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1.
Nat Immunol ; 17(8): 966-75, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27270402

RESUMO

The number of naive T cells decreases and susceptibility to new microbial infections increases with age. Here we describe a previously unknown subset of phenotypically naive human CD8(+) T cells that rapidly secreted multiple cytokines in response to persistent viral antigens but differed transcriptionally from memory and effector T cells. The frequency of these CD8(+) T cells, called 'memory T cells with a naive phenotype' (TMNP cells), increased with age and after severe acute infection and inversely correlated with the residual capacity of the immune system to respond to new infections with age. CD8(+) TMNP cells represent a potential new target for the immunotherapy of persistent infections and should be accounted for and subtracted from the naive pool if truly naive T cells are needed to respond to antigens.


Assuntos
Envelhecimento/imunologia , Linfócitos T CD8-Positivos/fisiologia , Memória Imunológica , Imunossenescência , Subpopulações de Linfócitos T/fisiologia , Viroses/imunologia , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Cultivadas , Humanos , Imunofenotipagem , Ativação Linfocitária , Pessoa de Meia-Idade , Fenótipo , Transcriptoma , Adulto Jovem
2.
Br J Clin Pharmacol ; 78(6): 1257-63, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25047693

RESUMO

Vitamin D is a particularly important sterol hormone and its effects beyond bone are increasingly recognized. Over the last decade clinical interest has grown in vitamin D, with increased recognition of deficiency and hence increased prescribing of vitamin D products. However, the increased prescription of vitamin D has generally been met with unlicensed vitamin D products which potentially expose the patient to clinical risk. This review discusses the issues relating to the clinical use of unlicensed vitamin D products, safety concerns that may arise from this, as well as discussing the medico-legal responsibilities of the prescriber and dispenser.


Assuntos
Vitamina D/uso terapêutico , Suplementos Nutricionais , Prescrições de Medicamentos , Humanos , Legislação de Medicamentos , Licenciamento , Vitamina D/efeitos adversos
3.
Sci Adv ; 9(30): eadg9845, 2023 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-37494434

RESUMO

T cell receptor (TCR)-engineered T cell therapy using high-affinity TCRs is a promising treatment modality for cancer. Discovery of high-affinity TCRs especially against self-antigens can require approaches that circumvent central tolerance, which may increase the risk of cross-reactivity. Despite the potential for toxicity, no standardized approach to screen cross-reactivity has been established in the context of preclinical safety evaluation. Here, we describe a practical framework to prospectively detect clinically prohibitive cross-reactivity of therapeutic TCR candidates. Cross-reactivity screening consisted of multifaceted series of assays including assessment of p-MHC tetramer binding, cell line recognition, and reactivity against candidate peptide libraries. Peptide libraries were generated using conventional contact residue motif-guided search, amino acid substitution matrix-based search unguided by motif information, and combinatorial peptide library scan-guided search. We demonstrate the additive nature of a layered approach, which efficiently identifies unsafe cross-reactivity including one undetected by conventional motif-guided search. These findings have important implications for the safe development of TCR-based therapies.


Assuntos
Biblioteca de Peptídeos , Receptores de Antígenos de Linfócitos T , Receptores de Antígenos de Linfócitos T/metabolismo
4.
Nat Commun ; 14(1): 3708, 2023 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-37349293

RESUMO

We describe the first cases of germline biallelic null mutations in ARPC5, part of the Arp2/3 actin nucleator complex, in two unrelated patients presenting with recurrent and severe infections, early-onset autoimmunity, inflammation, and dysmorphisms. This defect compromises multiple cell lineages and functions, and when protein expression is reestablished in-vitro, the Arp2/3 complex conformation and functions are rescued. As part of the pathophysiological evaluation, we also show that interleukin (IL)-6 signaling is distinctively impacted in this syndrome. Disruption of IL-6 classical but not trans-signaling highlights their differential roles in the disease and offers perspectives for therapeutic molecular targets.


Assuntos
Complexo 2-3 de Proteínas Relacionadas à Actina , Actinas , Humanos , Complexo 2-3 de Proteínas Relacionadas à Actina/genética , Complexo 2-3 de Proteínas Relacionadas à Actina/metabolismo , Actinas/genética , Actinas/metabolismo , Movimento Celular , Mutação em Linhagem Germinativa , Citocinas/genética
5.
J Immunother Cancer ; 10(7)2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35793866

RESUMO

BACKGROUND: Cell therapy has shown promise in the treatment of certain solid tumors, but its efficacy may be limited by inhibition of therapeutic T cells by the programmed cell death protein-1 (PD-1) receptor. Clinical trials are testing cell therapy in combination with PDCD1 disruption or PD-1-axis blockade. However, preclinical data to support these approaches and to guide the treatment design are lacking. METHODS: Mechanisms of tumor regression and interaction between cell therapy and PD-1 blockade were investigated in congenic murine tumor models based on targeting established, solid tumors with T-cell receptor T cells directed against tumor-restricted, non-self antigens (ie, tumor neoantigens). RESULTS: In solid tumor models of cell therapy, PD-1 blockade mediated a reproducible but non-synergistic increase in tumor regression following adoptive T-cell transfer. Tumor regression was associated with increased tumor infiltration by endogenous T cells but not by transferred T cells. The effect was independent of PD-1 receptor expression by transferred T cells and was dependent on the endogenous T-cell repertoire and on tumor antigenicity. PD-1 blockade primarily induced cell state changes in endogenous tumor-antigen-specific T cells rather than transferred T cells. CONCLUSIONS: Together, these findings support the concept that PD-1 blockade acts primarily through endogenous rather than transferred T cells to mediate a non-synergistic antitumor effect in solid tumor cell therapy. These findings have important implications for strategies to leverage PD-1 receptor disruption or blockade to enhance the efficacy of cell therapy.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Neoplasias , Receptor de Morte Celular Programada 1 , Animais , Antígenos de Neoplasias , Humanos , Camundongos , Neoplasias/imunologia , Neoplasias/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T/metabolismo
6.
Science ; 376(6595): 880-884, 2022 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-35587980

RESUMO

Systems immunology lacks a framework with which to derive theoretical understanding from high-dimensional datasets. We combined a robotic platform with machine learning to experimentally measure and theoretically model CD8+ T cell activation. High-dimensional cytokine dynamics could be compressed onto a low-dimensional latent space in an antigen-specific manner (so-called "antigen encoding"). We used antigen encoding to model and reconstruct patterns of T cell immune activation. The model delineated six classes of antigens eliciting distinct T cell responses. We generalized antigen encoding to multiple immune settings, including drug perturbations and activation of chimeric antigen receptor T cells. Such universal antigen encoding for T cell activation may enable further modeling of immune responses and their rational manipulation to optimize immunotherapies.


Assuntos
Antígenos , Linfócitos T CD8-Positivos , Citocinas , Ativação Linfocitária , Modelos Imunológicos , Antígenos/imunologia , Linfócitos T CD8-Positivos/imunologia , Humanos , Imunoterapia , Aprendizado de Máquina , Receptores de Antígenos de Linfócitos T/metabolismo
7.
Chem Res Toxicol ; 24(6): 794-6, 2011 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-21557537

RESUMO

C57BL/6 mice are widely used in biomedical research for the background of genetically engineered mice (GEM) and wild-type controls with the belief that the genetic background of GEM and control mice differ significantly by only one or more altered genes. This principle, however, does have limitations due in part to the existence of multiple substrains of C57BL/6 mice that should not be used interchangeably as they can differ both genetically and phenotypically. We show here that these mispairings do occur frequently and can lead to inaccurate and conflicting findings.


Assuntos
Acetaminofen/toxicidade , Analgésicos não Narcóticos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Concanavalina A/toxicidade , Camundongos Endogâmicos C57BL/genética , Camundongos Transgênicos/genética , Proteína Quinase 9 Ativada por Mitógeno/genética , Mitógenos/toxicidade , Animais , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Técnicas de Silenciamento de Genes , Genótipo , Camundongos , Camundongos Knockout
8.
J Immunother Cancer ; 8(1)2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31959727

RESUMO

BACKGROUND: Interleukin-12 (IL-12) is a potent, proinflammatory cytokine that holds promise for cancer immunotherapy, but its clinical use has been limited by its toxicity. To minimize systemic exposure and potential toxicity while maintaining the beneficial effects of IL-12, we developed a novel IL-12-based therapeutic system that combines tumor-specific T-cell-mediated delivery of IL-12 with membrane-restricted IL-12 localization and inducible IL-12 expression. METHODS: Therapeutic T cells targeting a tumor antigen were genetically engineered to express membrane-anchored IL-12 (aIL-12). Expression, function, and shedding of the aIL-12 molecule was assessed in vitro. Tumor treatment efficacy was assessed in vivo with T cell receptor (TCR) transgenic murine tumor models and a tumor xenograft model. Key outcomes were change in tumor size, circulating levels of IL-12 and other cytokines, and survival. Toxicity was assessed via change in body weight. Tumor growth curve measurements were compared using repeated-measures two-way analyses of variance. RESULTS: Retroviral gene transfer resulted in cell membrane expression of aIL-12 by transduced T cells. In each of two transgenic murine tumor models, tumor-specific T cells constitutively expressing aIL-12 demonstrated increased antitumor efficacy, low circulating IL-12 and interferon-γ, and no weight loss. Expression of aIL-12 via a NFAT-inducible promoter resulted in coordinate expression of aIL-12 with T cell activation. In an OT-I TCR transgenic murine tumor model, the NFAT-inducible aIL-12 molecule improved tumor treatment and did not result in detectable levels of IL-12 in serum or in weight loss. In a human tumor xenograft model, the NFAT-inducible aIL-12 molecule improved antitumor responses by human T cells coexpressing a tumor-specific engineered TCR. Serum IL-12 levels were undetectable with the NFAT-inducible construct in both models. CONCLUSION: Expression of aIL-12 by tumor-targeting therapeutic T cells demonstrated low systemic exposure and improved efficacy. This treatment strategy may have broad applications to cellular therapy with tumor-infiltrating lymphocytes, chimeric antigen receptor T cells, and TCR T cells.


Assuntos
Antígenos de Neoplasias/imunologia , Imunoterapia Adotiva/métodos , Interleucina-12/imunologia , Linfócitos do Interstício Tumoral/imunologia , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Animais , Linhagem Celular Tumoral , Membrana Celular/genética , Membrana Celular/metabolismo , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Vetores Genéticos/imunologia , Humanos , Interferon gama/metabolismo , Interleucina-12/administração & dosagem , Interleucina-12/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Gerontol A Biol Sci Med Sci ; 73(8): 1018-1026, 2018 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-28582491

RESUMO

Age-related changes in primary lymphoid organs are well described. Less is known about age-related changes affecting peripheral lymphoid organs, although defects in old peripheral lymph nodes (pLNs) were recently described in both steady state and during viral infection. To address whether such pLN defects were intrinsic to old T cells or extrinsic (due to aging microenvironment), we employed heterochronic parabiosis. We found no age-related intrinsic or extrinsic barriers to T cell circulation and seeding of pLN, spleen, and bone marrow. However, heterochronic parabiosis failed to improve cellularity of old pLN, suggesting an environment-based limit on pLN cellularity. Furthermore, upon parabiosis, pLN of the adult partner exhibited reduced, old-like stromal and T cell cellularity, which was restored following separation of parabionts. Decay measurement of adult and old T cell subsets following separation of heterochronic parabionts delineated both T cell-intrinsic and environmental changes in T cell maintenance. Moreover, parabiotic separation revealed differences between CD4 and CD8 T cell subset maintenance with aging, the basis of which will require further investigation. Reasons for this asymmetric and subset-specific pattern of differential maintenance are discussed in light of possible age-related changes in lymph nodes as the key sites for peripheral T cell maintenance.


Assuntos
Envelhecimento/fisiologia , Tecido Linfoide/fisiologia , Linfócitos T/fisiologia , Animais , Humanos , Linfonodos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Parabiose
10.
Vaccine ; 32(29): 3595-603, 2014 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-24837506

RESUMO

IL-17 and IFN-γ production by Th17 and Th1 cells, respectively, is critical for survival during primary respiratory infection with the pathogenic bacterium, Francisella tularensis Live Vaccine Strain (LVS). The importance, however, of these T cell subsets and their soluble mediators is not well understood during a secondary or memory response. We measured the number of CD4(+) T cells producing IFN-γ or IL-17 in the spleen and lungs of vaccinated mice on day four of the secondary response using intracellular cytokine staining in order to identify protective T cell subsets participating in the memory response. Few bacteria were present in spleens of vaccinated mice on day four and a T cell response was not observed. In the lung, where more bacteria were present, there was a robust Th1 response in vaccinated mice but Th17 cells were not present at higher numbers in vaccinated mice compared to unvaccinated mice. These data show that the lung is the dominant site of the secondary immune response and suggest that Th17 cells are not required for survival during secondary challenge. To further investigate the importance of IFN-γ and IL-17 during the secondary response to F. tularensis, we neutralized either IFN-γ or IL-17 in vivo using monoclonal antibody treatment. Vaccinated mice treated with anti-IFN-γ lost more weight and had higher bacterial burdens compared to vaccinated mice treated with isotype control antibody. In contrast, treatment with anti-IL-17A antibody did not alter weight loss profiles or bacterial burdens compared to mice treated with isotype control antibody. Together, these results suggested that IFN-γ is required during both primary and secondary respiratory F. tularensis infection. IL-17, on the other hand, is only critical during the primary response to respiratory F. tularensis but dispensable during the secondary response.


Assuntos
Vacinas Bacterianas/imunologia , Imunidade Celular , Interferon gama/imunologia , Interleucina-17/imunologia , Subpopulações de Linfócitos T/imunologia , Tularemia/prevenção & controle , Animais , Anticorpos Antibacterianos/sangue , Anticorpos Monoclonais/administração & dosagem , Carga Bacteriana , Feminino , Francisella tularensis/imunologia , Imunoglobulina G/sangue , Memória Imunológica , Pulmão/imunologia , Camundongos Endogâmicos C57BL , Baço/imunologia , Vacinas Atenuadas/imunologia
11.
J Pept Sci ; 9(8): 471-501, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12952390

RESUMO

Constricting the peptide backbone into a more defined conformational form through cyclization is an activity evolved in nature and in synthetic work, the latter straddling only the most recent decades. The resulting conformational constraints increase the probability of an optimum response with bio-receptors. The purpose of this review is to highlight developments that have proved to be reasonably efficient in the macrocyclization of linear precursors into cyclic peptides and depsipeptides.


Assuntos
Hidroxibenzoatos/química , Oligopeptídeos/química , Peptídeos Cíclicos/síntese química , Sequência de Aminoácidos , Animais , Ciclização , Depsídeos , Modelos Químicos , Dados de Sequência Molecular , Estrutura Molecular , Oligopeptídeos/síntese química , Fragmentos de Peptídeos/química , Peptídeos Cíclicos/química , Conformação Proteica
12.
J Pept Sci ; 8(12): 663-70, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12523643

RESUMO

Two building blocks, Boc-Lys(Bn4-DTPA)-OH and Fmoc-Lys(Bu4(t)-DTPA)-OH have been synthesized via the acylation of the epsilon-amino group of N(alpha)-protected lysine, using suitably protected tetra-esters of diethylene triamine pentaacetic acid (DTPA), a ligand with wide application as a chelating agent for complexing metal tons to peptides.


Assuntos
Lisina/análogos & derivados , Ácido Pentético/análogos & derivados , Peptídeos/síntese química , Acilação , Aminoácidos/química , Quelantes/química , Fluorenos/química , Lisina/química , Ácido Pentético/química , Peptídeos/química
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