Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 29.252
Filtrar
1.
Front Immunol ; 15: 1392535, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38846935

RESUMO

The pivotal role of Granzyme B (GzmB) in immune responses, initially tied to cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, has extended across diverse cell types and disease models. A number of studies have challenged conventional notions, revealing GzmB activity beyond apoptosis, impacting autoimmune diseases, inflammatory disorders, cancer, and neurotoxicity. Notably, the diverse functions of GzmB unfold through Perforin-dependent and Perforin-independent mechanisms, offering clinical implications and therapeutic insights. This review underscores the multifaceted roles of GzmB, spanning immunological and pathological contexts, which call for further investigations to pave the way for innovative targeted therapies.


Assuntos
Granzimas , Células Matadoras Naturais , Perforina , Linfócitos T Citotóxicos , Granzimas/metabolismo , Humanos , Perforina/metabolismo , Animais , Linfócitos T Citotóxicos/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Neoplasias/imunologia , Neoplasias/terapia
2.
Yakugaku Zasshi ; 144(5): 475-481, 2024.
Artigo em Japonês | MEDLINE | ID: mdl-38692920

RESUMO

Zinc is one of the essential trace elements, and is involved in various functions in the body. Zinc deficiency is known to cause immune abnormalities, but the mechanism is not fully understood. Therefore, we focused our research on tumor immunity to elucidate the effect of zinc on colorectal cancer and its mechanisms. Mice were treated with azoxymethane (AOM) and dextran sodium sulfate (DSS) to develop colorectal cancer, then the relationship between zinc content in the diet and the number and area of tumors in the colon was observed. The number of tumors in the colon was significantly higher in the no-zinc-added diet group compared to the normal zinc intake group, and about half the number in the high-zinc-intake group compared to the normal-zinc-intake group. In T-cell-deficient mice, the number of tumors in the high-zinc-intake group was similar to that in the normal-zinc-intake group, suggesting that the inhibitory effect of zinc was dependent on T cells. Furthermore, we found that the amount of granzyme B transcript released by cytotoxic T cells upon antigen stimulation was significantly increased by the addition of zinc. We also showed that granzyme B transcriptional activation by zinc addition was dependent on calcineurin activity. Collectively, we have shown that zinc exerts its tumor-suppressive effect by acting on cytotoxic T cells, the center of cellular immunity, and that it increases the transcription of granzyme B, one of the key molecules involved in tumor immunity. In this symposium, we would like to introduce our latest data on the relationship between zinc and tumor immunity.


Assuntos
Neoplasias Colorretais , Imunidade Celular , Zinco , Animais , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/prevenção & controle , Camundongos , Humanos , Granzimas/metabolismo , Linfócitos T Citotóxicos/imunologia , Azoximetano , Modelos Animais de Doenças
3.
Front Immunol ; 15: 1338218, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38742109

RESUMO

Cytotoxic T lymphocyte (CTL) motility is an important feature of effective CTL responses and is impaired when CTLs become exhausted, e.g. during chronic retroviral infections. A prominent T cell exhaustion marker is programmed cell death protein 1 (PD-1) and antibodies against the interaction of PD-1 and PD-ligand 1 (PD-L1) are known to improve CTL functions. However, antibody blockade affects all PD-1/PD-L1-expressing cell types, thus, the observed effects cannot be attributed selectively to CTLs. To overcome this problem, we performed CRISPR/Cas9 based knockout of the PD-1 coding gene PDCD1 in naïve Friend Retrovirus (FV)-specific CTLs. We transferred 1,000 of these cells into mice where they proliferated upon FV-infection. Using intravital two-photon microscopy we visualized CTL motility in the bone marrow and evaluated cytotoxic molecule expression by flow cytometry. Knockout of PDCD1 improved the CTL motility at 14 days post infection and enhanced the expression of cytotoxicity markers. Our data show the potential of genetic tuning of naive antiviral CTLs and might be relevant for future designs of improved T cell-mediated therapies.


Assuntos
Movimento Celular , Camundongos Knockout , Receptor de Morte Celular Programada 1 , Infecções por Retroviridae , Linfócitos T Citotóxicos , Animais , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/imunologia , Camundongos , Movimento Celular/genética , Infecções por Retroviridae/imunologia , Linfócitos T Citotóxicos/imunologia , Camundongos Endogâmicos C57BL , Vírus da Leucemia Murina de Friend/imunologia , Técnicas de Inativação de Genes , Linfócitos T CD8-Positivos/imunologia , Sistemas CRISPR-Cas , Citotoxicidade Imunológica
4.
Chaos ; 34(5)2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38809906

RESUMO

A time-delayed virus dynamic model is proposed with general monotonic incidence, different nonlinear CTL (cytotoxic T lymphocyte) responses [CTL elimination function pyg1(z) and CTL stimulation function cyg2(z)], and immune impairment. Indeed, the different CTL responses pose challenges in obtaining the dissipativeness of the model. By constructing appropriate Lyapunov functionals with some detailed analysis techniques, the global stability results of all equilibria of the model are obtained. By the way, we point out that the partial derivative fv(x,0) is increasing (but not necessarily strictly) in x>0 for the general monotonic incidence f(x,v). However, some papers defaulted that the partial derivative was strictly increasing. Our main results show that if the basic reproduction number R0≤1, the infection-free equilibrium E0 is globally asymptotically stable (GAS); if CTL stimulation function cyg2(z)=0 for z=0 and the CTL threshold parameter R1≤1

Assuntos
Linfócitos T Citotóxicos , Linfócitos T Citotóxicos/imunologia , Humanos , Fatores de Tempo , Vírus/imunologia , Viroses/imunologia , Modelos Imunológicos , Modelos Biológicos
5.
Sci Rep ; 14(1): 10842, 2024 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-38735993

RESUMO

Yellow fever outbreaks are prevalent, particularly in endemic regions. Given the lack of an established treatment for this disease, significant attention has been directed toward managing this arbovirus. In response, we developed a multiepitope vaccine designed to elicit an immune response, utilizing advanced immunoinformatic and molecular modeling techniques. To achieve this, we predicted B- and T-cell epitopes using the sequences from all structural (E, prM, and C) and nonstructural proteins of 196 YFV strains. Through comprehensive analysis, we identified 10 cytotoxic T-lymphocyte (CTL) and 5T-helper (Th) epitopes that exhibited overlap with B-lymphocyte epitopes. These epitopes were further evaluated for their affinity to a wide range of human leukocyte antigen system alleles and were rigorously tested for antigenicity, immunogenicity, allergenicity, toxicity, and conservation. These epitopes were linked to an adjuvant ( ß -defensin) and to each other using ligands, resulting in a vaccine sequence with appropriate physicochemical properties. The 3D structure of this sequence was created, improved, and quality checked; then it was anchored to the Toll-like receptor. Molecular Dynamics and Quantum Mechanics/Molecular Mechanics simulations were employed to enhance the accuracy of docking calculations, with the QM portion of the simulations carried out utilizing the density functional theory formalism. Moreover, the inoculation model was able to provide an optimal codon sequence that was inserted into the pET-28a( +) vector for in silico cloning and could even stimulate highly relevant humoral and cellular immunological responses. Overall, these results suggest that the designed multi-epitope vaccine can serve as prophylaxis against the yellow fever virus.


Assuntos
Epitopos de Linfócito T , Vacina contra Febre Amarela , Febre Amarela , Vírus da Febre Amarela , Vacina contra Febre Amarela/imunologia , Vírus da Febre Amarela/imunologia , Vírus da Febre Amarela/genética , Humanos , Febre Amarela/prevenção & controle , Febre Amarela/imunologia , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito B/imunologia , Vacinologia/métodos , Modelos Moleculares , Desenvolvimento de Vacinas , Simulação de Dinâmica Molecular , Linfócitos T Citotóxicos/imunologia
6.
ACS Nano ; 18(20): 13226-13240, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38712706

RESUMO

Oncogene activation and epigenome dysregulation drive tumor initiation and progression, contributing to tumor immune evasion and compromising the clinical response to immunotherapy. Epigenetic immunotherapy represents a promising paradigm in conquering cancer immunosuppression, whereas few relevant drug combination and delivery strategies emerge in the clinic. This study presents a well-designed triune nanomodulator, termed ROCA, which demonstrates robust capabilities in tumor epigenetic modulation and immune microenvironment reprogramming for cancer epigenetic immunotherapy. The nanomodulator is engineered from a nanoscale framework with epigenetic modulation and cascaded catalytic activity, which self-assembles into a nanoaggregate with tumor targeting polypeptide decoration that enables loading of the immunogenic cell death (ICD)-inducing agent. The nanomodulator releases active factors specifically triggered in the tumor microenvironment, represses oncogene expression, and initiates the type 1 T helper (TH1) cell chemokine axis by reversing DNA hypermethylation. This process, together with ICD induction, fundamentally reprograms the tumor microenvironment and significantly enhances the rejuvenation of exhausted cytotoxic T lymphocytes (CTLs, CD8+ T cells), which synergizes with the anti-PD-L1 immune checkpoint blockade and results in a boosted antitumor immune response. Furthermore, this strategy establishes long-term immune memory and effectively prevents orthotopic colon cancer relapse. Therefore, the nanomodulator holds promise as a standalone epigenetic immunotherapy agent or as part of a combination therapy with immune checkpoint inhibitors in preclinical cancer models, broadening the array of combinatorial strategies in cancer immunotherapy.


Assuntos
Epigênese Genética , Imunoterapia , Linfócitos T Citotóxicos , Microambiente Tumoral , Animais , Epigênese Genética/efeitos dos fármacos , Camundongos , Linfócitos T Citotóxicos/imunologia , Humanos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Nanopartículas/química , Camundongos Endogâmicos C57BL , Neoplasias/terapia , Neoplasias/imunologia
7.
J Math Biol ; 89(1): 6, 2024 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-38762831

RESUMO

Multiple infections enable the recombination of different strains, which may contribute to viral diversity. How multiple infections affect the competition dynamics between the two types of strains, the wild and the immune escape mutant, remains poorly understood. This study develops a novel mathematical model that includes the two strains, two modes of viral infection, and multiple infections. For the representative double-infection case, the reproductive numbers are derived and global stabilities of equilibria are obtained via the Lyapunov direct method and theory of limiting systems. Numerical simulations indicate similar viral dynamics regardless of multiplicities of infections though the competition between the two strains would be the fiercest in the case of quadruple infections. Through sensitivity analysis, we evaluate the effect of parameters on the set-point viral loads in the presence and absence of multiple infections. The model with multiple infections predict that there exists a threshold for cytotoxic T lymphocytes (CTLs) to minimize the overall viral load. Weak or strong CTLs immune response can result in high overall viral load. If the strength of CTLs maintains at an intermediate level, the fitness cost of the mutant is likely to have a significant impact on the evolutionary dynamics of mutant viruses. We further investigate how multiple infections alter the viral dynamics during the combination antiretroviral therapy (cART). The results show that viral loads may be underestimated during cART if multiple-infection is not taken into account.


Assuntos
Simulação por Computador , Infecções por HIV , Evasão da Resposta Imune , Conceitos Matemáticos , Modelos Biológicos , Linfócitos T Citotóxicos , Carga Viral , Humanos , Infecções por HIV/imunologia , Infecções por HIV/virologia , Infecções por HIV/tratamento farmacológico , Linfócitos T Citotóxicos/imunologia , Evasão da Resposta Imune/imunologia , Coinfecção/imunologia , Coinfecção/virologia , HIV-1/imunologia , HIV-1/genética , Número Básico de Reprodução/estatística & dados numéricos , Modelos Imunológicos , Mutação
8.
Biochem Biophys Res Commun ; 718: 150058, 2024 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-38729076

RESUMO

The therapeutic efficacy of radiotherapy (RT) is primarily driven by two factors: biophysical DNA damage in cancer cells and radiation-induced anti-tumor immunity. However, Anti-tumor immune responses between X-ray RT (XRT) and carbon-ion RT (CIRT) remain unclear. In this study, we, employed mouse models to assess the immunological contribution, especially cytotoxic T-lymphocyte (CTL)-mediated immunity, to the therapeutic effectiveness of XRT and CIRT in shrinking tumors. We irradiated mouse intradermal tumors of B16F10-ovalbumin (OVA) mouse melanoma cells and 3LL-OVA mouse lung cancer cells with carbon-ion beams or X-rays in the presence or absence of CTLs. CTL removal was performed by administration of anti-CD8 monoclonal antibody (mAb) in mice. Based on tumor growth delay, we determined the tumor growth and regression curves. The enhancement ratio (ER) of the slope of regression lines in the presence of CTLs, relative to the absence of CTLs, indicates the dependency of RT on CTLs for shrinking mouse tumors, and the biological effectiveness (RBE) of CIRT relative to XRT were calculated. Tumor growth curves revealed that the elimination of CD8+ CTLs by administrating anti-CD8 mAb accelerated tumor growth compared to the presence of CTLs in both RTs. The ERs were larger in CIRT compared to XRT in the B16F10-OVA tumor models, but not in the 3LL-OVA models, suggesting a greater contribution of CTL-mediated anti-tumor immunity to tumor reduction in CIRT compared to XRT in the B16F10-OVA tumor model. In addition, the RBE values for both models were larger in the presence of CTLs compared to models without CTLs, suggesting that CIRT may utilize CTL-mediated anti-tumor immunity more than X-ray. The findings from this study suggest that although immunological contribution to therapeutic efficacy may vary depending on the type of tumor cell, CIRT utilizes CTL-mediated immunity to a greater extent compared to XRT.


Assuntos
Camundongos Endogâmicos C57BL , Linfócitos T Citotóxicos , Animais , Linfócitos T Citotóxicos/imunologia , Camundongos , Linhagem Celular Tumoral , Melanoma Experimental/imunologia , Melanoma Experimental/radioterapia , Melanoma Experimental/terapia , Melanoma Experimental/patologia , Radioterapia com Íons Pesados/métodos , Terapia por Raios X , Feminino , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patologia
9.
Int J Biol Macromol ; 269(Pt 2): 132177, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38729484

RESUMO

Tumor vaccine, which can effectively prevent tumor recurrence and metastasis, is a promising tool in tumor immunotherapy. However, heterogeneity of tumors and the inability to achieve a cascade effect limit the therapeutic effects of most developing tumor vaccine. We have developed a cascading immunoinducible in-situ mannose-functionalized polydopamine loaded with imiquimod phenylboronic hyaluronic acid nanocomposite gel vaccine (M/P-PDA@IQ PHA) through a boronic ester-based reaction. This reaction utilizes mannose-functionalized polydopamine loaded with imiquimod (M/P-PDA@IQ NAs) as a cross-linking agent to react with phenylboronic-grafted hyaluronic acid. Under near-infrared light irradiation, the M/P-PDA@IQ PHA caused local hyperthermia to trigger immunogenic cell death of tumor cells and tumor-associated antigens (TAAs) releasing. Subsequently, the M/P-PDA@IQ NAs which were gradually released by the pH/ROS/GSH-triggered degradation of M/P-PDA@IQ PHA, could capture and deliver these TAAs to lymph nodes. Finally, the M/P-PDA@IQ NAs facilitated maturation and cross-presentation of dendritic cells, as well as activation of cytotoxic T lymphocytes. Overall, the M/P-PDA@IQ PHA could serve as a novel in situ vaccine to stimulate several key nodes including TAAs release and capture, targeting lymph nodes and enhanced dendritic cells uptake and maturation as well as T cells activation. This cascading immune activation strategy can effectively elicit antitumor immune response.


Assuntos
Vacinas Anticâncer , Ácido Hialurônico , Hidrogéis , Indóis , Nanopartículas , Polímeros , Ácido Hialurônico/química , Polímeros/química , Vacinas Anticâncer/química , Vacinas Anticâncer/imunologia , Indóis/química , Indóis/farmacologia , Animais , Camundongos , Hidrogéis/química , Nanopartículas/química , Humanos , Imiquimode/química , Imiquimode/farmacologia , Células Dendríticas/imunologia , Vacinação , Linhagem Celular Tumoral , Imunoterapia/métodos , Reagentes de Ligações Cruzadas/química , Neoplasias/imunologia , Neoplasias/terapia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/efeitos dos fármacos
10.
Exp Cell Res ; 439(1): 114073, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38704079

RESUMO

Determining the appropriate source of antigens for optimal antigen presentation to T cells is a major challenge in designing dendritic cell (DC) -based therapeutic strategies against hepatocellular carcinoma (HCC). Tumor-derived exosomes (Tex) express a wide range of tumor antigens, making them a promising source of antigens for DC vaccines. As reported, the exosomes secreted by tumor cells can inhibit the antitumor function of immune cells. In this study, we transfected hepatocellular carcinoma cells with Rab27a to enhance the yield of exosomes, which were characterized using transmission electron microscopy and Western blot analysis. We found that Tex secreted by overexpressing Rab27a Hepatocellular carcinoma cell lines pulsed DC is beneficial for the differentiation and maturation of DCs but inhibits the secretion of the IL-12 cytokine. Consequently, we developed a complementary immunotherapy approach by using Tex as an antigen loaded onto DCs, in combination with the cytokine IL-12 to induce antigen-specific cytotoxic T lymphocytes (CTLs). The results indicated that the combination of DC-Tex and IL-12 was more effective in stimulating T lymphocyte proliferation, releasing IFN-γ, and enhancing cytotoxicity compared to using exosomes or IL-12 alone. Additionally, the inclusion of IL-12 also compensated for the reduced IL-2 secretion by DCs caused by Tex. Moreover, in a BALB/c nude mice model of hepatocellular carcinoma, CTLs induced by DC-Tex combined with IL-12 maximized the tumor-specific T-cell immune effect and suppressed tumor growth. Thus, Tex provides a novel and promising source of antigens, with cytokines compensating for the shortcomings of Tex as a tumor antigen. This work helps to clarify the role of exosomes in tumor immunotherapy and may offer a safe and effective prospective strategy for the clinical application of exosome-based cellular immunotherapy.


Assuntos
Carcinoma Hepatocelular , Células Dendríticas , Exossomos , Interleucina-12 , Neoplasias Hepáticas , Proteínas rab27 de Ligação ao GTP , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Exossomos/metabolismo , Animais , Interleucina-12/metabolismo , Interleucina-12/genética , Proteínas rab27 de Ligação ao GTP/metabolismo , Proteínas rab27 de Ligação ao GTP/genética , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Camundongos , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Humanos , Linhagem Celular Tumoral , Proliferação de Células , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Camundongos Endogâmicos BALB C , Imunoterapia/métodos
11.
Oncoimmunology ; 13(1): 2358590, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38812569

RESUMO

Chimeric antigen receptor (CAR) T cells have demonstrated outstanding therapeutic success in hematological malignancies. Yet, their efficacy against solid tumors remains constrained due to inadequate infiltration of cytotoxic T and CAR-T cells in the tumor microenvironment (TME), a factor correlated with poor prognosis in patients with solid tumors. To overcome this limitation, we engineered CAR-T cells to secrete CXCL10 and IL15 (10 × 15 CAR-T), which sustain T cell viability and enhance their recruitment, thereby amplifying the long-term cytotoxic capacity of CAR-T cells in vitro. In a xenograft model employing NUGC4-T21 cells, mice receiving 10 × 15 CAR-T cells showed superior tumor reduction and extended survival rates compared to those treated with second-generation CAR-T cells. Histopathological evaluations indicated a pronounced increase in cytotoxic T cell accumulation in the TME post 10 × 15 CAR-T cell treatment. Therefore, the synergistic secretion of CXCL10 and IL15 in these CAR-T cells enhances T cell recruitment and adaptability within tumor tissues, improving tumor control. This approach may offer a promising strategy for advancing CAR-T therapies in the treatment of solid tumors.


Assuntos
Quimiocina CXCL10 , Imunoterapia Adotiva , Interleucina-15 , Receptores de Antígenos Quiméricos , Neoplasias Gástricas , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Quimiocina CXCL10/metabolismo , Quimiocina CXCL10/genética , Neoplasias Gástricas/terapia , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologia , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Antígenos Quiméricos/genética , Humanos , Camundongos , Interleucina-15/genética , Interleucina-15/metabolismo , Imunoterapia Adotiva/métodos , Microambiente Tumoral/imunologia , Linhagem Celular Tumoral , Linfócitos T Citotóxicos/imunologia , Sobrevivência Celular , Feminino
12.
Front Immunol ; 15: 1362621, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38812512

RESUMO

Introduction: HIV-1 infection may produce a detrimental effect on the immune response. Early start of antiretroviral therapy (ART) is recommended to preserve the integrity of the immune system. In fact, people with HIV (PWH) and normal CD4/CD8 ratio appear not to be more susceptible to severe forms of COVID-19 than the general population and they usually present a good seroconversion rate in response to vaccination against SARS-CoV-2. However, few studies have fully characterized the development of cytotoxic immune populations in response to COVID-19 vaccination in these individuals. Methods: In this study, we recruited PWH with median time of HIV-1 infection of 6 years, median CD4/CD8 ratio of 1.0, good adherence to ART, persistently undetectable viral load, and negative serology against SARS-CoV-2, who then received the complete vaccination schedule against COVID-19. Blood samples were taken before vaccination against COVID-19 and one month after receiving the complete vaccination schedule. Results: PWH produced high levels of IgG against SARS-CoV-2 in response to vaccination that were comparable to healthy donors, with a significantly higher neutralization capacity. Interestingly, the cytotoxic activity of PBMCs from PWH against SARS-CoV-2-infected cells was higher than healthy donors before receiving the vaccination schedule, pointing out the pre-existence of activated cell populations with likely unspecific antiviral activity. The characterization of these cytotoxic cell populations revealed high levels of Tgd cells with degranulation capacity against SARS-CoV-2-infected cells. In response to vaccination, the degranulation capacity of CD8+ T cells also increased in PWH but not in healthy donors. Discussion: The full vaccination schedule against COVID-19 did not modify the ability to respond against HIV-1-infected cells in PWH and these individuals did not show more susceptibility to breakthrough infection with SARS-CoV-2 than healthy donors after 12 months of follow-up. These results revealed the development of protective cell populations with broad-spectrum antiviral activity in PWH with normal CD4/CD8 ratio and confirmed the importance of early ART and treatment adherence to avoid immune dysfunctions.


Assuntos
Relação CD4-CD8 , COVID-19 , Infecções por HIV , SARS-CoV-2 , Humanos , SARS-CoV-2/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , Infecções por HIV/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Vacinas contra COVID-19/imunologia , Linfócitos T CD8-Positivos/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , HIV-1/imunologia , Citotoxicidade Imunológica , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Linfócitos T Citotóxicos/imunologia , Vacinação
13.
Hum Vaccin Immunother ; 20(1): 2352908, 2024 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-38780076

RESUMO

Cervical cancer, among the deadliest cancers affecting women globally, primarily arises from persistent infection with high-risk human papillomavirus (HPV). To effectively combat persistent infection and prevent the progression of precancerous lesions into malignancy, a therapeutic HPV vaccine is under development. This study utilized an immunoinformatics approach to predict epitopes of cytotoxic T lymphocytes (CTLs) and helper T lymphocytes (HTLs) using the E6 and E7 oncoproteins of the HPV16 strain as target antigens. Subsequently, through meticulous selection of T-cell epitopes and other necessary elements, a multi-epitope vaccine was constructed, exhibiting good immunogenic, physicochemical, and structural characteristics. Furthermore, in silico simulations showed that the vaccine not only interacted well with toll-like receptors (TLR2/TLR3/TLR4), but also induced a strong innate and adaptive immune response characterized by elevated Th1-type cytokines, such as interferon-gamma (IFN-γ) and interleukin-2 (IL2). Additionally, our study investigated the effects of different immunization intervals on immune responses, aiming to optimize a time-efficient immunization program. In animal model experiments, the vaccine exhibited robust immunogenic, therapeutic, and prophylactic effects. Administered thrice, it consistently induced the expansion of specific CD4 and CD8 T cells, resulting in substantial cytokines release and increased proliferation of memory T cell subsets in splenic cells. Overall, our findings support the potential of this multi-epitope vaccine in combating HPV16 infection and signify its candidacy for future HPV vaccine development.


Through the stringent selection of T-cell epitopes and other necessary elements, a novel multi-epitope vaccine targeting HPV 16 E6 and E7 oncoproteins was constructed using an immunoinformatics approach.The vaccine designed can induce both cellular and humoral immune responses, encompassing all the required immunogenic, physicochemical, and structural characteristics for an ideal vaccine design. Moreover, it offers decent worldwide coverage.In animal studies, the vaccine demonstrated strong immune responses, including expansion of CD4 and CD8 T cells, cytokine release, and enhanced memory T cell proliferation, resulting in long-term anti-tumor effects, inhibition of tumor growth, and prolonged survival in tumor-bearing mice.The immunological evaluation of the designed vaccine suggests its potential as a novel vaccine candidate against HPV 16.


Assuntos
Epitopos de Linfócito T , Papillomavirus Humano 16 , Proteínas Oncogênicas Virais , Infecções por Papillomavirus , Vacinas contra Papillomavirus , Neoplasias do Colo do Útero , Vacinas de DNA , Feminino , Vacinas contra Papillomavirus/imunologia , Vacinas contra Papillomavirus/administração & dosagem , Papillomavirus Humano 16/imunologia , Vacinas de DNA/imunologia , Vacinas de DNA/administração & dosagem , Infecções por Papillomavirus/prevenção & controle , Infecções por Papillomavirus/imunologia , Epitopos de Linfócito T/imunologia , Animais , Proteínas Oncogênicas Virais/imunologia , Proteínas Oncogênicas Virais/genética , Neoplasias do Colo do Útero/prevenção & controle , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/virologia , Proteínas E7 de Papillomavirus/imunologia , Camundongos , Humanos , Linfócitos T Citotóxicos/imunologia , Proteínas Repressoras/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Camundongos Endogâmicos C57BL , Interferon gama/metabolismo , Interferon gama/imunologia
15.
Oncoimmunology ; 13(1): 2338951, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38590800

RESUMO

Recently, we showed that an autologous DC-based vaccine induces an increase in immunosuppressive PD-L1+ tumor-associated macrophages (TAM) both in the tumor and the tumor draining lymph nodes, thereby blunting the efficacy of therapeutic immunization. Only the combination of the DC vaccine with anti-PD-L1 immune checkpoint inhibition, but not the use of antibodies targeting PD-1 alone, was able to set off CD8+ cytotoxic T lymphocyte (CTL)-mediated tumor suppression in mice. In sum, we delineated a PD-L1 checkpoint blockade-based strategy to avoid TAM-induced T cell exhaustion during DC vaccine therapy.


Assuntos
Antígeno B7-H1 , Vacinas , Animais , Camundongos , Linfócitos T Citotóxicos , Linfócitos T CD8-Positivos , Macrófagos
16.
Front Immunol ; 15: 1376962, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38562940

RESUMO

Tumors pose a significant global public health challenge, resulting in numerous fatalities annually. CD8+ T cells play a crucial role in combating tumors; however, their effectiveness is compromised by the tumor itself and the tumor microenvironment (TME), resulting in reduced efficacy of immunotherapy. In this dynamic interplay, extracellular vesicles (EVs) have emerged as pivotal mediators, facilitating direct and indirect communication between tumors and CD8+ T cells. In this article, we provide an overview of how tumor-derived EVs directly regulate CD8+ T cell function by carrying bioactive molecules they carry internally and on their surface. Simultaneously, these EVs modulate the TME, indirectly influencing the efficiency of CD8+ T cell responses. Furthermore, EVs derived from CD8+ T cells exhibit a dual role: they promote tumor immune evasion while also enhancing antitumor activity. Finally, we briefly discuss current prevailing approaches that utilize functionalized EVs based on tumor-targeted therapy and tumor immunotherapy. These approaches aim to present novel perspectives for EV-based tumor treatment strategies, demonstrating potential for advancements in the field.


Assuntos
Vesículas Extracelulares , Neoplasias , Humanos , Linfócitos T CD8-Positivos , Vesículas Extracelulares/metabolismo , Neoplasias/metabolismo , Linfócitos T Citotóxicos , Microambiente Tumoral
17.
Neurol Neuroimmunol Neuroinflamm ; 11(4): e200250, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38662990

RESUMO

BACKGROUND AND OBJECTIVES: The role of B cells in the pathogenic events leading to relapsing multiple sclerosis (R-MS) has only been recently elucidated. A pivotal step in defining this role has been provided by therapeutic efficacy of anti-CD20 monoclonal antibodies. Indeed, treatment with anti-CD20 can also alter number and function of other immune cells not directly expressing CD20 on their cell surface, whose activities can contribute to unknown aspects influencing therapeutic efficacy. We examined the phenotype and function of cytotoxic lymphocytes and Epstein-Barr virus (EBV)-specific immune responses in people with R-MS before and after ocrelizumab treatment. METHODS: In this prospective study, we collected blood samples from people with R-MS (n = 41) before and 6 and 12 months after initiating ocrelizumab to assess the immune phenotype and the indirect impact on cytotoxic functions of CD8+ T and NK cells. In addition, we evaluated the specific anti-EBV proliferative responses of both CD8+ T and NK lymphocytes as surrogate markers of anti-EBV activity. RESULTS: We observed that while ocrelizumab depleted circulating B cells, it also reduced the expression of activation and migratory markers on both CD8+ T and NK cells as well as their in vitro cytotoxic activity. A comparable pattern in the modulation of immune molecules by ocrelizumab was observed in cytotoxic cells even when patients with R-MS were divided into groups based on their prior disease-modifying treatment. These effects were accompanied by a significant and selective reduction of CD8+ T-cell proliferation in response to EBV antigenic peptides. DISCUSSION: Taken together, our findings suggest that ocrelizumab-while depleting B cells-affects the cytotoxic function of CD8+ and NK cells, whose reduced cross-activity against myelin antigens might also contribute to its therapeutic efficacy during MS.


Assuntos
Anticorpos Monoclonais Humanizados , Linfócitos T CD8-Positivos , Herpesvirus Humano 4 , Fatores Imunológicos , Humanos , Anticorpos Monoclonais Humanizados/farmacologia , Feminino , Adulto , Masculino , Herpesvirus Humano 4/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Pessoa de Meia-Idade , Fatores Imunológicos/farmacologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/sangue , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Estudos Prospectivos , Proliferação de Células/efeitos dos fármacos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Ativação Linfocitária/efeitos dos fármacos
18.
Front Immunol ; 15: 1337973, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38665920

RESUMO

Cytotoxic T lymphocytes are the primary effector immune cells responsible for protection against cancer, as they target peptide neoantigens presented through the major histocompatibility complex (MHC) on cancer cells, leading to cell death. Targeting peptide-MHC (pMHC) complex offers a promising strategy for immunotherapy due to their specificity and effectiveness against cancer. In this work, we exploit the acidic tumor micro-environment to selectively deliver antigenic peptides to cancer using pH(low) insertion peptides (pHLIP). We demonstrated the delivery of MHC binding peptides directly to the cytoplasm of melanoma cells resulted in the presentation of antigenic peptides on MHC, and activation of T cells. This work highlights the potential of pHLIP as a vehicle for the targeted delivery of antigenic peptides and its presentation via MHC-bound complexes on cancer cell surface for activation of T cells with implications for enhancing anti-cancer immunotherapy.


Assuntos
Apresentação de Antígeno , Proteínas de Membrana , Oligopeptídeos , Humanos , Apresentação de Antígeno/imunologia , Animais , Antígenos de Neoplasias/imunologia , Linhagem Celular Tumoral , Imunoterapia/métodos , Acidose/imunologia , Ativação Linfocitária/imunologia , Microambiente Tumoral/imunologia , Camundongos , Linfócitos T Citotóxicos/imunologia , Peptídeos/imunologia , Concentração de Íons de Hidrogênio , Melanoma/imunologia , Melanoma/terapia
19.
J Control Release ; 369: 556-572, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38580136

RESUMO

Vaccines represent one of the most powerful and cost-effective innovations for controlling a wide range of infectious diseases caused by various viruses and bacteria. Unlike mRNA and DNA-based vaccines, subunit vaccines carry no risk of insertional mutagenesis and can be lyophilized for convenient transportation and long-term storage. However, existing adjuvants are often associated with toxic effect and reactogenicity, necessitating expanding the repertoire of adjuvants with better biocompatibility, for instance, designing self-adjuvating polymeric carriers. We herein report a novel subunit vaccine delivery platform constructed via in situ free radical polymerization of C7A (2-(Hexamethyleneimino) ethyl methacrylate) and acrylamide around the surface of individual protein antigens. Using ovalbumin (OVA) as a model antigen, we observed substantial increases in both diameter (∼70 nm) and surface potential (-1.18 mV) following encapsulation, referred to as n(OVA)C7A. C7A's ultra pH sensitivity with a transition pH around 6.9 allows for rapid protonation in acidic environments. This property facilitates crucial processes such as endosomal escape and major histocompatibility complex (MHC)-I-mediated antigen presentation, culminating in the substantial CD8+ T cell activation. Additionally, compared to OVA nanocapsules without the C7A components and native OVA without modifications, we observed heightened B cell activation within the germinal center, along with remarkable increases in serum antibody and cytokine production. It's important to note that mounting evidence suggests that adjuvant effects, particularly its targeted stimulation of type I interferons (IFNs), can contribute to advantageous adaptive immune responses. Beyond its exceptional potency, the nanovaccine also demonstrated robust formation of immune memory and exhibited a favorable biosafety profile. These findings collectively underscore the promising potential of our nanovaccine in the realm of immunotherapy and vaccine development.


Assuntos
Camundongos Endogâmicos C57BL , Ovalbumina , Linfócitos T Citotóxicos , Animais , Ovalbumina/imunologia , Ovalbumina/administração & dosagem , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/farmacologia , Adjuvantes Imunológicos/química , Feminino , Metacrilatos/química , Polímeros/química , Polímeros/administração & dosagem , Nanopartículas/química , Nanopartículas/administração & dosagem , Camundongos , Vacinas/administração & dosagem , Vacinas/imunologia , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/imunologia , Nanovacinas
20.
Cancer Lett ; 591: 216893, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38636892

RESUMO

The oncogenic properties of Nucleobindin2 (NUCB2) have been observed in various cancer types. Nevertheless, the precise understanding of the biological functions and regulatory mechanisms of NUCB2 in osteosarcoma remains limited. This investigation reported that NUCB2 was significantly increased upon glucose deprivation-induced metabolic stress. Elevated NUCB2 suppressed glucose deprivation-induced cell death and reactive oxygen species (ROS) increase. Depletion of NUCB2 resulted in a reduction in osteosarcoma cell proliferation as well as metastatic potential in vitro and in vivo. Mechanically, NUCB2 ablation suppressed C-X-C Motif Chemokine Ligand 8 (CXCL8) expression which then reduced programmed cell death 1 ligand 1 (PD-L1) expression and stimulated anti-tumor immunity mediated through cytotoxic T cells. Importantly, a combination of NUCB2 depletion with anti-PD-L1 treatment improved anti-tumor T-cell immunity in vivo. Moreover, we further demonstrated that NUCB2 interacted with NUCKS1 to inhibit its degradation, which is responsible for the transcriptional regulation of CXCL8 expression. Altogether, the outcome emphasizes the function of NUCB2 in osteosarcoma and indicates that NUCB2 elevates osteosarcoma progression and immunosuppressive microenvironment through the NUCKS1/CXCL8 pathway.


Assuntos
Neoplasias Ósseas , Proteínas de Ligação ao Cálcio , Progressão da Doença , Interleucina-8 , Osteossarcoma , Microambiente Tumoral , Osteossarcoma/imunologia , Osteossarcoma/patologia , Osteossarcoma/metabolismo , Osteossarcoma/genética , Humanos , Animais , Linhagem Celular Tumoral , Interleucina-8/metabolismo , Interleucina-8/genética , Camundongos , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/patologia , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/genética , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/genética , Microambiente Tumoral/imunologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proliferação de Células , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/genética , Regulação Neoplásica da Expressão Gênica , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Linfócitos T Citotóxicos/imunologia , Transdução de Sinais , Espécies Reativas de Oxigênio/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA