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1.
Clin Immunol ; 209: 108276, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31669582

RESUMO

Inhibitory cell-surface receptors on lymphocytes, often called immune checkpoints, are powerful targets for cancer therapy. Despite their direct involvement in autoimmune pathology, they are currently not exploited therapeutically for autoimmune diseases. Understanding the expression pattern of these receptors in health and disease is essential for targeted drug design. Here, we designed three 23-colour flow cytometry panels for peripheral-blood T cells, including 15 lineage-defining markers and 21 immunomodulatory cell-surface receptors, and a 22-marker panel for B cells. Blood samples from healthy individuals, multiple sclerosis (MS), and lupus (SLE) patients were included in the study. Several receptors show differential expression on regulatory T cells (Treg) compared to T helper (Th) 1 and Th17 cells, and functional relevance of this difference could be shown for BTLA and CD5. Unbiased multiparametric analysis revealed a subset of activated CD8+ T cells and a subset of unswitched memory B cells that are diminished in MS and SLE, respectively.


Assuntos
Doenças Autoimunes/imunologia , Linfócitos B/imunologia , Fatores Imunológicos/imunologia , Subpopulações de Linfócitos T/imunologia , Adolescente , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Adulto Jovem
2.
Nanomedicine ; 13(4): 1495-1506, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28065731

RESUMO

Inflamed organs display marked spatial heterogeneity of inflammation, with patches of inflamed tissue adjacent to healthy tissue. To investigate how nanocarriers (NCs) distribute between such patches, we created a mouse model that recapitulates the spatial heterogeneity of the inflammatory lung disease ARDS. NCs targeting the epitope PECAM strongly accumulated in the lungs, but were shunted away from inflamed lung regions due to hypoxic vasoconstriction (HVC). In contrast, ICAM-targeted NCs, which had lower whole-lung uptake than PECAM/NCs in inflamed lungs, displayed markedly higher NC levels in inflamed regions than PECAM/NCs, due to increased regional ICAM. Regional HVC, epitope expression, and capillary leak were sufficient to predict intra-organ of distribution of NCs, antibodies, and drugs. Importantly, these effects were not observable with traditional spatially-uniform models of ARDS, nor when examining only whole-organ uptake. This study underscores how examining NCs' intra-organ distribution in spatially heterogeneous animal models can guide rational NC design.


Assuntos
Portadores de Fármacos/farmacocinética , Epitopos/imunologia , Inflamação/patologia , Pulmão/patologia , Nanopartículas/química , Animais , Anticorpos/química , Portadores de Fármacos/química , Epitopos/química , Hipóxia/fisiopatologia , Inflamação/metabolismo , Molécula 1 de Adesão Intercelular/imunologia , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Molécula-1 de Adesão Celular Endotelial a Plaquetas/imunologia , Síndrome do Desconforto Respiratório/metabolismo , Síndrome do Desconforto Respiratório/patologia , Vasoconstrição
3.
Am J Physiol Lung Cell Mol Physiol ; 311(6): L1062-L1075, 2016 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-27694472

RESUMO

Alveolar epithelial regeneration is essential for resolution of the acute respiratory distress syndrome (ARDS). Although neutrophils have traditionally been considered mediators of epithelial damage, recent studies suggest they promote type II pneumocyte (AT2) proliferation, which is essential for regenerating alveolar epithelium. These studies did not, however, evaluate this relationship in an in vivo model of alveolar epithelial repair following injury. To determine whether neutrophils influence alveolar epithelial repair in vivo, we developed a unilateral acid injury model that creates a severe yet survivable injury with features similar to ARDS. Mice that received injections of the neutrophil-depleting Ly6G antibody had impaired AT2 proliferation 24 and 72 h after acid instillation, which was associated with decreased reepithelialization and increased alveolar protein concentration 72 h after injury. As neutrophil depletion itself may alter the cytokine response, we questioned the contribution of neutrophils to alveolar epithelial repair in neutropenic granulocyte-colony stimulating factor (G-CSF)-/- mice. We found that the loss of G-CSF recapitulated the neutrophil response of Ly6G-treated mice and was associated with defective alveolar epithelial repair, similar to neutrophil-depleted mice, and was reversed by administration of exogenous G-CSF. To approach the mechanisms, we employed an unbiased protein analysis of bronchoalveolar lavage fluid from neutrophil-depleted and neutrophil-replete mice 12 h after inducing lung injury. Pathway analysis identified significant differences in multiple signaling pathways that may explain the differences in epithelial repair. These data emphasize an important link between the innate immune response and tissue repair in which neutrophils promote alveolar epithelial regeneration.


Assuntos
Lesão Pulmonar Aguda/patologia , Células Epiteliais Alveolares/patologia , Epitélio/patologia , Neutrófilos/patologia , Regeneração , Ácidos , Lesão Pulmonar Aguda/induzido quimicamente , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/metabolismo , Animais , Anticorpos/farmacologia , Líquido da Lavagem Broncoalveolar , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Epitélio/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/deficiência , Fator Estimulador de Colônias de Granulócitos/metabolismo , Camundongos Endogâmicos C57BL , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Proteômica , Regeneração/efeitos dos fármacos , Síndrome do Desconforto Respiratório/patologia , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Cicatrização/efeitos dos fármacos
4.
ACS Nano ; 18(33): 22275-22297, 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-39105696

RESUMO

Nanomedicine has long pursued the goal of targeted delivery to specific organs and cell types but has yet to achieve this goal with the vast majority of targets. One rare example of success in this pursuit has been the 25+ years of studies targeting the lung endothelium using nanoparticles conjugated to antibodies against endothelial surface molecules. However, here we show that such "endothelial-targeted" nanocarriers also effectively target the lungs' numerous marginated neutrophils, which reside in the pulmonary capillaries and patrol for pathogens. We show that marginated neutrophils' uptake of many of these "endothelial-targeted" nanocarriers is on par with endothelial uptake. This generalizes across diverse nanomaterials and targeting moieties and was even found with physicochemical lung tropism (i.e., without targeting moieties). Further, we observed this in ex vivo human lungs and in vivo healthy mice, with an increase in marginated neutrophil uptake of nanoparticles caused by local or distant inflammation. These findings have implications for nanomedicine development for lung diseases. These data also suggest that marginated neutrophils, especially in the lungs, should be considered a major part of the reticuloendothelial system (RES), with a special role in clearing nanoparticles that adhere to the lumenal surfaces of blood vessels.


Assuntos
Pulmão , Nanopartículas , Neutrófilos , Animais , Neutrófilos/metabolismo , Neutrófilos/imunologia , Humanos , Pulmão/imunologia , Pulmão/metabolismo , Camundongos , Nanopartículas/química , Sistema Fagocitário Mononuclear/metabolismo , Endotélio/metabolismo , Camundongos Endogâmicos C57BL , Nanomedicina
5.
ACS Nano ; 17(14): 13121-13136, 2023 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-37432926

RESUMO

Ex vivo-loaded white blood cells (WBC) can transfer cargo to pathological foci in the central nervous system (CNS). Here we tested affinity ligand driven in vivo loading of WBC in order to bypass the need for ex vivo WBC manipulation. We used a mouse model of acute brain inflammation caused by local injection of tumor necrosis factor alpha (TNF-α). We intravenously injected nanoparticles targeted to intercellular adhesion molecule 1 (anti-ICAM/NP). We found that (A) at 2 h, >20% of anti-ICAM/NP were localized to the lungs; (B) of the anti-ICAM/NP in the lungs >90% were associated with leukocytes; (C) at 6 and 22 h, anti-ICAM/NP pulmonary uptake decreased; (D) anti-ICAM/NP uptake in brain increased up to 5-fold in this time interval, concomitantly with migration of WBCs into the injured brain. Intravital microscopy confirmed transport of anti-ICAM/NP beyond the blood-brain barrier and flow cytometry demonstrated complete association of NP with WBC in the brain (98%). Dexamethasone-loaded anti-ICAM/liposomes abrogated brain edema in this model and promoted anti-inflammatory M2 polarization of macrophages in the brain. In vivo targeted loading of WBC in the intravascular pool may provide advantages of coopting WBC predisposed to natural rapid mobilization from the lungs to the brain, connected directly via conduit vessels.


Assuntos
Sistemas de Liberação de Medicamentos , Pulmão , Camundongos , Animais , Pulmão/metabolismo , Encéfalo/metabolismo , Lipossomos/metabolismo , Leucócitos/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo
6.
Best Pract Res Clin Rheumatol ; 36(1): 101742, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35248489

RESUMO

Rheumatoid arthritis is an autoimmune disease that causes significant morbidity. Application of cellular profiling techniques such as single-cell transcriptomics and spatial transcriptomics has uncovered novel pathogenic cell types in RA joint tissues and revealed marked heterogeneity in the cellular composition among RA patients. Together, these insights provide exciting opportunities to translate discoveries into precision medicine in RA. The present review aims to highlight novel insights into RA pathology and discuss key steps needed to translate these discoveries into actionable changes in clinical practice. We review the efforts to identify surrogate biomarkers that could be used to predict RA synovial tissue phenotypes and the corresponding responses to therapy. Finally, we discuss the opportunity to develop novel patient-derived organoid systems as a platform for therapeutic target validation.


Assuntos
Artrite Reumatoide , Medicina de Precisão , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/genética , Artrite Reumatoide/terapia , Biomarcadores/metabolismo , Humanos , Medicina de Precisão/efeitos adversos , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia
7.
Science ; 376(6590): eabi9591, 2022 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-35258337

RESUMO

In this work, we find that CD8+ T cells expressing inhibitory killer cell immunoglobulin-like receptors (KIRs) are the human equivalent of Ly49+CD8+ regulatory T cells in mice and are increased in the blood and inflamed tissues of patients with a variety of autoimmune diseases. Moreover, these CD8+ T cells efficiently eliminated pathogenic gliadin-specific CD4+ T cells from the leukocytes of celiac disease patients in vitro. We also find elevated levels of KIR+CD8+ T cells, but not CD4+ regulatory T cells, in COVID-19 patients, correlating with disease severity and vasculitis. Selective ablation of Ly49+CD8+ T cells in virus-infected mice led to autoimmunity after infection. Our results indicate that in both species, these regulatory CD8+ T cells act specifically to suppress pathogenic T cells in autoimmune and infectious diseases.


Assuntos
Doenças Autoimunes , COVID-19 , Animais , Linfócitos T CD8-Positivos , Humanos , Camundongos , Receptores KIR , Linfócitos T Reguladores
8.
bioRxiv ; 2021 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-34981055

RESUMO

Previous reports show that Ly49 + CD8 + T cells can suppress autoimmunity in mouse models of autoimmune diseases. Here we find a markedly increased frequency of CD8 + T cells expressing inhibitory Killer cell Immunoglobulin like Receptors (KIR), the human equivalent of the Ly49 family, in the blood and inflamed tissues of various autoimmune diseases. Moreover, KIR + CD8 + T cells can efficiently eliminate pathogenic gliadin-specific CD4 + T cells from Celiac disease (CeD) patients' leukocytes in vitro . Furthermore, we observe elevated levels of KIR + CD8 + T cells, but not CD4 + regulatory T cells, in COVID-19 and influenza-infected patients, and this correlates with disease severity and vasculitis in COVID-19. Expanded KIR + CD8 + T cells from these different diseases display shared phenotypes and similar T cell receptor sequences. These results characterize a regulatory CD8 + T cell subset in humans, broadly active in both autoimmune and infectious diseases, which we hypothesize functions to control self-reactive or otherwise pathogenic T cells. ONE-SENTENCE SUMMARY: Here we identified KIR + CD8 + T cells as a regulatory CD8 + T cell subset in humans that suppresses self-reactive or otherwise pathogenic CD4 + T cells.

9.
Front Immunol ; 11: 626820, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33658999

RESUMO

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B cell dysregulation and breaks in tolerance that lead to the production of pathogenic autoantibodies. We performed single-cell RNA sequencing of B cells from healthy donors and individuals with SLE which revealed upregulated CD52 expression in SLE patients. We further demonstrate that SLE patients exhibit significantly increased levels of B cell surface CD52 expression and plasma soluble CD52, and levels of soluble CD52 positively correlate with measures of lupus disease activity. Using CD52-deficient JeKo-1 cells, we show that cells lacking surface CD52 expression are hyperresponsive to B cell receptor (BCR) signaling, suggesting an inhibitory role for the surface-bound protein. In healthy donor B cells, antigen-specific BCR-activation initiated CD52 cleavage in a phospholipase C dependent manner, significantly reducing cell surface levels. Experiments with recombinant CD52-Fc showed that soluble CD52 inhibits BCR signaling in a manner partially-dependent on Siglec-10. Moreover, incubation of unstimulated B cells with CD52-Fc resulted in the reduction of surface immunoglobulin and CXCR5. Prolonged incubation of B cells with CD52 resulted in the expansion of IgD+IgMlo anergic B cells. In summary, our findings suggest that CD52 functions as a homeostatic protein on B cells, by inhibiting responses to BCR signaling. Further, our data demonstrate that CD52 is cleaved from the B cell surface upon antigen engagement, and can suppress B cell function in an autocrine and paracrine manner. We propose that increased expression of CD52 by B cells in SLE represents a homeostatic mechanism to suppress B cell hyperactivity.


Assuntos
Autoanticorpos/sangue , Linfócitos B/imunologia , Antígeno CD52/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Receptores de Antígenos de Linfócitos B/metabolismo , Linfócitos B/metabolismo , Antígeno CD52/sangue , Antígeno CD52/metabolismo , Quimiocina CXCL13/metabolismo , Regulação da Expressão Gênica/imunologia , Genes MHC da Classe II/imunologia , Humanos , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Lúpus Eritematoso Sistêmico/fisiopatologia , RNA-Seq , Receptores CXCR5/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais/imunologia , Análise de Célula Única , Fosfolipases Tipo C/metabolismo
10.
Nat Commun ; 9(1): 2684, 2018 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-29992966

RESUMO

Drug delivery by nanocarriers (NCs) has long been stymied by dominant liver uptake and limited target organ deposition, even when NCs are targeted using affinity moieties. Here we report a universal solution: red blood cell (RBC)-hitchhiking (RH), in which NCs adsorbed onto the RBCs transfer from RBCs to the first organ downstream of the intravascular injection. RH improves delivery for a wide range of NCs and even viral vectors. For example, RH injected intravenously increases liposome uptake in the first downstream organ, lungs, by ~40-fold compared with free NCs. Intra-carotid artery injection of RH NCs delivers >10% of the injected NC dose to the brain, ~10× higher than that achieved with affinity moieties. Further, RH works in mice, pigs, and ex vivo human lungs without causing RBC or end-organ toxicities. Thus, RH is a clinically translatable platform technology poised to augment drug delivery in acute lung disease, stroke, and several other diseases.


Assuntos
Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Eritrócitos/química , Nanopartículas/química , Adsorção , Animais , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/farmacocinética , Humanos , Pulmão/metabolismo , Pneumopatias/metabolismo , Pneumopatias/terapia , Camundongos Endogâmicos C57BL , Nanopartículas/administração & dosagem , Ratos , Suínos
11.
Front Immunol ; 8: 319, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28386257

RESUMO

Mature B lymphocytes (B cells) recognize antigens using their B cell receptor (BCR) and are activated to become antibody-producing cells. In addition, and integral to the development of a high-affinity antibodies, B cells utilize the specialized major histocompatibility complex class II (MHCII) antigen presentation pathway to process BCR-bound and internalized protein antigens and present selected peptides in complex with MHCII to CD4+ T cells. This interaction influences the fate of both types of lymphocytes and shapes immune outcomes. Specific, effective, and optimally timed antigen presentation by B cells requires well-controlled intracellular machinery, often regulated by the combined effects of several molecular events. Here, we delineate and summarize these events in four steps along the antigen presentation pathway: (1) antigen capture and uptake by B cells; (2) intersection of internalized antigen/BCRs complexes with MHCII in peptide-loading compartments; (3) generation and regulation of MHCII/peptide complexes; and (4) exocytic transport for presentation of MHCII/peptide complexes at the surface of B cells. Finally, we discuss modulation of the MHCII presentation pathway across B cell development and maturation to effector cells, with an emphasis on the shaping of the MHCII/peptide repertoire by two key antigen presentation regulators in B cells: HLA-DM and HLA-DO.

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