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1.
Nature ; 580(7801): 130-135, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32238926

RESUMO

Caspase-dependent apoptosis accounts for approximately 90% of homeostatic cell turnover in the body1, and regulates inflammation, cell proliferation, and tissue regeneration2-4. How apoptotic cells mediate such diverse effects is not fully understood. Here we profiled the apoptotic metabolite secretome and determined its effects on the tissue neighbourhood. We show that apoptotic lymphocytes and macrophages release specific metabolites, while retaining their membrane integrity. A subset of these metabolites is also shared across different primary cells and cell lines after the induction of apoptosis by different stimuli. Mechanistically, the apoptotic metabolite secretome is not simply due to passive emptying of cellular contents and instead is a regulated process. Caspase-mediated opening of pannexin 1 channels at the plasma membrane facilitated the release of a select subset of metabolites. In addition, certain metabolic pathways continued to remain active during apoptosis, with the release of only select metabolites from a given pathway. Functionally, the apoptotic metabolite secretome induced specific gene programs in healthy neighbouring cells, including suppression of inflammation, cell proliferation, and wound healing. Furthermore, a cocktail of apoptotic metabolites reduced disease severity in mouse models of inflammatory arthritis and lung-graft rejection. These data advance the concept that apoptotic cells are not inert cells waiting for removal, but instead release metabolites as 'good-bye' signals to actively modulate outcomes in tissues.


Assuntos
Apoptose/fisiologia , Microambiente Celular , Sistemas do Segundo Mensageiro/fisiologia , Animais , Artrite , Caspases/metabolismo , Linhagem Celular , Proliferação de Células/genética , Sobrevivência Celular/genética , Conexinas/metabolismo , Modelos Animais de Doenças , Rejeição de Enxerto , Humanos , Inflamação/genética , Transplante de Pulmão , Linfócitos/enzimologia , Linfócitos/metabolismo , Macrófagos/enzimologia , Macrófagos/metabolismo , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Fagócitos/metabolismo , Cicatrização/genética
2.
Proc Natl Acad Sci U S A ; 119(10): e2111537119, 2022 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-35238643

RESUMO

Ischemia reperfusion injury represents a common pathological condition that is triggered by the release of endogenous ligands. While neutrophils are known to play a critical role in its pathogenesis, the tissue-specific spatiotemporal regulation of ischemia-reperfusion injury is not understood. Here, using oxidative lipidomics and intravital imaging of transplanted mouse lungs that are subjected to severe ischemia reperfusion injury, we discovered that necroptosis, a nonapoptotic form of cell death, triggers the recruitment of neutrophils. During the initial stages of inflammation, neutrophils traffic predominantly to subpleural vessels, where their aggregation is directed by chemoattractants produced by nonclassical monocytes that are spatially restricted in this vascular compartment. Subsequent neutrophilic disruption of capillaries resulting in vascular leakage is associated with impaired graft function. We found that TLR4 signaling in vascular endothelial cells and downstream NADPH oxidase 4 expression mediate the arrest of neutrophils, a step upstream of their extravasation. Neutrophil extracellular traps formed in injured lungs and their disruption with DNase prevented vascular leakage and ameliorated primary graft dysfunction. Thus, we have uncovered mechanisms that regulate the initial recruitment of neutrophils to injured lungs, which result in selective damage to subpleural pulmonary vessels and primary graft dysfunction. Our findings could lead to the development of new therapeutics that protect lungs from ischemia reperfusion injury.


Assuntos
Endotélio Vascular/metabolismo , Pulmão/metabolismo , Necroptose , Infiltração de Neutrófilos , Neutrófilos/metabolismo , Traumatismo por Reperfusão/metabolismo , Animais , Endotélio Vascular/lesões , Humanos , Pulmão/irrigação sanguínea , Camundongos , Camundongos Knockout , Traumatismo por Reperfusão/genética , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
3.
Am J Transplant ; 24(2): 280-292, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37619922

RESUMO

The presence of bronchus-associated lymphoid tissue (BALT) in donor lungs has been suggested to accelerate graft rejection after lung transplantation. Although chronic smoke exposure can induce BALT formation, the impact of donor cigarette use on alloimmune responses after lung transplantation is not well understood. Here, we show that smoking-induced BALT in mouse donor lungs contains Foxp3+ T cells and undergoes dynamic restructuring after transplantation, including recruitment of recipient-derived leukocytes to areas of pre-existing lymphoid follicles and replacement of graft-resident donor cells. Our findings from mouse and human lung transplant data support the notion that a donor's smoking history does not predispose to acute cellular rejection or prevent the establishment of allograft acceptance with comparable outcomes to nonsmoking donors. Thus, our work indicates that BALT in donor lungs is plastic in nature and may have important implications for modulating proinflammatory or tolerogenic immune responses following transplantation.


Assuntos
Transplante de Pulmão , Tecido Linfoide , Camundongos , Humanos , Animais , Transplante de Pulmão/efeitos adversos , Tolerância Imunológica , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle , Pulmão , Brônquios , Fumar
4.
Am J Transplant ; 2024 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-38522826

RESUMO

Neutrophils exacerbate pulmonary ischemia-reperfusion injury (IRI) resulting in poor short and long-term outcomes for lung transplant recipients. Glycolysis powers neutrophil activation, but it remains unclear if neutrophil-specific targeting of this pathway will inhibit IRI. Lipid nanoparticles containing the glycolysis flux inhibitor 2-deoxyglucose (2-DG) were conjugated to neutrophil-specific Ly6G antibodies (NP-Ly6G[2-DG]). Intravenously administered NP-Ly6G(2-DG) to mice exhibited high specificity for circulating neutrophils. NP-Ly6G(2-DG)-treated neutrophils were unable to adapt to hypoglycemic conditions of the lung airspace environment as evident by the loss of demand-induced glycolysis, reductions in glycogen and ATP content, and an increased vulnerability to apoptosis. NP-Ly6G(2-DG) treatment inhibited pulmonary IRI following hilar occlusion and orthotopic lung transplantation. IRI protection was associated with less airspace neutrophil extracellular trap generation, reduced intragraft neutrophilia, and enhanced alveolar macrophage efferocytotic clearance of neutrophils. Collectively, our data show that pharmacologically targeting glycolysis in neutrophils inhibits their activation and survival leading to reduced pulmonary IRI.

5.
J Allergy Clin Immunol ; 152(2): 469-485.e10, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37028525

RESUMO

BACKGROUND: Group 2 innate lymphoid cells (ILC2s) are critical mediators of type 2 respiratory inflammation, releasing IL-5 and IL-13 and promoting the pulmonary eosinophilia associated with allergen provocation. Although ILC2s have been shown to promote eosinophil activities, the role of eosinophils in group 2 innate lymphoid cell (ILC2) responses is less well defined. OBJECTIVE: We sought to investigate the role of eosinophils in activation of ILC2s in models of allergic asthma and in vitro. METHODS: Inducible eosinophil-deficient mice were exposed to allergic respiratory inflammation models of asthma, such as ovalbumin or house dust mite challenge, or to innate models of type 2 airway inflammation, such as inhalation of IL-33. Eosinophil-specific IL-4/13-deficient mice were used to address the specific roles for eosinophil-derived cytokines. Direct cell interactions between ILC2s and eosinophils were assessed by in vitro culture experiments. RESULTS: Targeted depletion of eosinophils resulted in significant reductions of total and IL-5+ and IL-13+ lung ILC2s in all models of respiratory inflammation. This correlated with reductions in IL-13 levels and mucus in the airway. Eosinophil-derived IL-4/13 was necessary for both eosinophil and ILC2 accumulation in lung in allergen models. In vitro, eosinophils released soluble mediators that induced ILC2 proliferation and G protein-coupled receptor-dependent chemotaxis of ILC2s. Coculture of ILC2s and IL-33-activated eosinophils resulted in transcriptome changes in both ILC2s and eosinophils, suggesting potential novel reciprocal interactions. CONCLUSION: These studies demonstrate that eosinophils play a reciprocal role in ILC2 effector functions as part of both adaptive and innate type 2 pulmonary inflammatory events.


Assuntos
Asma , Imunidade Inata , Camundongos , Animais , Eosinófilos/metabolismo , Interleucina-33/metabolismo , Interleucina-13/metabolismo , Interleucina-5/metabolismo , Interleucina-4/metabolismo , Linfócitos , Pulmão , Citocinas/metabolismo , Asma/metabolismo , Inflamação/metabolismo , Alérgenos/metabolismo
6.
Am J Transplant ; 23(1): 101-107, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36695611

RESUMO

Although the risk of SARS-CoV-2 transmission through lung transplantation from acutely infected donors is high, the risks of virus transmission and long-term lung allograft outcomes are not as well described when using pulmonary organs from COVID-19-recovered donors. We describe successful lung transplantation for a COVID-19-related lung injury using lungs from a COVID-19-recovered donor who was retrospectively found to have detectable genomic SARS-CoV-2 RNA in the lung tissue by multiple highly sensitive assays. However, SARS-CoV-2 subgenomic RNA (sgRNA), a marker of viral replication, was not detectable in the donor respiratory tissues. One year after lung transplantation, the recipient has a good functional status, walking 1 mile several times per week without the need for supplemental oxygen and without any evidence of donor-derived SARS-CoV-2 transmission. Our findings highlight the limitations of current clinical laboratory diagnostic assays in detecting the persistence of SARS-CoV-2 RNA in the lung tissue. The persistence of SARS-CoV-2 RNA in the donor tissue did not appear to represent active viral replication via sgRNA testing and, most importantly, did not negatively impact the allograft outcome in the first year after lung transplantation. sgRNA is easily performed and may be a useful assay for assessing viral infectivity in organs from donors with a recent infection.


Assuntos
COVID-19 , Transplante de Pulmão , Humanos , SARS-CoV-2/genética , RNA Subgenômico , RNA Viral/genética , Estudos Retrospectivos , Aloenxertos
7.
Cell Immunol ; 383: 104657, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36603504

RESUMO

Mature IL-33 (MIL33) acting through its receptor, ST2, is known to regulate fibrosis. The precursor, full-length IL-33 (FLIL33), may function differently from MIL33 and independently of ST2. Here we report that genetic deletion of either IL-33 or ST2 attenuates pulmonary fibrosis in the bleomycin model, as does Cre-induced IL-33 deficiency in response to either acute or chronic bleomycin challenge. However, adenovirus-mediated gene delivery of FLIL33, but not MIL33, to the lungs of either wild-type or ST2-deficient mice potentiates the profibrotic effect of bleomycin without inducing a Th2 phenotype. In cultured mouse lung cells, FLIL33 overexpression induces moderate and distinct transcriptomic changes compared with a robust response induced by MIL33, whereas ST2 deletion abrogates the effects of both IL-33 forms. Thus, FLIL33 may contribute to fibrosis in an ST2-independent, Th2-independent, non-transcriptomic fashion, suggesting that pharmacological targeting of both FLIL33 and MIL33 may prove efficacious in patients with pulmonary fibrosis.


Assuntos
Fibrose Pulmonar , Camundongos , Animais , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/genética , Interleucina-33/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Fibrose , Bleomicina , Camundongos Endogâmicos C57BL
8.
Cell Mol Life Sci ; 79(7): 359, 2022 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-35689679

RESUMO

Tertiary lymphoid organs (TLOs) are collections of immune cells resembling secondary lymphoid organs (SLOs) that form in peripheral, non-lymphoid tissues in response to local chronic inflammation. While their formation mimics embryologic lymphoid organogenesis, TLOs form after birth at ectopic sites in response to local inflammation resulting in their ability to mount diverse immune responses. The structure of TLOs can vary from clusters of B and T lymphocytes to highly organized structures with B and T lymphocyte compartments, germinal centers, and lymphatic vessels (LVs) and high endothelial venules (HEVs), allowing them to generate robust immune responses at sites of tissue injury. Although our understanding of the formation and function of these structures has improved greatly over the last 30 years, their role as mediators of protective or pathologic immune responses in certain chronic inflammatory diseases remains enigmatic and may differ based on the local tissue microenvironment in which they form. In this review, we highlight the role of TLOs in the regulation of immune responses in chronic infection, chronic inflammatory and autoimmune diseases, cancer, and solid organ transplantation.


Assuntos
Centro Germinativo , Linfócitos T , Humanos , Imunidade , Inflamação/patologia , Linfonodos/patologia , Linfócitos T/patologia
9.
Immunol Rev ; 292(1): 194-208, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31536165

RESUMO

Regulatory T cells (Treg) have proven to be a powerful immunologic force in nearly every organ system and hold therapeutic potential for a wide range of diseases. Insights gained from non-transplant pathologies, such as infection, cancer, and autoimmunity, are now being translated to the field of solid organ transplantation, particularly for livers and kidneys. Recent insights from animal models of lung transplantation have established that Tregs play a vital role in suppressing rejection and facilitating tolerance of lung allografts, and such discoveries are being validated in human studies and preclinical trials. Given that long-term outcomes following lung transplantation remain profoundly limited by chronic rejection, Treg therapy holds the potential to significantly improve patient outcomes and should be aggressively investigated.


Assuntos
Rejeição de Enxerto/imunologia , Transplante de Pulmão/métodos , Tolerância ao Transplante/imunologia , Aloenxertos , Animais , Humanos , Transplante de Rim/métodos , Transplante de Fígado/métodos , Linfócitos T Reguladores , Imunologia de Transplantes/imunologia
10.
Proc Natl Acad Sci U S A ; 116(47): 23662-23670, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31685621

RESUMO

The impact of intratumoral heterogeneity (ITH) and the resultant neoantigen landscape on T cell immunity are poorly understood. ITH is a widely recognized feature of solid tumors and poses distinct challenges related to the development of effective therapeutic strategies, including cancer neoantigen vaccines. Here, we performed deep targeted DNA sequencing of multiple metastases from melanoma patients and observed ubiquitous sharing of clonal and subclonal single nucleotide variants (SNVs) encoding putative HLA class I-restricted neoantigen epitopes. However, spontaneous antitumor CD8+ T cell immunity in peripheral blood and tumors was restricted to a few clonal neoantigens featuring an oligo-/monoclonal T cell-receptor (TCR) repertoire. Moreover, in various tumors of the 4 patients examined, no neoantigen-specific TCR clonotypes were identified despite clonal neoantigen expression. Mature dendritic cell (mDC) vaccination with tumor-encoded amino acid-substituted (AAS) peptides revealed diverse neoantigen-specific CD8+ T responses, each composed of multiple TCR clonotypes. Isolation of T cell clones by limiting dilution from tumor-infiltrating lymphocytes (TILs) permitted functional validation regarding neoantigen specificity. Gene transfer of TCRαß heterodimers specific for clonal neoantigens confirmed correct TCR clonotype assignments based on high-throughput TCRBV CDR3 sequencing. Our findings implicate immunological ignorance of clonal neoantigens as the basis for ineffective T cell immunity to melanoma and support the concept that therapeutic vaccination, as an adjunct to checkpoint inhibitor treatment, is required to increase the breadth and diversity of neoantigen-specific CD8+ T cells.


Assuntos
Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos do Interstício Tumoral/imunologia , Melanoma/imunologia , Subpopulações de Linfócitos T/imunologia , Substituição de Aminoácidos , Antígenos de Neoplasias/genética , Vacinas Anticâncer/imunologia , Células Clonais , DNA de Neoplasias/genética , Células Dendríticas/imunologia , Antígenos HLA/imunologia , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/secundário , Melanoma/genética , Melanoma/secundário , Polimorfismo de Nucleotídeo Único , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Neoplasias Retroperitoneais/imunologia , Neoplasias Retroperitoneais/secundário , Análise de Sequência de DNA , Especificidade do Receptor de Antígeno de Linfócitos T , Evasão Tumoral , Vacinação
11.
Am J Transplant ; 21(1): 353-361, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32786174

RESUMO

Although postoperative bacterial infections can trigger rejection of pulmonary allografts, the impact of bacterial colonization of donor grafts on alloimmune responses to transplanted lungs remains unknown. Here, we tested the hypothesis that bacterial products present within donor grafts at the time of implantation promote lung allograft rejection. Administration of the toll-like receptor 2 (TLR2) agonist Pam3 Cys4 to Balb/c wild-type grafts triggered acute cellular rejection after transplantation into B6 wild-type recipients that received perioperative costimulatory blockade. Pam3 Cys4 -triggered rejection was associated with an expansion of CD8+ T lymphocytes and CD11c+ CD11bhi MHC (major histocompatibility complex) class II+ antigen-presenting cells within the transplanted lungs. Rejection was prevented when lungs were transplanted into TLR2-deficient recipients but not when MyD88-deficient donors were used. Adoptive transfer of B6 wild-type monocytes, but not T cells, following transplantation into B6 TLR2-deficient recipients restored the ability of Pam3 Cys4 to trigger acute cellular rejection. Thus, we have demonstrated that activation of TLR2 by a bacterial lipopeptide within the donor airways prevents the induction of lung allograft tolerance through a process mediated by recipient-derived monocytes. Our work suggests that donor lungs harboring bacteria may precipitate an inflammatory response that can facilitate allograft rejection.


Assuntos
Transplante de Pulmão , Tolerância ao Transplante , Animais , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle , Pulmão , Transplante de Pulmão/efeitos adversos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout
12.
Am J Transplant ; 21(2): 460-474, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32969590

RESUMO

Patients undergoing evaluation for solid organ transplantation (SOT) often have a history of malignancy. Although the cancer has been treated in these patients, the benefits of transplantation need to be balanced against the risk of tumor recurrence, especially in the setting of immunosuppression. Prior guidelines of when to transplant patients with a prior treated malignancy do not take in to account current staging, disease biology, or advances in cancer treatments. To develop contemporary recommendations, the American Society of Transplantation held a consensus workshop to perform a comprehensive review of current literature regarding cancer therapies, cancer stage-specific prognosis, the kinetics of cancer recurrence, and the limited data on the effects of immunosuppression on cancer-specific outcomes. This document contains prognosis based on contemporary treatment and transplant recommendations for breast, colorectal, anal, urological, gynecological, and nonsmall cell lung cancers. This conference and consensus documents aim to provide recommendations to assist in the evaluation of patients for SOT given a history of a pretransplant malignancy.


Assuntos
Prova Pericial , Transplante de Órgãos , Consenso , Humanos , Recidiva Local de Neoplasia , Prognóstico
13.
Am J Transplant ; 21(2): 475-483, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32976703

RESUMO

Patients undergoing evaluation for solid organ transplantation (SOT) frequently have a history of malignancy. Only patients with treated cancer are considered for SOT but the benefits of transplantation need to be balanced against the risk of tumor recurrence, taking into consideration the potential effects of immunosuppression. Prior guidelines on timing to transplant in patients with a prior treated malignancy do not account for current staging, disease biology, or advances in cancer treatments. To update these recommendations, the American Society of Transplantation (AST) facilitated a consensus workshop to comprehensively review contemporary literature regarding cancer therapies, cancer stage specific prognosis, the kinetics of cancer recurrence, as well as the limited data on the effects of immunosuppression on cancer-specific outcomes. This document contains prognosis, treatment, and transplant recommendations for melanoma and hematological malignancies. Given the limited data regarding the risk of cancer recurrence in transplant recipients, the goal of the AST-sponsored conference and the consensus documents produced are to provide expert opinion recommendations that help in the evaluation of patients with a history of a pretransplant malignancy for transplant candidacy.


Assuntos
Neoplasias Hematológicas , Melanoma , Transplante de Órgãos , Consenso , Prova Pericial , Humanos , Recidiva Local de Neoplasia , Prognóstico
14.
Am J Transplant ; 20(1): 250-261, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31452317

RESUMO

Although neutropenia is a common complication after lung transplant, its relationship with recipient outcomes remains understudied. We evaluated a retrospective cohort of 228 adult lung transplant recipients between 2008 and 2013 to assess the association of neutropenia and granulocyte colony-stimulating factor (GCSF) treatment with outcomes. Neutropenia was categorized as mild (absolute neutrophil count 1000-1499), moderate (500-999), or severe (<500) and as a time-varying continuous variable. Associations with survival, acute rejection, and chronic lung allograft dysfunction (CLAD) were assessed with the use of Cox proportional hazards regression. GCSF therapy impact on survival, CLAD, and acute rejection development was analyzed by propensity score matching. Of 228 patients, 101 (42.1%) developed neutropenia. Recipients with severe neutropenia had higher mortality rates than those of recipients with no (adjusted hazard ratio [aHR] 2.97, 95% confidence interval [CI] 1.05-8.41, P = .040), mild (aHR 14.508, 95% CI 1.58-13.34, P = .018), or moderate (aHR 3.27, 95% CI 0.89-12.01, P = .074) neutropenia. Surprisingly, GCSF treatment was associated with a higher risk for CLAD in mildly neutropenic patients (aHR 3.49, 95% CI 0.93-13.04, P = .063), although it did decrease death risk in severely neutropenic patients (aHR 0.24, 95% CI 0.07-0.88, P = .031). Taken together, our data point to an important relationship between neutropenia severity and GCSF treatment in lung transplant outcomes.


Assuntos
Rejeição de Enxerto/mortalidade , Sobrevivência de Enxerto/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Pneumopatias/mortalidade , Transplante de Pulmão/mortalidade , Neutropenia/mortalidade , Índice de Gravidade de Doença , Aloenxertos , Feminino , Seguimentos , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/patologia , Humanos , Pneumopatias/cirurgia , Transplante de Pulmão/efeitos adversos , Masculino , Pessoa de Meia-Idade , Neutropenia/tratamento farmacológico , Neutropenia/etiologia , Neutropenia/patologia , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Transplantados
15.
Am J Transplant ; 20(5): 1251-1261, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31721409

RESUMO

Long-term survival after lung transplantation remains profoundly limited by graft rejection. Recent work has shown that bronchus-associated lymphoid tissue (BALT), characterized by the development of peripheral nodal addressin (PNAd)-expressing high endothelial venules and enriched in B and Foxp3+ T cells, is important for the maintenance of allograft tolerance. Mechanisms underlying BALT induction in tolerant pulmonary allografts, however, remain poorly understood. Here, we show that the development of PNAd-expressing high endothelial venules within intragraft lymphoid follicles and the recruitment of B cells, but not Foxp3+ cells depends on IL-22. We identify graft-infiltrating gamma-delta (γδ) T cells and Type 3 innate lymphoid cells (ILC3s) as important producers of IL-22. Reconstitution of IL-22 at late time points through retransplantation into wildtype hosts mediates B cell recruitment into lymphoid follicles within the allograft, resulting in a significant increase in their size, but does not induce PNAd expression. Our work has identified cellular and molecular requirements for the induction of BALT in pulmonary allografts during tolerance induction and may provide a platform for the development of new therapies for lung transplant patients.


Assuntos
Imunidade Inata , Tecido Linfoide , Aloenxertos , Brônquios , Rejeição de Enxerto/etiologia , Humanos , Interleucinas , Pulmão , Linfócitos , Interleucina 22
16.
Pharmacogenomics J ; 20(1): 69-79, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-30992538

RESUMO

Single-nucleotide polymorphisms (SNPs) in genes involved in mycophenolic acid (MPA) metabolism have been shown to contribute to variable MPA exposure, but their clinical effects are unclear. We aimed to determine if SNPs in key genes in MPA metabolism affect outcomes after lung transplantation. We performed a retrospective cohort study of 275 lung transplant recipients, 228 receiving mycophenolic acid and a control group of 47 receiving azathioprine. Six SNPs known to regulate MPA exposure from the SLCO, UGT and MRP2 families were genotyped. Primary outcome was 1-year survival. Secondary outcomes were 3-year survival, nonminimal (≥A2 or B2) acute rejection, and chronic lung allograft dysfunction (CLAD). Statistical analyses included time-to-event Kaplan-Meier with log-rank test and Cox regression modeling. We found that SLCO1B3 SNPs rs4149117 and rs7311358 were associated with decreased 1-year survival [rs7311358 HR 7.76 (1.37-44.04), p = 0.021; rs4149117 HR 7.28 (1.27-41.78), p = 0.026], increased risk for nonminimal acute rejection [rs4149117 TT334/T334G: OR 2.01 (1.06-3.81), p = 0.031; rs7311358 GG699/G699A: OR 2.18 (1.13-4.21) p = 0.019] and lower survival through 3 years for MPA patients but not for azathioprine patients. MPA carriers of either SLCO1B3 SNP had shorter survival after CLAD diagnosis (rs4149117 p = 0.048, rs7311358 p = 0.023). For the MPA patients, Cox regression modeling demonstrated that both SNPs remained independent risk factors for death. We conclude that hypofunctional SNPs in the SLCO1B3 gene are associated with an increased risk for acute rejection and allograft failure in lung transplant recipients treated with MPA.


Assuntos
Aloenxertos/efeitos dos fármacos , Transplante de Pulmão/efeitos adversos , Ácido Micofenólico/administração & dosagem , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/genética , Adulto , Aloenxertos/transplante , Azatioprina/administração & dosagem , Feminino , Genótipo , Humanos , Imunossupressores/administração & dosagem , Pulmão/metabolismo , Pulmão/patologia , Transplante de Pulmão/métodos , Masculino , Pessoa de Meia-Idade , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Ácido Micofenólico/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Transplantados
17.
J Immunol ; 200(2): 847-856, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29212908

RESUMO

TLR agonists are effective at treating superficial cancerous lesions, but their use internally for other types of tumors remains challenging because of toxicity. In this article, we report that murine and human naive CD4+ T cells that sequester Pam3Cys4 (CD4+ TPam3) become primed for Th1 differentiation. CD4+ TPam3 cells encoding the OVA-specific TCR OT2, when transferred into mice bearing established TGF-ß-OVA-expressing thymomas, produce high amounts of IFN-γ and sensitize tumors to PD-1/programmed cell death ligand 1 blockade-induced rejection. In contrast, naive OT2 cells without Pam3Cys4 cargo are prone to TGF-ß-dependent inducible regulatory Foxp3+ CD4+ T cell conversion and accelerate tumor growth that is largely unaffected by PD-1/programmed cell death ligand 1 blockade. Ex vivo analysis reveals that CD4+ TPam3 cells are resistant to TGF-ß-mediated gene expression through Akt activation controlled by inputs from the TCR and a TLR2-MyD88-dependent PI3K signaling pathway. These data show that CD4+ TPam3 cells are capable of Th1 differentiation in the presence of TGF-ß, suggesting a novel approach to adoptive cell therapy.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Receptor 2 Toll-Like/agonistas , Fator de Crescimento Transformador beta/metabolismo , Evasão Tumoral/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Expressão Gênica , Interferon gama/genética , Interferon gama/metabolismo , Ligantes , Ativação Linfocitária/imunologia , Camundongos , Camundongos Knockout , Modelos Biológicos , Fator 88 de Diferenciação Mieloide/metabolismo , Neoplasias/genética , Neoplasias/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Receptor 2 Toll-Like/genética , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
18.
Am J Transplant ; 19(2): 597-600, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30063120

RESUMO

Pulmonary masses occasionally occur after lung transplantation and vary in etiology, which includes malignant and benign conditions, such as infection. Here, we report a case of a patient presenting with a lung mass 3 years after lung transplant. To our knowledge, this is the first described case of pulmonary malakoplakia due to Rhodococcus equi infection in an allograft post-lung transplantation. This case outlines the challenges of differentiating benign from malignant masses after transplantation.


Assuntos
Infecções por Actinomycetales/complicações , Pneumopatias/diagnóstico , Neoplasias Pulmonares/diagnóstico , Transplante de Pulmão/efeitos adversos , Malacoplasia/diagnóstico , Complicações Pós-Operatórias , Rhodococcus equi/isolamento & purificação , Infecções por Actinomycetales/epidemiologia , Infecções por Actinomycetales/microbiologia , Idoso , Diagnóstico Diferencial , Humanos , Pneumopatias/etiologia , Neoplasias Pulmonares/etiologia , Malacoplasia/etiologia , Masculino , Prognóstico
19.
Am J Transplant ; 19(4): 1011-1023, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30378766

RESUMO

Neutrophil extracellular traps (NETs) have been shown to worsen acute pulmonary injury including after lung transplantation. The breakdown of NETs by DNAse-1 can help restore lung function, but whether there is an impact on allograft tolerance remains less clear. Using intravital 2-photon microscopy, we analyzed the effects of DNAse-1 on NETs in mouse orthotopic lung allografts damaged by ischemia-reperfusion injury. Although DNAse-1 treatment rapidly degrades intragraft NETs, the consequential release of NET fragments induces prolonged interactions between infiltrating CD4+ T cells and donor-derived antigen presenting cells. DNAse-1 generated NET fragments also promote human alveolar macrophage inflammatory cytokine production and prime dendritic cells for alloantigen-specific CD4+ T cell proliferation through activating toll-like receptor (TLR) - Myeloid Differentiation Primary Response 88 (MyD88) signaling pathways. Furthermore, and in contrast to allograft recipients with a deficiency in NET generation due to a neutrophil-specific ablation of Protein Arginine Deiminase 4 (PAD4), DNAse-1 administration to wild-type recipients promotes the recognition of allo- and self-antigens and prevents immunosuppression-mediated lung allograft acceptance through a MyD88-dependent pathway. Taken together, these data show that the rapid catalytic release of NET fragments promotes innate immune responses that prevent lung transplant tolerance.


Assuntos
Armadilhas Extracelulares/imunologia , Imunidade Inata/imunologia , Transplante de Pulmão , Tolerância ao Transplante , Animais , Células Cultivadas , Células Dendríticas/imunologia , Desoxirribonucleases/metabolismo , Ensaio de Imunoadsorção Enzimática , Armadilhas Extracelulares/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Macrófagos Alveolares/citologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Traumatismo por Reperfusão
20.
Am J Transplant ; 19(5): 1464-1477, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30582269

RESUMO

Primary graft dysfunction (PGD) is a major limitation in short- and long-term lung transplant survival. Recent work has shown that mitochondrial damage-associated molecular patterns (mtDAMPs) can promote solid organ injury, but whether they contribute to PGD severity remains unclear. We quantitated circulating plasma mitochondrial DNA (mtDNA) in 62 patients, before lung transplantation and shortly after arrival to the intensive care unit. Although all recipients released mtDNA, high levels were associated with severe PGD development. In a mouse orthotopic lung transplant model of PGD, we detected airway cell-free damaged mitochondria and mtDNA in the peripheral circulation. Pharmacologic inhibition or genetic deletion of formylated peptide receptor 1 (FPR1), a chemotaxis sensor for N-formylated peptides released by damaged mitochondria, inhibited graft injury. An analysis of intragraft neutrophil-trafficking patterns reveals that FPR1 enhances neutrophil transepithelial migration and retention within airways but does not control extravasation. Using donor lungs that express a mitochondria-targeted reporter protein, we also show that FPR1-mediated neutrophil trafficking is coupled with the engulfment of damaged mitochondria, which in turn triggers reactive oxygen species (ROS)-induced pulmonary edema. Therefore, our data demonstrate an association between mtDAMP release and PGD development and suggest that neutrophil trafficking and effector responses to damaged mitochondria are drivers of graft damage.


Assuntos
Alarminas/metabolismo , Pneumopatias/imunologia , Pneumopatias/cirurgia , Transplante de Pulmão/efeitos adversos , Mitocôndrias/metabolismo , Disfunção Primária do Enxerto , Idoso , Animais , Separação Celular , DNA Mitocondrial/sangue , Feminino , Citometria de Fluxo , Sobrevivência de Enxerto , Humanos , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Edema Pulmonar/complicações , Edema Pulmonar/imunologia , Espécies Reativas de Oxigênio/metabolismo , Receptores de Formil Peptídeo/metabolismo , Traumatismo por Reperfusão , Estudos Retrospectivos , Doadores de Tecidos
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