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1.
J Med Chem ; 67(18): 16222-16234, 2024 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-39235949

RESUMO

Toll-like receptor (TLR) activation converts immunologically inactive tumors into immunologically active tumors by activating tumor residing antigen-presenting cells and recruitment of cytotoxic T lymphocytes. Targeted immune agonists (TIAs) are antibody drug conjugates with small-molecule TLR agonist payloads. The mechanism of action of TIAs involves tumor antigen recognition, Fcγ-receptor-dependent phagocytosis, and TLR-mediated activation to drive tumor killing by myeloid cells. Several new low DAR anti-HER2 TIAs conjugated with novel TLR7 or dual-TLR7/8 agonists with cleavable and noncleavable linkers were synthesized and profiled. In vitro studies demonstrated that these TIAs activate myeloid cells only in the presence of antigen-expressing cancer cells. Evaluation in ELISpot-based assays confirmed the low immunogenicity of these constructs. Systemic administration of the novel TIAs in tumor-bearing mice resulted in tumor reduction at low doses. These results provide a strong rationale for further development of the TIAs as a novel class of immunotherapeutics.


Assuntos
Receptor 7 Toll-Like , Animais , Humanos , Camundongos , Receptor 7 Toll-Like/agonistas , Linhagem Celular Tumoral , Receptor 8 Toll-Like/agonistas , Imunoconjugados/farmacologia , Imunoconjugados/química , Feminino , Receptor ErbB-2/metabolismo , Receptor ErbB-2/imunologia , Descoberta de Drogas , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Receptores Toll-Like/agonistas
2.
Oncoimmunology ; 13(1): 2395067, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39188754

RESUMO

Toll-like receptor (TLR) agonists are being developed as anti-cancer therapeutics due to their potent immunostimulatory properties. However, clinical trials testing TLR agonists as monotherapy have often failed to demonstrate significant improvement over standard of care. We hypothesized that the anti-cancer efficacy of TLR agonist immunotherapy could be improved by combinatorial approaches. To prevent increased toxicity, often seen with systemic combination therapies, we developed a hydrogel to deliver TLR agonist combinations at low doses, locally, during cancer debulking surgery. Using tumor models of WEHI 164 and bilateral M3-9-M sarcoma and CT26 colon carcinoma, we assessed the efficacy of pairwise combinations of poly(I:C), R848, and CpG in controlling local and distant tumor growth. We show that combination of the TLR3 agonist poly(I:C) and TLR7/8 agonist R848 drives anti-tumor immunity against local and distant tumors. In addition, combination of local poly(I:C) and R848 sensitized tumors to systemic immune checkpoint blockade, improving tumor control. Mechanistically, we demonstrate that local therapy with poly(I:C) and R848 recruits inflammatory monocytes to the tumor draining lymph nodes early in the anti-tumor response. Finally, we provide proof of concept for intraoperative delivery of poly(I:C) and R848 together via a surgically applicable biodegradable hydrogel.


Assuntos
Imidazóis , Inibidores de Checkpoint Imunológico , Poli I-C , Animais , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/administração & dosagem , Inibidores de Checkpoint Imunológico/uso terapêutico , Camundongos , Poli I-C/administração & dosagem , Poli I-C/farmacologia , Poli I-C/uso terapêutico , Imidazóis/farmacologia , Imidazóis/administração & dosagem , Imidazóis/uso terapêutico , Imunoterapia/métodos , Humanos , Receptores Toll-Like/agonistas , Linhagem Celular Tumoral , Feminino , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/terapia , Camundongos Endogâmicos C57BL , Hidrogéis/administração & dosagem , Hidrogéis/química , Agonistas do Receptor Semelhante a Toll
3.
Acta Biomater ; 186: 369-382, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-39097127

RESUMO

Immunotherapy, as a promising treatment strategy for cancer, has been widely employed in clinics, while its efficiency is limited by the immunosuppression of tumor microenvironment (TME). Tumor-associate macrophages (TAMs) are the most abundant immune cells infiltrating the TME and play a crucial role in immune regulation. Herein, a M0-type macrophage-mediated drug delivery system (PR-M) was designed for carrying Toll-like receptors (TLRs) agonist-loaded nanoparticles. When TLR agonist R848 was released by responding to the TME, the PR-Ms were polarized from M0-type to M1-type and TAMs were also stimulated from M2-type to M1-type, which eventually reversed the immunosuppressive states of TME. By synergizing with the released R848 agonists, the PR-M significantly activated CD4+ and CD8+ T cells in the TME and turned the 'cold' tumor into 'hot' tumor by regulating the secretion of cytokines including IFN-γ, TNF-α, IL-10, and IL-12, thus ultimately promoting the activation of antitumor immunity. In a colorectal cancer mouse model, the PR-M treatment effectively accumulated at the tumor site, with a 5.47-fold increase in M1-type and a 65.08 % decrease in M2-type, resulting in an 85.25 % inhibition of tumor growth and a 87.55 % reduction of tumor volume compared with the non-treatment group. Our work suggests that immune cell-mediated drug delivery systems can effectively increase drug accumulation at the tumor site and reduce toxic side effects, resulting in a strong immune system for tumor immunotherapy. STATEMENT OF SIGNIFICANCE: The formation of TME and the activation of TAMs create an immunosuppressive network that allows tumor to escape the immune system and promotes its growth and spread. In this study, we designed an M0-type macrophage-mediated drug delivery system (PR-M). It leverages the synergistic effect of macrophages and agonists to improve the tumor immunosuppressive micro-environment by increasing M1-type macrophages and decreasing M2-type macrophages. As part of the treatment, the drug-loaded macrophages endowed the system with excellent tumor targeting. Furthermore, loading R848 into TME-responsive nanoparticles could protect macrophages and reduce the potential toxicity of agonists. Further investigations demonstrated that the designed PR-M could be a feasible strategy with high efficacy in tumor targeting, drug loading, autoimmunity activation, and lower side effects.


Assuntos
Imunoterapia , Microambiente Tumoral , Microambiente Tumoral/efeitos dos fármacos , Animais , Imunoterapia/métodos , Camundongos , Macrófagos/metabolismo , Macrófagos/imunologia , Macrófagos/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Células RAW 264.7 , Imidazóis/farmacologia , Imidazóis/química , Linhagem Celular Tumoral , Nanopartículas/química , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia , Receptores Toll-Like/agonistas , Camundongos Endogâmicos BALB C , Humanos , Feminino , Camundongos Endogâmicos C57BL , Citocinas/metabolismo
4.
Clin Transl Med ; 14(7): e1765, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39031979

RESUMO

BACKGROUND: The meticulous selection of appropriate vaccine adjuvants is crucial for optimizing immune responses. Traditionally, pemphigus vulgaris (PV), an autoimmune disorder, has been modelled using complete Freund's adjuvant (CFA). In this study, we aimed to discern potential variations in immune responses elicited by Toll-like receptor (TLR) ligands as compared to CFA. METHODS: A comprehensive investigation was conducted, comparing the effects of these adjuvants in conjunction with ovalbumin or desmoglein-3. Flow cytometry was employed to analyse distinct cell subsets, while enzyme-linked immunosorbent assay quantified antigen-specific antibodies and cytokine levels. Histological examination of harvested skin tissues and transcriptome analysis of skin lesions were performed to identify differentially expressed genes. RESULTS: TLR ligands demonstrated efficacy in inducing PV-like symptoms in wild-type mice, in contrast to CFA. This underscored the substantial impact of the adjuvant on self-antigen tolerance. Furthermore, we proposed an enhanced method for establishing a PV model through adoptive transfer, substituting CFA with TLR ligands. Our results revealed that in contrast to the perception that CFA being the most potent immunopotentiator reported, CFA promoted regulatory T cells (Treg), follicular regulatory T cells and IL-10-producing neutrophils, whereas TLR ligands downregulated CCL17 and IL-10. This suggested potential implications for the recruitment and activation of Treg subsets. While B cell and CD8+ T cell responses exhibited similarity, CFA induced less activation in dendritic cell subsets. A novel mouse model of PV and systemic comparison of immunostimulatory effects of adjuvants were provided by this study. CONCLUSIONS: The systematic comparison of CFA and TLR ligands shed light on the distinctive properties of these adjuvants, presenting innovative mouse models for the investigation of pemphigus. This study significantly contributes to adjuvant research and advances our understanding of PV pathogenesis. KEY POINTS/HIGHLIGHTS: Immunization with desmoglein 3 and Toll-like receptor (TLR) ligands effectively induces pemphigus symptoms in wild-type mice, whereas complete Freund's adjuvant (CFA) fails. TLR ligands heightened the autoreactivity of donor cells in the adoptive transfer pemphigus model. CFA promoted regulatory T cells and IL-10-producing neutrophils, whereas TLR ligands downregulated CCL17 and IL-10, leading to more effective immune responses.


Assuntos
Adjuvantes Imunológicos , Modelos Animais de Doenças , Pênfigo , Receptores Toll-Like , Animais , Pênfigo/imunologia , Camundongos , Receptores Toll-Like/metabolismo , Receptores Toll-Like/imunologia , Receptores Toll-Like/agonistas , Adjuvantes Imunológicos/farmacologia , Adjuvante de Freund/imunologia , Camundongos Endogâmicos C57BL , Ligantes , Ovalbumina/imunologia , Feminino
5.
Int J Mol Sci ; 25(13)2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-39000607

RESUMO

Natural killer (NK) cells play a crucial role in innate immunity, particularly in combating infections and tumors. However, in hematological cancers, NK cells often exhibit impaired functions. Therefore, it is very important to activate its endosomal Toll-like receptors (TLRs) as a potential strategy to restore its antitumor activity. We stimulated NK cells from the peripheral blood mononuclear cells from children with acute lymphoblastic leukemia and NK cells isolated, and the NK cells were stimulated with specific TLR ligands (Poly I:C, Imiquimod, R848, and ODN2006) and we evaluated changes in IFN-γ, CD107a, NKG2D, NKp44 expression, Granzyme B secretion, cytokine/chemokine release, and cytotoxic activity. Results revealed that Poly I:C and Imiquimod enhanced the activation of both immunoregulatory and cytotoxic NK cells, increasing IFN-γ, CD107a, NKG2D, and NKp44 expression. R848 activated immunoregulatory NK cells, while ODN2006 boosted CD107a, NKp44, NKG2D, and IFN-γ secretion in cytotoxic NK cells. R848 also increased the secretion of seven cytokines/chemokines. Importantly, R848 and ODN 2006 significantly improved cytotoxicity against leukemic cells. Overall, TLR stimulation enhances NK cell activation, suggesting TLR8 (R848) and TLR9 (ODN 2006) ligands as promising candidates for antitumor immunotherapy.


Assuntos
Imiquimode , Células Matadoras Naturais , Ativação Linfocitária , Poli I-C , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores Toll-Like , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Poli I-C/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Imiquimode/farmacologia , Receptores Toll-Like/metabolismo , Receptores Toll-Like/agonistas , Criança , Oligodesoxirribonucleotídeos/farmacologia , Citocinas/metabolismo , Feminino , Interferon gama/metabolismo , Masculino , Imidazóis/farmacologia , Citotoxicidade Imunológica/efeitos dos fármacos , Pré-Escolar , Agonistas do Receptor Semelhante a Toll
6.
Curr Opin Allergy Clin Immunol ; 24(5): 380-389, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39079155

RESUMO

PURPOSE OF REVIEW: Allergic conjunctivitis is characterized by the development of pathophysiological changes to the ocular surface, which occurs when pro-allergic and pro-inflammatory mediators interact with their cognate receptors expressed on immune and nonimmune cells. Traditional treatments with antihistamines and corticosteroids provide relief, but there is a need for more efficacious and tolerable long-term therapy with a better safety profile. This article aims to provide an overview of the mode of action and clinical application of agonist therapies targeting glucocorticoid, melanocortin, and toll-like receptors, as well as antagonist therapies targeting cytokine, chemokine, integrin, and histamine receptors. RECENT FINDINGS: There has been considerable advancement in immunology and pharmacology, as well as a greater understanding of the cellular and molecular mechanisms of allergic conjunctivitis. Recent research advancing therapy for allergic conjunctivitis has focused on developing synthetic molecules and biologics that can interfere with the process of the allergic immune reaction. SUMMARY: This review discusses novel therapeutic receptors being explored agonistically or antagonistically to develop alternative treatment options for allergic conjunctivitis. These novel approaches hold promise for improving the management of allergic eye diseases, offering patients hope for more effective and safer treatment options in the future.


Assuntos
Conjuntivite Alérgica , Humanos , Conjuntivite Alérgica/tratamento farmacológico , Conjuntivite Alérgica/imunologia , Animais , Antialérgicos/uso terapêutico , Antialérgicos/farmacologia , Receptores Toll-Like/agonistas , Receptores Toll-Like/antagonistas & inibidores , Receptores Toll-Like/imunologia , Receptores Toll-Like/metabolismo , Antagonistas dos Receptores Histamínicos/uso terapêutico
7.
Int J Mol Sci ; 25(13)2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-39000127

RESUMO

The prevalence of prenatal alcohol exposure (PAE) is increasing, with evidence suggesting that PAE is linked to an increased risk of infections. PAE is hypothesized to affect the innate immune system, which identifies pathogens through pattern recognition receptors, of which toll-like receptors (TLRs) are key components. We hypothesized that light-to-moderate PAE would impair immune responses, as measured by a heightened response in cytokine levels following TLR stimulation. Umbilical cord samples (10 controls and 8 PAE) from a subset of the Ethanol, Neurodevelopment, Infant and Child Health Study-2 cohort were included. Peripheral blood mononuclear cells (PMBCs) were stimulated with one agonist (TLR2, TLR3, TLR4, or TLR9). TLR2 agonist stimulation significantly increased pro-inflammatory interleukin-1-beta in the PAE group after 24 h. Pro- and anti-inflammatory cytokines were increased following stimulation with the TLR2 agonists. Stimulation with TLR3 or TLR9 agonists displayed minimal impact overall, but there were significant increases in the percent change of the control compared to PAE after 24 h. The results of this pilot investigation support further work into the impact on TLR2 and TLR4 response following PAE to delineate if alterations in levels of pro- and anti-inflammatory cytokines have clinical significance that could be used in patient management and/or attention to follow-up.


Assuntos
Sangue Fetal , Receptores Toll-Like , Humanos , Feminino , Gravidez , Sangue Fetal/metabolismo , Projetos Piloto , Receptores Toll-Like/metabolismo , Receptores Toll-Like/agonistas , Citocinas/metabolismo , Citocinas/sangue , Adulto , Recém-Nascido , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Etanol/farmacologia , Receptor 2 Toll-Like/metabolismo , Receptor 2 Toll-Like/agonistas
8.
Sci Rep ; 14(1): 17173, 2024 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-39060412

RESUMO

Toll-like receptors (TLRs) are critical components to stimulate immune responses against various infections. Recently, TLR agonists have emerged as a promising way to activate anti-tumor immunity. L-pampo, a TLR1/2 and TLR3 agonist, induces humoral and cellular immune responses and also causes cancer cell death. In this study, we investigated the L-pampo-induced signals and delineated their interactions with molecular signaling pathways using RNA-seq in immune cells and colon and prostate cancer cells. We first constructed a template network with differentially expressed genes and influential genes from network propagation using the weighted gene co-expression network analysis. Next, we obtained perturbed modules using the above method and extracted core submodules from them by conducting Walktrap. Finally, we reconstructed the subnetworks of major molecular signals utilizing a shortest path-finding algorithm, TOPAS. Our analysis suggests that TLR signaling activated by L-pampo is transmitted to oxidative phosphorylation (OXPHOS) with reactive oxygen species (ROS) through PI3K-AKT and JAK-STAT only in immune and prostate cancer cells that highly express TLRs. This signal flow may further sensitize prostate cancer to L-pampo due to its high basal expression level of OXPHOS and ROS. Our computational approaches can be applied for inferring underlying molecular mechanisms from complex gene expression profiles.


Assuntos
Redes Reguladoras de Genes , Transdução de Sinais , Receptores Toll-Like , Humanos , Receptores Toll-Like/agonistas , Receptores Toll-Like/metabolismo , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Masculino , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Fosforilação Oxidativa , Agonistas do Receptor Semelhante a Toll
9.
Sci Transl Med ; 16(758): eadq5644, 2024 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-39083583

RESUMO

Adjuvants that combine TLR agonists and inflammatory agonists promote robust and durable vaccine responses (Bechtold et al. and Arunachalam et al.).


Assuntos
Adjuvantes Imunológicos , Receptores Toll-Like , Humanos , Adjuvantes Imunológicos/uso terapêutico , Receptores Toll-Like/agonistas , Receptores Toll-Like/metabolismo , Receptores Toll-Like/imunologia , Vacinas/imunologia , Animais
10.
Int Immunopharmacol ; 138: 112538, 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-38924865

RESUMO

Leishmaniasis, caused by Leishmania (L.) species, remains a neglected infection. Therapeutic vaccination presents a promising strategy for its treatment. In this study, we aimed to develop a therapeutic vaccine candidate using Leishmaniaantigens (SLA) and Toll-like receptor (TLR) 7/8 agonist (R848) encapsulated into the poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs). Moreover, TLR1/2 agonist (Pam3CSK4) was loaded onto the NPs. The therapeutic effects of these NPs were evaluated in L. major-infected BALB/c mice. Footpad swelling, parasite load, cellular and humoral immune responses, and nitric oxide (NO) production were analyzed. The results demonstrated that the PLGA NPs (SLA-R848-Pam3CSK4) therapeutic vaccine effectively stimulated Th1 cell responses, induced humoral responses, promoted NO production, and restricted parasite burden and lesion size.Our findings suggest that vaccination with SLA combined with TLR1/2 and TLR7/8 agonists in PLGA NPs as a therapeutic vaccine confers strong protection againstL. majorinfection. These results represent a novel particulate therapeutic vaccine against Old World cutaneous leishmaniasis.


Assuntos
Antígenos de Protozoários , Vacinas contra Leishmaniose , Leishmaniose Cutânea , Camundongos Endogâmicos BALB C , Nanopartículas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Animais , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/tratamento farmacológico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Antígenos de Protozoários/imunologia , Nanopartículas/química , Vacinas contra Leishmaniose/imunologia , Camundongos , Feminino , Óxido Nítrico/metabolismo , Imidazóis/farmacologia , Imidazóis/química , Células Th1/imunologia , Leishmania major/imunologia , Receptores Toll-Like/agonistas , Humanos , Receptor 7 Toll-Like/agonistas , Agonistas do Receptor Semelhante a Toll
11.
In Vivo ; 38(4): 1636-1648, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38936936

RESUMO

BACKGROUND/AIM: The small intestine is one of the organs most vulnerable to ionizing radiation (IR) damage. However, methods to protect against IR-induced intestinal injury are limited. CBLB502, a Toll-like receptor 5 (TLR5) agonist from Salmonella flagellin, exerts radioprotective effects on various tissues and organs. However, the molecular mechanisms by which CBLB502 protects against IR-induced intestinal injury remain unclear. Thus, this study aimed to elucidate the mechanisms underlying IR-induced intestinal injury and the protective effects of CBLB502 against this condition in mice. MATERIALS AND METHODS: Mice were administered 0.2 mg/kg CBLB502 before IR at different doses for different time points, and then the survival rate, body weight, hemogram, and histopathology of the mice were analyzed. RESULTS: CBLB502 reduced IR-induced intestinal injury. RNA-seq analysis revealed that different doses and durations of IR induced different regulatory patterns. CBLB502 protected against intestinal injury mainly after IR by reversing the expression of IR-induced genes and regulating immune processes and metabolic pathways. CONCLUSION: This study preliminarily describes the regulatory mechanism of IR-induced intestinal injury and the potential molecular protective mechanism of CBLB502, providing a basis for identifying the functional genes and molecular mechanisms that mediate protection against IR-induced injury.


Assuntos
Protetores contra Radiação , Animais , Camundongos , Protetores contra Radiação/farmacologia , Receptor 5 Toll-Like/agonistas , Receptor 5 Toll-Like/genética , Receptor 5 Toll-Like/metabolismo , Masculino , Radiação Ionizante , Receptores Toll-Like/metabolismo , Receptores Toll-Like/agonistas , Lesões por Radiação/tratamento farmacológico , Lesões por Radiação/patologia , Intestinos/efeitos dos fármacos , Intestinos/patologia , Intestinos/efeitos da radiação , Modelos Animais de Doenças , Agonistas do Receptor Semelhante a Toll , Peptídeos
12.
Int J Biol Macromol ; 274(Pt 1): 133322, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38908646

RESUMO

CD47, a cell surface protein known for inhibiting phagocytosis, plays a critical role in the tumor microenvironment (TME) and is a potential biomarker for cancer. However, directly applying αCD47, a hydrophilic macromolecular antibody that targets CD47, in vivo for cancer detection can have adverse effects on normal cells, cause systemic toxicities, and lead to resistance against anti-cancer therapies. In this study, we developed a novel complex incorporating aluminum-based metal-organic frameworks (Al-MOF) loaded with indocyanine green (ICG), αCD47, and resiquimod (R848), a hydrophobic small molecule Toll-like receptor 7/8 (TLR7/8) agonist. Upon activation with an infrared 808 nm laser, the nanocomposites exhibited photothermal effects that triggered the release of the loaded reagents, induced ROS production, and induced changes in the TME. This led to the polarization of immune-suppressive M2 macrophages towards an immune-stimulatory M1 phenotype, promoted dendritic cell (DC) maturation, and enabled mature DCs to facilitate antigen presentation, T-cell activation, and critical roles in tumor immunity. Furthermore, in vivo imaging successfully detected the specific binding of αCD47 with CD47 on tumor cells. Overall, the complex composed of αCD47 antibody and toll-like receptor agonist showed promising efficacy in both tumor diagnosis and therapy, providing a potential strategy for detecting early lung cancer and modulating the tumor microenvironment for improved treatment outcomes.


Assuntos
Antígeno CD47 , Neoplasias Pulmonares , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Animais , Humanos , Camundongos , Antígeno CD47/imunologia , Microambiente Tumoral/efeitos dos fármacos , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Verde de Indocianina/química , Verde de Indocianina/farmacologia , Receptores Toll-Like/agonistas , Receptores Toll-Like/metabolismo , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/imunologia , Macrófagos/efeitos dos fármacos , Agonistas do Receptor Semelhante a Toll
13.
Cell Rep Methods ; 4(5): 100782, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38772343

RESUMO

In a recent issue of Nature Nanotechnology, Zeng et al. report that arraying immuno-stimulatory CpG molecules with specific nanoscale spacing on DNA origami nanoparticles enhanced Th1-polarized immune responses. These results highlight spatial presentation of adjuvants as a design strategy to optimize cancer vaccine efficacy, safety, and tolerability.


Assuntos
Imunoterapia , Neoplasias , Imunoterapia/métodos , Humanos , Neoplasias/imunologia , Neoplasias/terapia , Ligantes , Receptores Toll-Like/agonistas , Receptores Toll-Like/imunologia , Nanopartículas/química , Nanopartículas/uso terapêutico , Animais , Vacinas Anticâncer/imunologia , Adjuvantes Imunológicos/farmacologia
14.
Front Immunol ; 15: 1407649, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38812510

RESUMO

Infection with human papillomavirus (HPV) typically leads to cervical cancer, skin related cancers and many other tumors. HPV is mainly responsible for evading immune tumor monitoring in HPV related cancers. Toll like receptors (TLRs) are particular pattern recognition molecules. When the body is facing immune danger, it can lead to innate and direct adaptive immunity. TLR plays an important role in initiating antiviral immune responses. HPV can affect the expression level of TLR and interfere with TLR related signaling pathways, resulting in sustained viral infection and even carcinogenesis. This paper introduces the HPV virus and HPV related cancers. We discussed the present comprehension of TLR, its expression and signaling, as well as its role in HPV infection. We also provided a detailed introduction to immunotherapy methods for HPV related diseases based on TLR agonists. This will provide insights into methods that support the therapeutic method of HPV related conditions with TLR agonists.


Assuntos
Papillomaviridae , Infecções por Papillomavirus , Receptores Toll-Like , Humanos , Receptores Toll-Like/metabolismo , Receptores Toll-Like/agonistas , Receptores Toll-Like/imunologia , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/terapia , Infecções por Papillomavirus/virologia , Papillomaviridae/fisiologia , Papillomaviridae/imunologia , Transdução de Sinais , Neoplasias/terapia , Neoplasias/imunologia , Animais , Imunoterapia/métodos , Feminino , Neoplasias do Colo do Útero/virologia , Neoplasias do Colo do Útero/terapia , Neoplasias do Colo do Útero/imunologia , Interações Hospedeiro-Patógeno/imunologia
15.
Exp Mol Pathol ; 137: 104897, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38691979

RESUMO

BACKGROUND: Signaling by toll-like receptors (TLRs) initiates important immune responses against viral infection. The role of TLRs in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is not well elucidated. Thus, we investigated the interaction of TLRs agonists and SARS-COV-2 antigens with immune cells in vitro. MATERIAL & METHODS: 30 coronavirus disease 2019 (COVID-19) patients (15 severe and 15 moderate) and 10 age and sex-matched healthy control (HC) were enrolled. Peripheral blood mononuclear cells (PBMCs) were isolated and activated with TLR3, 7, 8, and 9 agonists, the spike protein (SP) of SARS-CoV-2, and the receptor binding domain (RBD) of SP. Frequencies of CD3+IFN-ß+ T cells, and CD3+IFN-γ+ T cells were evaluated by flow cytometry. Interferon (IFN)-ß gene expression was assessed by qRT-PCR. RESULTS: The frequency of CD3+IFN-ß+ T cells was higher in PBMCs from moderate (p < 0.0001) and severe (p = 0.009) patients at baseline in comparison with HCs. The highest increase in the frequency of CD3+IFN-ß+ T cells in cell from moderate patients was induced by TLR8 agonist and SP (p < 0.0001 for both) when compared to HC, while, the highest increase of the frequency of CD3+IFN-ß+ T cells in sample of severe patients was seen with TLR8 and TLR7 agonists (both p = 0.002). The frequency of CD3+IFN-γ+ T cells was significantly increased upon stimulation with TLR agonists in cell from patients with moderate and severe COVID-19, compared with HC (all p < 0.01), except with TLR7 and TLR8 agonists. The TLR8 agonist did not significantly increase the frequency of CD3+IFN-γ+ T cells in PBMCs of severe patients, but did so in cells from patients with moderate disease (p = 0.01). Moreover, IFN-ß gene expression was significantly upregulated in CD3+T cells from moderate (p < 0.0001) and severe (p = 0.002) COVID-19 patients, compared to HC after stimulation with the TLR8 agonist, while, stimulation of T cells with SP, significantly up-regulated IFN-ß mRNA expression in cells from patients with moderate (p = 0.0003), but not severe disease. CONCLUSION: Stimulation of PBMCs from COVID-19 patients, especially patients with moderate disease, with TLR8 agonist and SP increased the frequency of IFN-ß-producing T cells and IFN-ß gene expression.


Assuntos
Complexo CD3 , COVID-19 , SARS-CoV-2 , Linfócitos T , Receptores Toll-Like , Humanos , COVID-19/imunologia , COVID-19/virologia , SARS-CoV-2/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Receptores Toll-Like/agonistas , Receptores Toll-Like/genética , Complexo CD3/imunologia , Complexo CD3/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/efeitos dos fármacos , Adulto , Interferon gama/metabolismo , Interferon gama/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Interferon beta/genética , Interferon beta/imunologia , Idoso , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Agonistas do Receptor Semelhante a Toll
16.
Int Immunopharmacol ; 135: 112283, 2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-38772299

RESUMO

Toll-like receptors (TLRs) play a crucial role in mediating immune responses by recognizing pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), as well as facilitating apoptotic cell (ACs) clearance (efferocytosis), thus contributing significantly to maintaining homeostasis and promoting tissue resolution. In this study, we investigate the impact of TLR agonists on macrophage efferocytosis. Our findings demonstrate that pretreatment with the TLR agonist lipopolysaccharide (LPS) significantly enhances macrophage phagocytic ability, thereby promoting efferocytosis both in vitro and in vivo. Moreover, LPS pretreatment confers tissue protection against damage by augmenting macrophage efferocytic capacity in murine models. Further examination reveals that LPS modulates efferocytosis by upregulating the expression of Tim4.These results underscore the pivotal role of TLR agonists in regulating the efferocytosis process and suggest potential therapeutic avenues for addressing inflammatory diseases. Overall, our study highlights the intricate interplay between LPS pretreatment and efferocytosis in maintaining tissue homeostasis and resolving inflammation.


Assuntos
Lipopolissacarídeos , Macrófagos , Camundongos Endogâmicos C57BL , Fagocitose , Animais , Fagocitose/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Receptores Toll-Like/metabolismo , Receptores Toll-Like/agonistas , Inflamação/tratamento farmacológico , Inflamação/imunologia , Masculino , Humanos , Apoptose/efeitos dos fármacos , Células RAW 264.7 , Proteínas de Membrana/metabolismo , Eferocitose
17.
DNA Cell Biol ; 43(6): 267-270, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38579130

RESUMO

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have shown efficacy in the treatment of metabolic disease-related complications, partially attributable to their anti-inflammatory properties. However, the specific cell types and pathways involved in these effects were not fully understood. A recent study by Wong et al. demonstrated the importance of the brain GLP-1R in mediating the anti-inflammatory effects of GLP-1RAs in Toll-like receptor and sepsis-mediated inflammation. In this discussion, we review the existing literature on the action of GLP-1RAs in inflammation and explore the implications of these recent findings.


Assuntos
Anti-Inflamatórios , Receptor do Peptídeo Semelhante ao Glucagon 1 , Inflamação , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Animais , Neuroimunomodulação/efeitos dos fármacos , Receptores Toll-Like/agonistas , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon
18.
J Thromb Haemost ; 22(4): 1215-1222, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38159649

RESUMO

BACKGROUND: Respiratory infection is associated with microvascular thrombus formation and marked elevation in cytokine levels. The role of cytokines elaborated by the pulmonary epithelium in thrombotic responses is poorly understood. OBJECTIVES: Our goal was to identify cytokines of pulmonary epithelial cell origin that enhance thrombin generation in the endothelium at concentrations equal to or less than those found in the circulation during infection. METHODS: We screened multiple cytokines produced by the pulmonary epithelium for the ability to enhance toll-like receptor (TLR)-mediated endothelial thrombin generation. Effects of cytokines on tissue factor and thrombomodulin expression, cytokine selectivity for different TLRs, and prothrombotic activity of endogenous cytokines in conditioned medium from pulmonary human epithelial cells were evaluated. RESULTS: MIP-1ß, MCP-1, IL-10, IL-6, IL-1ß, TNFα, IFNα, IFNß, and IFNγ were tested for their ability to enhance TLR3-mediated thrombin generation on endothelial cells. Only interferons (IFNs) and TNFα promoted TLR3-mediated thrombin generation at levels that circulate during infection. IFNs robustly enhanced tissue factor expression when used in conjunction with TLR agonists and reduced thrombomodulin expression in the endothelium independently of TLRs. IFNα, which is typically elevated with viral infection, only synergized with TLR3 agonists mimicking viral pathogen-associated molecular patterns. In contrast, IFNγ, which is typically observed in bacterial infection, synergized more effectively with TLR4 agonists released by bacteria. Conditioned media from inflamed pulmonary epithelial cells primed the endothelium for TLR-mediated thrombin generation. Anti-IFN type I antibodies blocked this effect, indicating that endogenous IFNs prime the endothelium for TLR-mediated thrombin generation. CONCLUSION: IFNs elaborated by the pulmonary epithelium are necessary and sufficient to enhance TLR-mediated thrombin generation.


Assuntos
Interferon Tipo I , Trombina , Humanos , Trombomodulina , Receptor 3 Toll-Like , Fator de Necrose Tumoral alfa , Células Endoteliais/metabolismo , Tromboplastina , Receptores Toll-Like/agonistas , Receptores Toll-Like/metabolismo , Citocinas/metabolismo , Endotélio/metabolismo
19.
Methods Mol Biol ; 2709: 241-251, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37572285

RESUMO

Nanoparticles can be used to formulate Toll-like receptor (TLR) agonists as vaccine and immunotherapy adjuvants or contain undesirable contaminants (e.g., endotoxin, CpG DNA, flagellin) with TLR-agonist activity. In both scenarios, the activation of the innate immune pattern recognition receptor leads to the inflammatory response that can be beneficial as in the case with vaccines and immunotherapies or adverse as in the case with contaminants. The protocol described herein utilizes commercially available reporter cell lines expressing individual TLRs, which, upon activation with their cognate agonists, stimulate the cells to produce secreted alkaline phosphatase detectable using a plate reader.


Assuntos
Receptores Toll-Like , Vacinas , Receptores Toll-Like/agonistas , Adjuvantes Imunológicos , Receptores de Reconhecimento de Padrão , Endotoxinas , Linhagem Celular , Receptor Toll-Like 9/metabolismo
20.
Viruses ; 15(5)2023 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-37243284

RESUMO

Interferon-γ (IFN-γ) is a cytokine that plays an important role in immune regulation, especially in the activation and differentiation of immune cells. Toll-like receptors (TLRs) are a family of pattern-recognition receptors that sense structural motifs related to pathogens and alert immune cells to the invasion. Both IFN-γ and TLR agonists have been used as immunoadjuvants to augment the efficacy of cancer immunotherapies and vaccines against infectious diseases or psychoactive compounds. In this study, we aimed to explore the potential of IFN-γ and TLR agonists being applied simultaneously to boost dendritic cell activation and the subsequent antigen presentation. In brief, murine dendritic cells were treated with IFN-γ and/or the TLR agonists, polyinosinic-polycytidylic acid (poly I:C), or resiquimod (R848). Next, the dendritic cells were stained for an activation marker, a cluster of differentiation 86 (CD86), and the percentage of CD86-positive cells was measured by flow cytometry. From the cytometric analysis, IFN-γ efficiently stimulated a considerable number of the dendritic cells, while the TLR agonists by themselves could merely activate a few compared to the control. The combination of IFN-γ with poly I:C or R848 triggered a higher amount of dendritic cell activation than IFN-γ alone. For instance, 10 ng/mL IFN-γ with 100 µg/mL poly I:C achieved 59.1% cell activation, which was significantly higher than the 33.4% CD86-positive cells obtained by 10 ng/mL IFN-γ. These results suggested that IFN-γ and TLR agonists could be applied as complementary systems to promote dendritic cell activation and antigen presentation. There might be a synergy between the two classes of molecules, but further investigation is warranted to ascertain the interaction of their promotive activities.


Assuntos
Interferon gama , Receptores Toll-Like , Camundongos , Animais , Interferon gama/farmacologia , Receptores Toll-Like/agonistas , Adjuvantes Imunológicos , Poli I-C/farmacologia , Células Dendríticas
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