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The purpose of this review was to summarize the evidence with regard to behavioral and psychosocial assessment of the periodontitis patient, the candidate for implant therapy, and the peri-implantitis patient. Periodontitis has an adverse effect on quality of life and its treatment can lead to significant improvements experienced by the patient. The latter is true for rehabilitation with dental implants, although patients harbor diverse expectations and perceptions of implant therapy, which can often interfere with satisfaction and/or influence long-term success. A thorough behavioral assessment of the candidate for implant therapy is essential, which should include, perceptions, expectations, as well as risk for behavioral disorders. Remedial action is essential to correct misperceptions and any identified risks. Finally, patients have limited awareness of limited ability to identify signs of peri-implantitis. The diagnosis of peri-implantitis can be a cause of significant distress, resentment, and loss of trust to the treatment and the caregivers. Despite documented value in clinical research, currently available instruments assessing patient-reported outcomes have little application in day-to-day clinical practice. Face-to-face patient to doctor open-ended communication remains the most effective way to comprehensively establish the long-term "therapeutic alliance" essential for the long journey for the periodontitis patient.
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Classic Hodgkin Lymphoma (cHL) is a tumor composed of rare malignant Hodgkin and Reed-Sternberg (HRS) cells nested within a T-cell rich inflammatory immune infiltrate. cHL is associated with Epstein-Barr Virus (EBV) in 25% of cases. The specific contributions of EBV to the pathogenesis of cHL remain largely unknown, in part due to technical barriers in dissecting the tumor microenvironment (TME) in high detail. Herein, we applied multiplexed ion beam imaging (MIBI) spatial pro-teomics on 6 EBV-positive and 14 EBV-negative cHL samples. We identify key TME features that distinguish between EBV-positive and EBV-negative cHL, including the relative predominance of memory CD8 T cells and increased T-cell dysfunction as a function of spatial proximity to HRS cells. Building upon a larger multi-institutional cohort of 22 EBV-positive and 24 EBV-negative cHL samples, we orthogonally validated our findings through a spatial multi-omics approach, coupling whole transcriptome capture with antibody-defined cell types for tu-mor and T-cell populations within the cHL TME. We delineate contrasting transcriptomic immunological signatures between EBV-positive and EBV-negative cases that differently impact HRS cell proliferation, tumor-immune interactions, and mecha-nisms of T-cell dysregulation and dysfunction. Our multi-modal framework enabled a comprehensive dissection of EBV-linked reorganization and immune evasion within the cHL TME, and highlighted the need to elucidate the cellular and molecular fac-tors of virus-associated tumors, with potential for targeted therapeutic strategies.
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Imaging mass cytometry (IMC) is a powerful spatial technology that utilizes cytometry time of flight to acquire multiplexed image datasets with up to 40 markers, via metal-tagged antibodies. Recent advances in IMC have led to the inclusion of RNAScope probes and multiple new analysis pipelines have led to faster analyses and better results. However, IMC still suffers from lower resolution (1 µm2 pixels) and relatively small regions of interest (ROIs) (<2 mm2 ) compared to other, light-based microscope technologies. Capturing higher-resolution images on serial sections causes great difficulty when attempting to align cells and structures across serial sections, especially when observing smaller cell types and structures. Therefore, we demonstrate the combination of H&E and multiplex immunofluorescence imaging, for much higher resolution of the structural and cellular compartments found throughout the entire tissue section, with the high-dimensionality of IMC for specific ROIs on a single slide. Additionally, we demonstrate a simple and effective open-source cell segmentation and IMC analysis pipeline with previously published and freely available software.
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Anticorpos , Citometria por Imagem , Imunofluorescência , Citometria por Imagem/métodosRESUMO
Hematopoiesis and lineage commitment are regulated by several conserved cell-intrinsic signaling pathways, including MAPKs and ß-catenin/TCF/LEF. The Inhibitor of MyoD Family A (I-MFA), a transcriptional repressor and tumor suppressor gene, interacts with these pathways and is dysregulated in chronic and acute myeloid leukemias, suggesting it may play a role in development and differentiation during hematopoiesis. To study this, immune cell populations in the bone marrow (BM) and periphery were analyzed in mice lacking Mdfi, encoding I-MFA (I-MFA-/-), and wild type (WT) controls. I-MFA-/- mice had reduced spleen and BM cellularity, with significant hyposplenism, compared to WT mice. In blood, total red blood cells and platelet counts were significantly reduced in I-MFA-/- mice, accompanied by a reduction in megakaryocyte (MK)/erythrocyte progenitor cells and an increase in myeloid progenitors in BM compared to WT mice. The K562 cell line exhibits PMA-induced MK differentiation, and shRNA knockdown of I-MFA resulted in reduced differentiation compared to control, with an increase and prolongation in phospho-JNK and phospho-ERK signaling. Overexpression of I-MFA promoted MK differentiation. These results suggest I-MFA plays a cell-intrinsic role in the response to differentiation signals, an effect that can be explored in the context of hematological cancers or other blood proliferative disorders.
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Medula Óssea , Megacariócitos , Camundongos , Animais , Medula Óssea/metabolismo , Diferenciação Celular , Hematopoese , Células da Medula Óssea/patologia , Linhagem da CélulaRESUMO
Diffuse large B-cell lymphoma (DLBCL) not otherwise specified is the most common aggressive non-Hodgkin lymphoma and a biologically heterogeneous disease. Despite the development of effective immunotherapies, the organization of the DLBCL tumor-immune microenvironment (TIME) remains poorly understood.We interrogated the intact TIME of 51 de novo DLBCLs with triplicate sampling to characterize 337 995 tumor and immune cells using a 27-plex antibody panel that captured cell lineage, architectural, and functional markers. We spatially assigned individual cells, identified local cell neighborhoods, and established their topographical organization in situ. We found that the organization of local tumor and immune cells can be modeled by 6 composite cell neighborhood types (CNTs). Differential CNT representation divided cases into 3 aggregate TIME categories: immune-deficient, dendritic cell-enriched (DC-enriched), and macrophage-enriched (Mac-enriched). Cases with immune-deficient TIMEs have tumor cell-rich CNTs, in which the few infiltrating immune cells are enriched near CD31+ vessels, in keeping with limited immune activity. Cases with DC-enriched TIMEs selectively include tumor cell-poor/immune cell-rich CNTs with high numbers of CD11c+ DCs and antigen-experienced T cells also enriched near CD31+ vessels, in keeping with increased immune activity. Cases with Mac-enriched TIMEs selectively include tumor cell-poor/immune cell-rich CNTs with high numbers of CD163+ macrophages and CD8 T cells throughout the microenvironment, accompanied by increased IDO-1 and LAG-3 and decreased HLA-DR expression and genetic signatures in keeping with immune evasion. Our findings reveal that the heterogenous cellular components of DLBCL are not randomly distributed but organized into CNTs that define aggregate TIMEs with distinct cellular, spatial, and functional features.
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Linfoma Difuso de Grandes Células B , Linfoma não Hodgkin , Humanos , Diagnóstico por Imagem , Linfócitos T CD8-Positivos , Indolamina-Pirrol 2,3,-Dioxigenase , Microambiente TumoralRESUMO
Cancers avoid immune surveillance through an array of mechanisms, including perturbation of HLA class I antigen presentation. Merkel cell carcinoma (MCC) is an aggressive, HLA-I-low, neuroendocrine carcinoma of the skin often caused by the Merkel cell polyomavirus (MCPyV). Through the characterization of 11 newly generated MCC patient-derived cell lines, we identified transcriptional suppression of several class I antigen presentation genes. To systematically identify regulators of HLA-I loss in MCC, we performed parallel, genome-scale, gain- and loss-of-function screens in a patient-derived MCPyV-positive cell line and identified MYCL and the non-canonical Polycomb repressive complex 1.1 (PRC1.1) as HLA-I repressors. We observed physical interaction of MYCL with the MCPyV small T viral antigen, supporting a mechanism of virally mediated HLA-I suppression. We further identify the PRC1.1 component USP7 as a pharmacologic target to restore HLA-I expression in MCC.
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Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , Infecções por Polyomavirus , Neoplasias Cutâneas , Antígenos Virais de Tumores/genética , Antígenos Virais de Tumores/metabolismo , Carcinoma de Célula de Merkel/genética , Carcinoma de Célula de Merkel/patologia , Epigênese Genética , Humanos , Poliomavírus das Células de Merkel/genética , Poliomavírus das Células de Merkel/metabolismo , Infecções por Polyomavirus/genética , Neoplasias Cutâneas/patologia , Peptidase 7 Específica de Ubiquitina/metabolismoAssuntos
Avaliação Educacional , Licenciamento em Odontologia , Estados Unidos , Psicometria , CurrículoRESUMO
T-cell/histiocyte-rich large B-cell lymphoma (TCRLBCL) is an aggressive variant of diffuse large B-cell lymphoma (DLBCL) characterized by rare malignant B cells within a robust but ineffective immune cell infiltrate. The mechanistic basis of immune escape in TCRLBCL is poorly defined and not targeted therapeutically. We performed a genetic and quantitative spatial analysis of the PD-1/PD-L1 pathway in a multi-institutional cohort of TCRLBCLs and found that malignant B cells harbored PD-L1/PD-L2 copy gain or amplification in 64% of cases, which was associated with increased PD-L1 expression (P = .0111). By directed and unsupervised spatial analyses of multiparametric cell phenotypic data within the tumor microenvironment, we found that TCRLBCL is characterized by tumor-immune "neighborhoods" in which malignant B cells are surrounded by exceptionally high numbers of PD-L1-expressing TAMs and PD-1+ T cells. Furthermore, unbiased clustering of spatially resolved immune signatures distinguished TCRLBCL from related subtypes of B-cell lymphoma, including classic Hodgkin lymphoma (cHL) and DLBCL-NOS. Finally, we observed clinical responses to PD-1 blockade in 3 of 5 patients with relapsed/refractory TCRLBCL who were enrolled in clinical trials for refractory hematologic malignancies (NCT03316573; NCT01953692), including 2 complete responses and 1 partial response. Taken together, these data implicate PD-1 signaling as an immune escape pathway in TCRLBCL and also support the potential utility of spatially resolved immune signatures to aid the diagnostic classification and immunotherapeutic prioritization of diverse tumor types.
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Histiócitos/imunologia , Linfoma Difuso de Grandes Células B/imunologia , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T/imunologia , Evasão Tumoral , Antígeno B7-H1/análise , Antígeno B7-H1/imunologia , Histiócitos/patologia , Humanos , Linfoma Difuso de Grandes Células B/patologia , Receptor de Morte Celular Programada 1/análise , Linfócitos T/patologiaRESUMO
Patients with immune deficiencies from cancers and associated treatments represent a growing population within the intensive care unit with increased risk of morbidity and mortality from sepsis. Mesenchymal stromal cells (MSCs) are an integral part of the hematopoietic niche and express toll-like receptors, making them candidate cells to sense and translate pathogenic signals into an innate immune response. In this study, we demonstrate that MSCs administered therapeutically in a murine model of radiation-associated neutropenia have dual actions to confer a survival benefit in Pseudomonas aeruginosa pneumo-sepsis that is not from improved bacterial clearance. First, MSCs augment the neutrophil response to infection, an effect that is enhanced when MSCs are preconditioned with CpG oligodeoxynucleotide, a toll-like receptor 9 agonist. Using cytometry by time of flight, we identified proliferating neutrophils (Ly6GlowKi-67+) as the main expanded cell population within the bone marrow. Further analysis revealed that CpG-MSCs expand a lineage restricted progenitor population (Lin-Sca1+C-kit+CD150-CD48+) in the bone marrow, which corresponded to a doubling in the myeloid proliferation and differentiation potential in response to infection compared with control. Despite increased neutrophils, no reduction in organ bacterial count was observed between experimental groups. However, the second effect exerted by CpG-MSCs is to attenuate organ damage, particularly in the lungs. Neutrophils obtained from irradiated mice and cocultured with CpG-MSCs had decreased neutrophil extracellular trap formation, which was associated with decreased citrullinated H3 staining in the lungs of mice given CpG-MSCs in vivo. Thus, this preclinical study provides evidence for the therapeutic potential of MSCs in neutropenic sepsis.
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Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Neutropenia , Sepse , Animais , Hematopoese , Humanos , Camundongos , Neutropenia/terapia , Sepse/terapiaAssuntos
Cryptococcus neoformans/isolamento & purificação , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hospedeiro Imunocomprometido , Meningite Criptocócica/diagnóstico , Infecções Oportunistas/diagnóstico , Biópsia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Diagnóstico Diferencial , Evolução Fatal , Febre/etiologia , Doença Enxerto-Hospedeiro/etiologia , Cefaleia/etiologia , Humanos , Linfonodos/microbiologia , Linfo-Histiocitose Hemofagocítica/complicações , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/terapia , Imageamento por Ressonância Magnética , Masculino , Meningite Criptocócica/etiologia , Pessoa de Meia-Idade , Infecções Oportunistas/etiologia , Tomografia por Emissão de Pósitrons combinada à Tomografia ComputadorizadaRESUMO
PURPOSE: Axicabtagene ciloleucel (axi-cel) was approved by the Food and Drug Administration for relapsed aggressive B-cell non-Hodgkin lymphoma in part on the basis of durable remission rates of approximately 40% in a clinical trial population. Whether this efficacy, and the rates of toxicity, would be consistent in a postcommercial setting, with relaxed eligibility criteria and bridging therapy, is unknown. This study describes the efficacy and safety correlates and outcomes in this setting. PATIENTS AND METHODS: One hundred twenty-two patients from 7 medical centers in the United States were treated with axi-cel and were included in a modified intent-to-treat (mITT) analysis. Seventy-six patients (62%) were ineligible for the ZUMA-1 trial. Response and toxicity rates, duration of response (DOR), survival, and covariates are described on the basis of the mITT population. Correlative studies on blood and tumor samples were performed to investigate potential biomarkers of response and resistance. RESULTS: Median follow-up was 10.4 months. In the mITT population, the best overall and complete response (CR) rates were 70% and 50%, respectively. Median DOR and progression-free survival (PFS) were 11.0 and 4.5 months in all patients and were not reached (NR) in CR patients. Median overall survival (OS) was NR; 1-year OS was 67% (95% CI, 59% to 77%). Although response rates were similar in the ZUMA-1-eligible and ZUMA-1-ineligible groups (70% v 68%), there was a statistically significant improvement in CR rate (63% v 42%, P = .016), DOR (median, NR v 5.0 months; P = .014), PFS (median, NR v 3.3 months; P = .020), and OS (1-year OS, 89% v 54%; P < .001) in patients who were ZUMA-1 eligible. Rates of grade ≥ 3 cytokine release syndrome and neurotoxicty were 16% and 35%, respectively. CONCLUSION: Axi-cel yields similar rates of overall response and toxicity in commercial and trial settings, although CR rates and DOR were more favorable in patients eligible for ZUMA-1.
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Antígenos CD19/uso terapêutico , Linfoma Difuso de Grandes Células B/terapia , Adulto , Idoso , Antígenos CD19/efeitos adversos , Antígenos CD19/metabolismo , Antígeno B7-H1/metabolismo , Produtos Biológicos , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Ensaios Clínicos como Assunto , Síndrome da Liberação de Citocina/etiologia , Ferritinas/sangue , Humanos , Imunoterapia Adotiva/efeitos adversos , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Pessoa de Meia-Idade , Gradação de Tumores , Síndromes Neurotóxicas/etiologia , Seleção de Pacientes , Intervalo Livre de Progressão , Receptores de Antígenos Quiméricos/metabolismo , Recidiva , Estudos Retrospectivos , Taxa de Sobrevida , Linfócitos T/metabolismo , Adulto JovemRESUMO
Mechanisms of chimeric antigen receptor (CAR) T cell-mediated antitumor immunity and toxicity remain poorly characterized because few studies examine the intact tumor microenvironment (TME) following CAR T cell infusion. Axicabtagene ciloleucel is an autologous anti-CD19 CAR T cell therapy approved for patients with large B cell lymphoma. We devised multiplex immunostaining and ISH assays to interrogate CAR T cells and other immune cell infiltrates in biopsies of diffuse large B cell lymphoma following axicabtagene ciloleucel infusion. We found that a majority of intratumoral CAR T cells expressed markers of T cell activation but, unexpectedly, constituted ≤5% of all T cells within the TME 5 days or more after therapy. Large numbers of T cells without CAR were also activated within the TME after axicabtagene ciloleucel infusion; these cells were positive for Ki-67, IFN-γ, granzyme B (GzmB), and/or PD-1 and were found at the highest levels in biopsies with CAR T cells. Additionally, non-CAR immune cells were the exclusive source of IL-6, a cytokine associated with cytokine release syndrome, and were found at their highest numbers in biopsies with CAR T cells. These data suggest that intratumoral CAR T cells are associated with non-CAR immune cell activation within the TME with both beneficial and pathological effects.
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Antígenos CD19/uso terapêutico , Linfoma Difuso de Grandes Células B/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Microambiente Tumoral/imunologia , Antígenos CD19/imunologia , Produtos Biológicos , Biomarcadores/análise , Humanos , Imunoterapia Adotiva/métodos , Linfoma Difuso de Grandes Células B/patologia , Linfócitos T/imunologiaRESUMO
Metastatic tumors that have become resistant to androgen deprivation therapy represent the major challenge in treating prostate cancer. Although these recurrent tumors typically remain dependent on the androgen receptor (AR), non-AR-driven tumors that also emerge are particularly deadly and becoming more prevalent. Here, we present a new genetically engineered mouse model for non-AR-driven prostate cancer that centers on a negative regulator of G protein-coupled receptors that is downregulated in aggressive human prostate tumors. Thus, prostate-specific expression of a dominant-negative G protein-coupled receptor kinase 2 (GRK2-DN) transgene diminishes AR and AR target gene expression in the prostate, and confers resistance to castration-induced involution. Further, the GRK2-DN transgene dramatically accelerates oncogene-initiated prostate tumorigenesis by increasing primary tumor size, potentiating visceral organ metastasis, suppressing AR, and inducing neuroendocrine marker mRNAs. In summary, GRK2 enforces AR-dependence in the prostate, and the loss of GRK2 function in prostate tumors accelerates disease progression toward the deadliest stage.
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Quinase 2 de Receptor Acoplado a Proteína G/metabolismo , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Masculino , Camundongos , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologiaAssuntos
Granuloma/patologia , Linfoma de Zona Marginal Tipo Células B/complicações , Úlceras Orais/patologia , Idoso , Feminino , Granuloma/complicações , Granuloma/diagnóstico , Humanos , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Mucosa Bucal/lesões , Mucosa Bucal/patologia , Úlceras Orais/complicações , Úlceras Orais/diagnósticoRESUMO
MYD88 L265P is the most common mutation in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) and one of the most frequent in poor-prognosis subtypes of diffuse large B-cell lymphoma (DLBCL). Although inhibition of the mutated MYD88 pathway has an adverse impact on LPL/WM and DLBCL cell survival, its role in lymphoma initiation remains to be clarified. We show that in mice, human MYD88L265P promotes development of a non-clonal, low-grade B-cell lymphoproliferative disorder with several clinicopathologic features that resemble human LPL/WM, including expansion of lymphoplasmacytoid cells, increased serum immunoglobulin M (IgM) concentration, rouleaux formation, increased number of mast cells in the bone marrow, and proinflammatory signaling that progresses sporadically to clonal, high-grade DLBCL. Murine findings regarding differences in the pattern of MYD88 staining and immune infiltrates in the bone marrows of MYD88 wild-type (MYD88WT) and MYD88L265P mice are recapitulated in the human setting, which provides insight into LPL/WM pathogenesis. Furthermore, histologic transformation to DLBCL is associated with acquisition of secondary genetic lesions frequently seen in de novo human DLBCL as well as LPL/WM-transformed cases. These findings indicate that, although the MYD88L265P mutation might be indispensable for the LPL/WM phenotype, it is insufficient by itself to drive malignant transformation in B cells and relies on other, potentially targetable cooperating genetic events for full development of lymphoma.
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Substituição de Aminoácidos , Linfócitos B/metabolismo , Biomarcadores Tumorais , Transformação Celular Neoplásica/genética , Mutação , Fator 88 de Diferenciação Mieloide/genética , Alelos , Animais , Linfócitos B/patologia , Biópsia , Modelos Animais de Doenças , Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Imunofenotipagem , Camundongos , Camundongos Transgênicos , Fator 88 de Diferenciação Mieloide/metabolismo , Gradação de Tumores , Transcriptoma , Macroglobulinemia de Waldenstrom/etiologia , Macroglobulinemia de Waldenstrom/metabolismo , Macroglobulinemia de Waldenstrom/patologiaRESUMO
Patients with common variable immunodeficiency (CVID) can develop granulomatous-lymphocytic interstitial lung disease (GLILD), which is associated with increased morbidity and mortality. Treating GLILD is a significant challenge because it is rare and can be pathologically heterogeneous. Here we describe two cases of patients with CVID-associated GLILD with biopsies demonstrating loosely organized tertiary lymphoid structures (TLSs). Based on the pivotal role that B cells play in TLS initiation and maintenance, we hypothesized that using rituximab monotherapy for B-cell depletion alone would be sufficient for the disruption of the pathologic process underlying GLILD. These two cases demonstrate that adapting a strategy of B cell depletion monotherapy may be effective in TLS-associated conditions such as GLILD.
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Imunodeficiência de Variável Comum/complicações , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/patologia , Rituximab/uso terapêutico , Nódulo Pulmonar Solitário/tratamento farmacológico , Nódulo Pulmonar Solitário/patologia , Adulto , Antineoplásicos Imunológicos/uso terapêutico , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Biópsia por Agulha , Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/imunologia , Feminino , Seguimentos , Granuloma/imunologia , Granuloma/patologia , Humanos , Imuno-Histoquímica , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/etiologia , Masculino , Pneumonectomia/métodos , Estudos de Amostragem , Nódulo Pulmonar Solitário/diagnóstico por imagem , Nódulo Pulmonar Solitário/cirurgia , Tomografia Computadorizada por Raios X/métodos , Resultado do TratamentoAssuntos
Forâmen Jugular , Imageamento por Ressonância Magnética , Mieloma Múltiplo , Plasmocitoma , Neoplasias da Base do Crânio , Tomografia Computadorizada por Raios X , Adulto , Feminino , Humanos , Forâmen Jugular/diagnóstico por imagem , Forâmen Jugular/patologia , Mieloma Múltiplo/diagnóstico por imagem , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Plasmocitoma/diagnóstico por imagem , Plasmocitoma/metabolismo , Plasmocitoma/patologia , Plasmocitoma/terapia , Neoplasias da Base do Crânio/diagnóstico por imagem , Neoplasias da Base do Crânio/metabolismo , Neoplasias da Base do Crânio/patologia , Neoplasias da Base do Crânio/terapiaRESUMO
BACKGROUND: Programmed death cell 1 (PD-1) is an inhibitor of T cell activation and is also functionally linked to glycolysis. We hypothesized that PD-1 expression is defective in activated T cells from children with type 1 diabetes (T1D), resulting in abnormal T cell glucose metabolism. METHODS: In this pilot study, we enrolled children with new onset T1D within 2 weeks of diagnosis (T1D), unaffected siblings of T1D (SIBS), unaffected, unrelated children (CTRL), children with new onset, and untreated Crohn disease (CD). We repeated the assays 4-6 months post-diagnosis in T1D (T1D follow up). We analyzed anti-CD3/-CD28-stimulated peripheral blood mononuclear cells (PBMC) subsets for PD-1 expression by flow cytometry at baseline and after 24 h in culture. We measured cytokines in the culture medium by multiplex ELISA and glycolytic capacity with a flux analyzer. RESULTS: We enrolled 37 children. T cells derived from subjects with T1D had decreased PD-1 expression compared to the other study groups. However, in T1D follow-up T cells expressed PD-1 similarly to controls, but had no differences in PBMC cytokine production. Nonetheless, T1D follow up PBMCs had enhanced glycolytic capacity compared to T1D. CONCLUSIONS: Activated T cells from T1D fail to upregulate PD-1 upon T-cell receptor stimulation, which may contribute to the pathogenesis of T1D. T1D follow up PBMC expression of PD-1 normalizes, together with a significant increase in glycolysis compared to T1D. Thus, insulin therapy in T1D children is associated with normal PD1 expression and heightened glycolytic capacity in PBMC.
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Diabetes Mellitus Tipo 1/fisiopatologia , Receptor de Morte Celular Programada 1/fisiologia , Linfócitos T/fisiologia , Adolescente , Estudos de Casos e Controles , Morte Celular/fisiologia , Criança , Citocinas/fisiologia , Diabetes Mellitus Tipo 1/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Glicólise/fisiologia , Humanos , Leucócitos Mononucleares/fisiologia , Masculino , Projetos PilotoRESUMO
Classical Hodgkin lymphoma (cHL) is characterized by nearly universal genetic alterations in 9p24.1, resulting in constitutive expression of PD-1 ligands. This likely underlies the unique sensitivity of cHL to PD-1 blockade, with response rates of â¼70% in relapsed/refractory disease. There are now numerous clinical trials testing PD-1 inhibitors in earlier stages of treatment and in combination with many other therapies. In general, non-Hodgkin lymphomas (NHLs) do not display a high frequency of 9p24.1 alterations and do not share cHL's vulnerability to PD-1 blockade. However, a few entities have genetic or immunologic features that may predict sensitivity to immune checkpoint blockade. These include primary mediastinal B cell lymphoma, primary central nervous system lymphoma, and primary testicular lymphoma, which harbor frequent alterations in 9p24.1, as well as Epstein Barr virus (EBV)-infected lymphomas, where EBV infection leads to increased PD-L1 expression. Although these subtypes may be specifically vulnerable to PD-1 blockade, the majority of NHLs appear to be minimally sensitive to PD-1 blockade monotherapy. Current investigations in NHL are therefore focusing on targeting other checkpoints or studying PD-1-based combination therapy. Looking forward, additional insight into the most common mechanisms of resistance to immune checkpoint inhibitors will be important to guide rational clinical trial design. In this review, we describe the biological basis for checkpoint blockade in cHL and NHL and summarize the clinical data generated to date. Guided by our rapidly evolving understanding of the pathobiology of various lymphoma subtypes, we are hopeful that the role of checkpoint inhibitors in lymphoma treatment will continue to grow.