a PRISMA-compliant methodology up to February 2019 was conducted. Pre-transplant, procedural and long-term outcome data were collected and recorded for all VCA recipients on an individual patient basis. RESULTS: The search revealed 3,847 records of which 114 met inclusion criteria and reported clinical data related to 100 patients who underwent 129 VCA transplants. Trauma (50%) and burns (15%) were the most frequent indications for VCA. Of all 114 studies, only one reported acute resuscitative management. Fifteen patients were sensitised prior to reconstructive transplantation with an 80%%incidence of acute rejection in the first post-operative year. Seven patients demonstrated graft vasculopathy, only one of whom had demonstrated panel reactive antibodies. CONCLUSIONS: Currently employed acute management strategies may predispose to the development of anti-HLA antibodies, adding to the already complex immunological challenge of VCA. To determine whether association between pre-transplant management and outcomes exists, further refinement of international registries is required.


Assuntos
Antígenos HLA/imunologia , Alotransplante de Tecidos Compostos Vascularizados , Queimaduras/cirurgia , Rejeição de Enxerto/imunologia , Humanos , Tolerância Imunológica , Lesões dos Tecidos Moles/cirurgia , Infecção da Ferida Cirúrgica/etiologia
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