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1.
Kidney Int Rep ; 5(11): 1906-1913, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33163711

RESUMO

INTRODUCTION: The factors that influence deceased donor kidney procurement biopsy reliability are not well established. We examined the impact of biopsy technique and pathologist training on procurement biopsy accuracy. METHODS: We retrospectively identified all deceased donor kidney-only transplants at our center from 2006 to 2016 with both procurement and reperfusion biopsies performed and information available on procurement biopsy technique and pathologist (n = 392). Biopsies were scored using a previously validated system, classifying "suboptimal" histology as the presence of at least 1 of the following: glomerulosclerosis ≥11%, moderate/severe interstitial fibrosis/tubular atrophy, or moderate/severe vascular disease. We calculated relative risk ratios (RRR) to determine the influence of technique (core vs. wedge) and pathologist (renal vs. nonrenal) on concordance between procurement and reperfusion biopsy histologic classification. RESULTS: A total of 171 (44%) procurement biopsies used wedge technique, and 221 (56%) used core technique. Results of only 36 biopsies (9%) were interpreted by renal pathologists. Correlation between procurement and reperfusion glomerulosclerosis was poor for both wedge (r 2 = 0.11) and core (r 2 = 0.14) biopsies. Overall, 34% of kidneys had discordant classification on procurement versus reperfusion biopsy. Neither biopsy technique nor pathologist training was associated with concordance between procurement and reperfusion histology, but a larger number of sampled glomeruli was associated with a higher likelihood of concordance (adjusted RRR = 1.12 per 10 glomeruli, 95% confidence interval = 1.04-1.22). CONCLUSIONS: Biopsy technique and pathologist training were not associated with procurement biopsy histologic accuracy in this retrospective study. Prospective trials are needed to determine how to optimize procurement biopsy practices.

2.
Cell ; 180(4): 749-763.e13, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-32059780

RESUMO

Immune responses in diverse tissue sites are critical for protective immunity and homeostasis. Here, we investigate how tissue localization regulates the development and function of human natural killer (NK) cells, innate lymphocytes important for anti-viral and tumor immunity. Integrating high-dimensional analysis of NK cells from blood, lymphoid organs, and mucosal tissue sites from 60 individuals, we identify tissue-specific patterns of NK cell subset distribution, maturation, and function maintained across age and between individuals. Mature and terminally differentiated NK cells with enhanced effector function predominate in blood, bone marrow, spleen, and lungs and exhibit shared transcriptional programs across sites. By contrast, precursor and immature NK cells with reduced effector capacity populate lymph nodes and intestines and exhibit tissue-resident signatures and site-specific adaptations. Together, our results reveal anatomic control of NK cell development and maintenance as tissue-resident populations, whereas mature, terminally differentiated subsets mediate immunosurveillance through diverse peripheral sites. VIDEO ABSTRACT.


Assuntos
Envelhecimento/imunologia , Células Matadoras Naturais/citologia , Linfopoese , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/genética , Antígenos CD/metabolismo , Células Cultivadas , Criança , Feminino , Humanos , Imunidade Inata , Mucosa Intestinal/citologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/fisiologia , Pulmão/citologia , Linfonodos/citologia , Masculino , Pessoa de Meia-Idade , Baço/citologia
3.
Clin J Am Soc Nephrol ; 15(2): 257-264, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-31974289

RESUMO

BACKGROUND AND OBJECTIVES: Unfavorable histology on procurement biopsies is the most common reason for deceased donor kidney discard. We sought to assess the reproducibility of procurement biopsy findings. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We compiled a continuous cohort of deceased donor kidneys transplanted at our institution from 1/1/2006 to 12/31/2016 that had at least one procurement biopsy performed, and excluded cases with missing biopsy reports and those used in multiorgan transplants. Suboptimal histology was defined as the presence of advanced sclerosis in greater than or equal to one biopsy compartment (glomeruli, tubules/interstitium, vessels). We calculated κ coefficients to assess agreement in optimal versus suboptimal classification between sequential biopsy reports for kidneys that underwent multiple procurement biopsies and used time-to-event analysis to evaluate the association between first versus second biopsies and patient and allograft survival. RESULTS: Of the 1011 kidneys included in our cohort, 606 (60%) had multiple procurement biopsies; 98% had first biopsy performed at another organ procurement organization and their second biopsy performed locally. Categorical agreement was highest for vascular disease (κ=0.17) followed by interstitial fibrosis and tubular atrophy (κ=0.12) and glomerulosclerosis (κ=0.12). Overall histologic agreement (optimal versus suboptimal) was κ=0.15. First biopsy histology had no association with allograft survival in unadjusted or adjusted analyses. However, second biopsy optimal histology was associated with a higher probability of death-censored allograft survival, even after adjusting for donor and recipient factors (adjusted hazard ratio, 0.50; 95% confidence interval, 0.34 to 0.75; P=0.001). CONCLUSIONS: Deceased donor kidneys that underwent multiple procurement biopsies often displayed substantial differences in histologic categorization in sequential biopsies, and there was no association between first biopsy findings and post-transplant outcomes.


Assuntos
Seleção do Doador , Transplante de Rim , Rim/patologia , Doadores de Tecidos , Adulto , Biópsia , Feminino , Sobrevivência de Enxerto , Humanos , Transplante de Rim/efeitos adversos , Transplante de Rim/mortalidade , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fatores de Tempo , Obtenção de Tecidos e Órgãos , Resultado do Tratamento
4.
Cell Rep ; 29(12): 3916-3932.e5, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31851923

RESUMO

Non-recirculating tissue-resident memory T cells (TRMs) are the predominant T cell subset in diverse tissue sites, where they mediate protective immune responses in situ. Here, we reveal a role for TRM in maintaining immune homeostasis in the human pancreas through interactions with resident macrophages and the PD-1/PD-L1 inhibitory pathway. Using tissues obtained from organ donors, we identify that pancreas T cells comprise CD8+PD-1hi TRMs, which are phenotypically, functionally, and transcriptionally distinct compared to TRMs in neighboring jejunum and lymph node sites. Pancreas TRMs cluster with resident macrophages throughout the exocrine areas; TRM effector functions are enhanced by macrophage-derived co-stimulation and attenuated by the PD-1/PD-L1 pathways. Conversely, in samples from chronic pancreatitis, TRMs exhibit reduced PD-1 expression and reduced interactions with macrophages. These findings suggest important roles for PD-1 and TRM-macrophage interactions in controlling tissue homeostasis and immune dysfunctions underlying inflammatory disease, with important implications for PD-1-based immunotherapies.


Assuntos
Antígeno B7-H1/metabolismo , Memória Imunológica/fisiologia , Pâncreas/metabolismo , Pancreatite/imunologia , Pancreatite/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Subpopulações de Linfócitos T/metabolismo , Antígeno B7-H1/genética , Antígenos CD58/metabolismo , Humanos , Imunidade nas Mucosas/genética , Imunidade nas Mucosas/fisiologia , Memória Imunológica/genética , Macrófagos/imunologia , Macrófagos/metabolismo , Pâncreas/imunologia , Pâncreas/patologia , Pancreatite/genética , Receptor de Morte Celular Programada 1/genética , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia
5.
Sci Immunol ; 4(33)2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30850393

RESUMO

Tissue-resident memory T cells (TRM) maintain immunity in diverse sites as determined in mouse models, whereas their establishment and role in human tissues have been difficult to assess. Here, we investigated human lung TRM generation, maintenance, and function in airway samples obtained longitudinally from human leukocyte antigen (HLA)-disparate lung transplant recipients, where donor and recipient T cells could be localized and tracked over time. Donor T cells persist specifically in the lungs (and not blood) of transplant recipients and express high levels of TRM signature markers including CD69, CD103, and CD49a, whereas lung-infiltrating recipient T cells gradually acquire TRM phenotypes over months in vivo. Single-cell transcriptome profiling of airway T cells reveals that donor T cells comprise two TRM-like subsets with varying levels of expression of TRM-associated genes, whereas recipient T cells comprised non-TRM and similar TRM-like subpopulations, suggesting de novo TRM generation. Transplant recipients exhibiting higher frequencies of persisting donor TRM experienced fewer adverse clinical events such as primary graft dysfunction and acute cellular rejection compared with recipients with low donor TRM persistence, suggesting that monitoring TRM dynamics could be clinically informative. Together, our results provide spatial and temporal insights into how human TRM develop, function, persist, and affect tissue integrity within the complexities of lung transplantation.


Assuntos
Memória Imunológica , Transplante de Pulmão , Pulmão/imunologia , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Rejeição de Enxerto , Humanos , Masculino , Pessoa de Meia-Idade , Transcriptoma
6.
Transpl Int ; 32(7): 702-709, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30721545

RESUMO

Most transplant centers decline morbidly obese people for living kidney donation. Their inclusion in the living donor pool after weight loss and reversal of comorbidities by bariatric surgery could reverse the downward living donation trend. We investigated whether bariatric surgery in the morbidly obese altered their candidacy for donation, complicated their subsequent donor nephrectomy, and impacted their early postoperative outcomes in a series of 22 donors who had bariatric surgery 0.7-22 years prior to laparoscopic living donor nephrectomy. Eighteen would have been excluded from donation prior to bariatric surgery based on a body mass index (BMI) > 40. Seventeen reached a BMI < 35 after bariatric surgery. One had hypertension that resolved after bariatric surgery. Prior bariatric surgery did not influence port placement and laterality of donor nephrectomy. None required open conversion or blood transfusion. In an exploratory comparison with 37 donors with a BMI 35-40, length of stay and warm ischemic time were shorter, blood loss and postoperative complications were similar, and operative time was longer. We therefore advocate the consideration of bariatric surgery in preparation for donation in morbidly obese people since it positively alters their candidacy without major impact on the subsequent living donor nephrectomy and early outcomes.


Assuntos
Cirurgia Bariátrica , Seleção do Doador , Transplante de Rim/métodos , Doadores Vivos , Nefrectomia , Obesidade Mórbida/complicações , Obesidade Mórbida/cirurgia , Adulto , Índice de Massa Corporal , Feminino , Humanos , Laparoscopia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Período Pós-Operatório , Período Pré-Operatório , Estudos Retrospectivos , Coleta de Tecidos e Órgãos , Resultado do Tratamento
7.
Transplantation ; 103(7): 1392-1404, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30444802

RESUMO

BACKGROUND: Understanding factors that contribute to liver discards and nonusage is urgently needed to improve organ utilization. METHODS: Using Scientific Registry of Transplant Recipient data, we studied a national cohort of all US adult, deceased brain dead donor, isolated livers available for transplantation from 2003 to 2016, including organ-specific and system-wide factors that may affect organ procurement and discard rates. RESULTS: Of 73 686 available livers, 65 316 (88.64%) were recovered for transplant, of which 6454 (9.88%) were ultimately discarded. Livers that were not procured or, on recovery, discarded were more frequently from older, heavier, hepatitis B virus (HCV)+, and more comorbid donors (P < 0.001). However, even after adjustment for organ quality, the odds of liver nonusage were 11% higher on the weekend (defined as donor procurements with cross-clamping occurring from 5:00 PM Friday until 11:59 AM Sunday) compared with weekdays (P < 0.001). Nonuse rates were also higher at night (P < 0.001), defined as donor procurements with cross-clamping occurring from 5:00 PM to 5:00 AM; however, weekend nights had significantly higher nonuse rates compared with weekday nights (P = 0.005). After Share 35, weekend nonusage rates decreased from 21.77% to 19.51% but were still higher than weekday nonusage rates (P = 0.065). Weekend liver nonusage was higher in all 11 United Network of Organ Sharing regions, with an absolute average of 2.00% fewer available livers being used on the weekend compared with weekdays. CONCLUSIONS: Although unused livers frequently have unfavorable donor characteristics, there are also systemic and operational factors, including time of day and day of the week a liver becomes available, that impact the chance of liver nonprocurement and discard.


Assuntos
Plantão Médico/tendências , Morte Encefálica , Seleção do Doador/tendências , Transplante de Fígado/tendências , Padrões de Prática Médica/tendências , Doadores de Tecidos/provisão & distribuição , Adulto , Idoso , Bases de Dados Factuais , Feminino , Humanos , Transplante de Fígado/efeitos adversos , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Estados Unidos
8.
Mucosal Immunol ; 12(2): 378-389, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30523311

RESUMO

Defining adaptive immunity with the complex structures of the human gastrointestinal (GI) tract over life is essential for understanding immune responses to ingested antigens, commensal and pathogenic microorganisms, and dysfunctions in disease. We present here an analysis of lymphocyte localization and T cell subset composition across the human GI tract including mucosal sites (jejunum, ileum, colon), gut-associated lymphoid tissues (isolated lymphoid follicles (ILFs), Peyer's patches (PPs), appendix), and mesenteric lymph nodes (MLNs) from a total of 68 donors spanning eight decades of life. In pediatric donors, ILFs and PP containing naïve T cells and regulatory T cells (Tregs) are prevalent in the jejunum and ileum, respectively; these decline in frequency with age, contrasting stable frequencies of ILFs and T cell subsets in the colon. In the mucosa, tissue resident memory T cells develop during childhood, and persist in high frequencies into advanced ages, while T cell composition changes with age in GALT and MLN. These spatial and temporal features of human intestinal T cell immunity define signatures that can be used to train predictive machine learning algorithms. Our findings demonstrate an anatomic basis for age-associated alterations in immune responses, and establish a quantitative baseline for intestinal immunity to define disease pathologies.


Assuntos
Envelhecimento/fisiologia , Duodeno/imunologia , Íleo/imunologia , Mucosa Intestinal/imunologia , Jejuno/imunologia , Linfonodos/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Células Cultivadas , Criança , Humanos , Imunidade Celular , Especificidade de Órgãos , Nódulos Linfáticos Agregados/imunologia
9.
JCI Insight ; 3(22)2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30429372

RESUMO

Tissue-resident memory T cells (TRMs) accelerate pathogen clearance through rapid and enhanced functional responses in situ. TRMs are prevalent in diverse anatomic sites throughout the human lifespan, yet their phenotypic and functional diversity has not been fully described. Here, we identify subpopulations of human TRMs based on the ability to efflux fluorescent dyes [efflux(+) TRMs] located within mucosal and lymphoid sites with distinct transcriptional profiles, turnover, and functional capacities. Compared with efflux(-) TRMs, efflux(+) TRMs showed transcriptional and phenotypic features of quiescence including reduced turnover, decreased expression of exhaustion markers, and increased proliferative capacity and signaling in response to homeostatic cytokines. Moreover, upon activation, efflux(+) TRMs secreted lower levels of inflammatory cytokines such as IFN-γ and IL-2 and underwent reduced degranulation. Interestingly, analysis of TRM subsets following activation revealed that both efflux(+) and efflux(-) TRMs undergo extensive transcriptional changes following TCR ligation but retain core TRM transcriptional properties including retention markers, suggesting that TRMs carry out effector function in situ. Overall, our results suggest a model for tissue-resident immunity wherein heterogeneous subsets have differential capacities for longevity and effector function.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células , Corantes Fluorescentes , Humanos , Tecido Linfoide/citologia , Mitocôndrias/metabolismo , Modelos Imunológicos , Fenótipo , Receptores de Antígenos de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Distribuição Tecidual , Transcriptoma
10.
Clin J Am Soc Nephrol ; 13(12): 1876-1885, 2018 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-30361336

RESUMO

BACKGROUND AND OBJECTIVES: Biopsies taken at deceased donor kidney procurement continue to be cited as a leading reason for discard; however, the reproducibility and prognostic capability of these biopsies are controversial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We compiled a retrospective, single-institution, continuous cohort of deceased donor kidney transplants performed from 2006 to 2009. Procurement biopsy information-percentage of glomerulosclerosis, interstitial fibrosis/tubular atrophy, and vascular disease-was obtained from the national transplant database. Using univariable, multivariable, and time-to-event analyses for death-censored graft survival, we compared procurement frozen section biopsy reports with reperfusion paraffin-embedded biopsies read by trained kidney pathologists (n=270). We also examined agreement for sequential procurement biopsies performed on the same kidney (n=116 kidneys). RESULTS: For kidneys on which more than one procurement biopsy was performed (n=116), category agreement was found in only 64% of cases (κ=0.14). For all kidneys (n=270), correlation between procurement and reperfusion biopsies was poor: overall, biopsies were classified into the same category (optimal versus suboptimal) in only 64% of cases (κ=0.25). This discrepancy was most pronounced when categorizing percentage of glomerulosclerosis, which had 63% agreement (κ=0.15). Interstitial fibrosis/tubular atrophy and vascular disease had agreement rates of 82% (κ=0.13) and 80% (κ=0.15), respectively. Ninety-eight (36%) recipients died, and 56 (21%) allografts failed by the end of follow-up. Reperfusion biopsies were more prognostic than procurement biopsies (hazard ratio for graft failure, 2.02; 95% confidence interval, 1.09 to 3.74 versus hazard ratio for graft failure, 1.30; 95% confidence interval, 0.61 to 2.76), with procurement biopsies not significantly associated with graft failure. CONCLUSIONS: We found that procurement biopsies are poorly reproducible, do not correlate well with paraffin-embedded reperfusion biopsies, and are not significantly associated with transplant outcomes.


Assuntos
Seleção do Doador/métodos , Rim/patologia , Obtenção de Tecidos e Órgãos/métodos , Adulto , Cadáver , Correlação de Dados , Feminino , Humanos , Transplante de Rim , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Doadores de Tecidos
11.
J Immunol ; 201(7): 2132-2140, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30111633

RESUMO

Translating studies on T cell function and modulation from mouse models to humans requires extrapolating in vivo results on mouse T cell responses in lymphoid organs (spleen and lymph nodes [LN]) to human peripheral blood T cells. However, our understanding of T cell responses in human lymphoid sites and their relation to peripheral blood remains sparse. In this study, we used a unique human tissue resource to study human T cells in different anatomical compartments within individual donors and identify a subset of memory CD8+ T cells in LN, which maintain a distinct differentiation and functional profile compared with memory CD8+ T cells in blood, spleen, bone marrow, and lungs. Whole-transcriptome and high-dimensional cytometry by time-of-flight profiling reveals that LN memory CD8+ T cells express signatures of quiescence and self-renewal compared with corresponding populations in blood, spleen, bone marrow, and lung. LN memory T cells exhibit a distinct transcriptional signature, including expression of stem cell-associated transcription factors TCF-1 and LEF-1, T follicular helper cell markers CXCR5 and CXCR4, and reduced expression of effector molecules. LN memory T cells display high homology to a subset of mouse CD8+ T cells identified in chronic infection models that respond to checkpoint blockade immunotherapy. Functionally, human LN memory T cells exhibit increased proliferation to TCR-mediated stimulation and maintain higher TCR clonal diversity compared with memory T cells from blood and other sites. These findings establish human LN as reservoirs for memory T cells with high capacities for expansion and diverse recognition and important targets for immunotherapies.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunoterapia/métodos , Linfonodos/imunologia , Fator 1 de Transcrição de Linfócitos T/metabolismo , Animais , Anticorpos Monoclonais , Biodiversidade , Autorrenovação Celular , Células Clonais , Receptores Coestimuladores e Inibidores de Linfócitos T/imunologia , Humanos , Memória Imunológica , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Camundongos , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Transcriptoma
12.
Kidney Int ; 94(1): 187-198, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29735310

RESUMO

The proportion of deceased donor kidneys procured for transplant but subsequently discarded has been growing steadily in the United States, but factors contributing to the rising discard rate remain unclear. To assess the reasons for and probability of organ discard we assembled a cohort of 212,305 deceased donor kidneys recovered for transplant from 2000-2015 in the SRTR registry that included 36,700 kidneys that were discarded. 'Biopsy Findings' (38.2%) was the most commonly reported reason for discard. The median Kidney Donor Risk Index of discarded kidneys was significantly higher than transplanted organs (1.78 vs 1.12), but a large overlap in the quality of discarded and transplanted kidneys was observed. Kidneys of donors who were older, female, Black, obese, diabetic, hypertensive or HCV-positive experienced a significantly increased odds of discard. Kidneys from donors with multiple unfavorable characteristics were more likely to be discarded, whereas unilaterally discarded kidneys had the most desirable donor characteristics and the recipients of their partner kidneys experienced a one-year death-censored graft survival rate over 90%. There was considerable geographic variation in the odds of discard across the United States, which further supports the notion that factors beyond organ quality contributed to kidney discard. Thus, while the discard of a small fraction of organs procured from donors may be inevitable, the discard of potentially transplantable kidneys needs to be avoided. This will require a better understanding of the factors contributing to organ discard in order to remove the disincentives to utilize less-than-ideal organs for transplantation.


Assuntos
Seleção do Doador/normas , Falência Renal Crônica/cirurgia , Transplante de Rim/normas , Rim/patologia , Doadores de Tecidos/estatística & dados numéricos , Adulto , Fatores Etários , Idoso , Biópsia , Seleção do Doador/estatística & dados numéricos , Feminino , Sobrevivência de Enxerto , Humanos , Rim/cirurgia , Transplante de Rim/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Razão de Chances , Avaliação de Resultados em Cuidados de Saúde , Sistema de Registros/estatística & dados numéricos , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Resultado do Tratamento , Estados Unidos , Adulto Jovem
13.
Nature ; 549(7671): 282-286, 2017 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-28869965

RESUMO

The type 2 cytokines interleukin (IL)-4, IL-5, IL-9 and IL-13 have important roles in stimulating innate and adaptive immune responses that are required for resistance to helminth infection, promotion of allergic inflammation, metabolic homeostasis and tissue repair. Group 2 innate lymphoid cells (ILC2s) produce type 2 cytokines, and although advances have been made in understanding the cytokine milieu that promotes ILC2 responses, how ILC2 responses are regulated by other stimuli remains poorly understood. Here we demonstrate that ILC2s in the mouse gastrointestinal tract co-localize with cholinergic neurons that express the neuropeptide neuromedin U (NMU). In contrast to other haematopoietic cells, ILC2s selectively express the NMU receptor 1 (NMUR1). In vitro stimulation of ILC2s with NMU induced rapid cell activation, proliferation, and secretion of the type 2 cytokines IL-5, IL-9 and IL-13 that was dependent on cell-intrinsic expression of NMUR1 and Gαq protein. In vivo administration of NMU triggered potent type 2 cytokine responses characterized by ILC2 activation, proliferation and eosinophil recruitment that was associated with accelerated expulsion of the gastrointestinal nematode Nippostrongylus brasiliensis or induction of lung inflammation. Conversely, worm burden was higher in Nmur1-/- mice than in control mice. Furthermore, use of gene-deficient mice and adoptive cell transfer experiments revealed that ILC2s were necessary and sufficient to mount NMU-elicited type 2 cytokine responses. Together, these data indicate that the NMU-NMUR1 neuronal signalling circuit provides a selective mechanism through which the enteric nervous system and innate immune system integrate to promote rapid type 2 cytokine responses that can induce anti-microbial, inflammatory and tissue-protective type 2 responses at mucosal sites.


Assuntos
Citocinas/imunologia , Imunidade Inata , Inflamação/imunologia , Linfócitos/imunologia , Neuropeptídeos/metabolismo , Transferência Adotiva , Animais , Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Colinérgicos/metabolismo , Citocinas/metabolismo , Eosinófilos/citologia , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Feminino , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Trato Gastrointestinal/citologia , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/inervação , Imunidade Inata/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/patologia , Interleucina-13/imunologia , Interleucina-13/metabolismo , Interleucina-5/imunologia , Interleucina-5/metabolismo , Interleucina-9/imunologia , Interleucina-9/metabolismo , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Masculino , Camundongos , Neuropeptídeos/farmacologia , Nippostrongylus/imunologia , Pneumonia/induzido quimicamente , Pneumonia/imunologia , Pneumonia/patologia , Receptores de Neurotransmissores/deficiência , Receptores de Neurotransmissores/genética , Receptores de Neurotransmissores/metabolismo , Transdução de Sinais/efeitos dos fármacos
14.
Cell Rep ; 20(12): 2921-2934, 2017 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-28930685

RESUMO

Tissue-resident memory T cells (TRMs) in mice mediate optimal protective immunity to infection and vaccination, while in humans, the existence and properties of TRMs remain unclear. Here, we use a unique human tissue resource to determine whether human tissue memory T cells constitute a distinct subset in diverse mucosal and lymphoid tissues. We identify a core transcriptional profile within the CD69+ subset of memory CD4+ and CD8+ T cells in lung and spleen that is distinct from that of CD69- TEM cells in tissues and circulation and defines human TRMs based on homology to the transcriptional profile of mouse CD8+ TRMs. Human TRMs in diverse sites exhibit increased expression of adhesion and inhibitory molecules, produce both pro-inflammatory and regulatory cytokines, and have reduced turnover compared with circulating TEM, suggesting unique adaptations for in situ immunity. Together, our results provide a unifying signature for human TRM and a blueprint for designing tissue-targeted immunotherapies.


Assuntos
Perfilação da Expressão Gênica , Memória Imunológica , Tecido Linfoide/imunologia , Mucosa/imunologia , Linfócitos T/imunologia , Transcrição Gênica , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Linhagem da Célula/genética , Células Clonais , Humanos , Lectinas Tipo C/metabolismo , Ativação Linfocitária/imunologia , Camundongos , Fenótipo , Transcriptoma/genética
15.
Nat Biotechnol ; 35(9): 879-884, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28829438

RESUMO

B-cell responses result in clonal expansion, and can occur in a variety of tissues. To define how B-cell clones are distributed in the body, we sequenced 933,427 B-cell clonal lineages and mapped them to eight different anatomic compartments in six human organ donors. We show that large B-cell clones partition into two broad networks-one spans the blood, bone marrow, spleen and lung, while the other is restricted to tissues within the gastrointestinal (GI) tract (jejunum, ileum and colon). Notably, GI tract clones display extensive sharing of sequence variants among different portions of the tract and have higher frequencies of somatic hypermutation, suggesting extensive and serial rounds of clonal expansion and selection. Our findings provide an anatomic atlas of B-cell clonal lineages, their properties and tissue connections. This resource serves as a foundation for studies of tissue-based immunity, including vaccine responses, infections, autoimmunity and cancer.


Assuntos
Linfócitos B/citologia , Linhagem da Célula/genética , Especificidade de Órgãos/genética , Adulto , Células Clonais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
17.
Immunity ; 46(3): 504-515, 2017 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-28329707

RESUMO

Maturation and migration to lymph nodes (LNs) constitutes a central paradigm in conventional dendritic cell (cDC) biology but remains poorly defined in humans. Using our organ donor tissue resource, we analyzed cDC subset distribution, maturation, and migration in mucosal tissues (lungs, intestines), associated lymph nodes (LNs), and other lymphoid sites from 78 individuals ranging from less than 1 year to 93 years of age. The distribution of cDC1 (CD141hiCD13hi) and cDC2 (Sirp-α+CD1c+) subsets was a function of tissue site and was conserved between donors. We identified cDC2 as the major mature (HLA-DRhi) subset in LNs with the highest frequency in lung-draining LNs. Mature cDC2 in mucosal-draining LNs expressed tissue-specific markers derived from the paired mucosal site, reflecting their tissue-migratory origin. These distribution and maturation patterns were largely maintained throughout life, with site-specific variations. Our findings provide evidence for localized DC tissue surveillance and reveal a lifelong division of labor between DC subsets, with cDC2 functioning as guardians of the mucosa.


Assuntos
Células Dendríticas/citologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Imunofluorescência , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto Jovem
18.
World J Pediatr Congenit Heart Surg ; 5(3): 478-80, 2014 07.
Artigo em Inglês | MEDLINE | ID: mdl-24958058

RESUMO

Left ventricle to aortic conduits were used for the treatment of complex left ventricular outflow tract obstruction in the pediatric population in the mid-1970s. Although this technique has been largely replaced by the Ross-Konno procedure, many patients still have functioning apicoaortic conduits in place today. Few clinical reports or case series exist in pediatric cohorts documenting the natural history or potential long-term complications of this prosthesis. In this report, we describe our experience managing a patient with Shone's syndrome and an apical aortic porcine-valved conduit remnant that became infected 17 years postconduit valve excision for valvular insufficiency.


Assuntos
Aorta Torácica , Bioprótese/efeitos adversos , Ventrículos do Coração/cirurgia , Infecções Relacionadas à Prótese/diagnóstico , Infecções Estreptocócicas/diagnóstico , Obstrução do Fluxo Ventricular Externo/cirurgia , Adulto , Animais , Feminino , Humanos , Suínos , Fatores de Tempo , Tomografia Computadorizada por Raios X
19.
Accid Anal Prev ; 56: 110-7, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23647699

RESUMO

BACKGROUND: Examination of teen driver compliance with graduated driver licensing (GDL) laws could be instrumental in identifying factors associated with persistently high motor vehicle mortality rates. METHODS: Fatality analysis reporting system (FARS) data from the years 2006 to 2009 were used in this nation-wide cross-sectional study of drivers covered by a state nighttime GDL law (n=3492). A new definition of weekend, based on the school night in relation to the teenage social landscape, redefined Friday night as a weekend night and Sunday night as a weekday/school night and compared it to previous weekend definitions. Multiple logistic regression was used to examine independent effects of demographic, behavioral, environmental, contextual, and other factors on compliance with nighttime GDL laws. All analyses were performed in Stata version 11. RESULTS: Given coverage under nighttime GDL laws, drivers aged 15-17 years were non-compliant in 14.9% of the fatal MVCs in which they were involved, and nearly one-fifth (18.8%) of all fatalities aged 15-17 years were associated with non-compliance. Mortality risk was 10% higher using a revised social (school night) versus traditional (Sat-Sun) weekend definitions. In multivariable analysis, drivers non-compliant with nighttime GDL laws were more likely to be drinking (OR=4.97, 3.85-6.40), unbelted (OR=1.58, 1.25-1.99), driving on the weekend (OR=1.82, 1.47-2.24), and killed (OR=1.31, 1.04-1.65). CONCLUSION: GDL non-compliance contributes to teen motor vehicle mortality. Legislative and enforcement efforts targeting non-school night driving, seatbelt nonuse and alcohol have potential to further reduce teen driving mortality.


Assuntos
Acidentes de Trânsito/mortalidade , Comportamento do Adolescente , Condução de Veículo/psicologia , Crime/psicologia , Licenciamento , Acidentes de Trânsito/prevenção & controle , Acidentes de Trânsito/psicologia , Acidentes de Trânsito/estatística & dados numéricos , Adolescente , Condução de Veículo/legislação & jurisprudência , Condução de Veículo/estatística & dados numéricos , Estudos Transversais , Feminino , Humanos , Modelos Logísticos , Masculino , Análise Multivariada , Fatores de Risco , Fatores de Tempo , Estados Unidos/epidemiologia
20.
Prehosp Disaster Med ; 28(3): 223-9, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23388622

RESUMO

UNLABELLED: Introduction The number of civilians killed in Iraq following the 2003 invasion has proven difficult to measure and contentious in recent years. The release of the Wikileaks War Logs (WL) has created the potential to conduct a sensitivity analysis of the commonly-cited Iraq Body Count's (IBC's) tally, which is based on press, government, and other public sources. Hypothesis The 66,000 deaths reported in the Wikileaks War Logs are mostly the same events as those previously reported in the press and elsewhere as tallied by iraqbodycount.org. METHODS: A systematic random sample of 2500 violent fatal War Log incidents was selected and evaluated to determine whether these incidents were also found in IBC's press-based listing. Each selected event was ranked on a scale of 0 (no match present) to 3 (almost certainly matched) with regard to the likelihood it was listed in the IBC database. RESULTS: Of the two thousand four hundred and nine War Log records, 488 (23.8%) were found to have likely matches in IBC records. Events that killed more people were far more likely to appear in both datasets, with 94.1% of events in which ≥20 people were killed being likely matches, as compared with 17.4% of singleton killings. Because of this skew towards the recording of large events in both datasets, it is estimated that 2035 (46.3%) of the 4394 deaths reported in the Wikileaks War Logs had been previously reported in IBC. CONCLUSIONS: Passive surveillance systems, widely seen as incomplete, may also be selective in the types of events detected in times of armed conflict. Bombings and other events during which many people are killed, and events in less violent areas, appear to be detected far more often, creating a skewed image of the mortality profile in Iraq. Members of the press and researchers should be hesitant to draw conclusions about the nature or extent of violence from passive surveillance systems of low or unknown sensitivity.


Assuntos
Confidencialidade , Guerra do Iraque 2003-2011 , Mortalidade , Bases de Dados Factuais , Violação de Direitos Humanos , Humanos
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