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1.
Surg Clin North Am ; 100(1): 161-173, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31753110

RESUMO

Advanced/metastatic melanoma is an aggressive cancer with a low survival rate. Traditional cytotoxic chemotherapies do not appreciably extend life and systemic cytokine/chemokine administration produces toxic side effects. By harnessing the surveillance and cytotoxic features of the immune system, immunotherapies can provide a durable response and are proved to improve disease outcomes in patients with advanced/metastatic melanoma and other cancers. Close monitoring is necessary, however, to identify and treat immune system-related adverse events before they become life-threatening. Because metastatic lesions can respond differently to immunotherapies, modified response criteria have been developed to assist physicians in tracking patient response to treatment.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Imunoterapia/métodos , Melanoma/terapia , Neoplasias Cutâneas/terapia , Antineoplásicos Imunológicos/imunologia , Humanos , Fatores Imunológicos/imunologia , Fatores Imunológicos/uso terapêutico , Melanoma/imunologia , Neoplasias Cutâneas/imunologia
2.
Cancer Immunol Immunother ; 68(11): 1791-1804, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31620858

RESUMO

The perspective of combining cancer vaccines with immunomodulatory drugs is currently regarded as a highly promising approach for boosting tumor-specific T cell immunity and eradicating residual malignant cells. The efficacy of dendritic cell (DC) vaccination in combination with lenalidomide, an anticancer drug effective in several hematologic malignancies, was investigated in a follicular lymphoma (FL) model. First, we evaluated the in vitro activity of lenalidomide in modulating the immune responses of lymphocytes co-cultured with a new DC subset differentiated with IFN-α (IFN-DC) and loaded with apoptotic lymphoma cells. We next evaluated the efficacy of lenalidomide and IFN-DC-based vaccination, either alone or in combination, in hu-PBL-NOD/SCID mice bearing established human lymphoma. We found that lenalidomide reduced Treg frequency and IL-10 production in vitro, improved the formation of immune synapses of CD8 + lymphocytes with lymphoma cells and enhanced anti-lymphoma cytotoxicity. Treatment of lymphoma-bearing mice with either IFN-DC vaccination or lenalidomide led to a significant decrease in tumor growth and lymphoma cell spread. Lenalidomide treatment was shown to substantially inhibit tumor-induced neo-angiogenesis rather than to exert a direct cytotoxic effect on lymphoma cells. Notably, the combined treatment with the vaccine plus lenalidomide was more effective than either single treatment, resulting in the significant regression of established tumors and delayed tumor regrowth upon treatment discontinuation. In conclusion, our data demonstrate that IFN-DC-based vaccination plus lenalidomide exert an additive therapeutic effect in xenochimeric mice bearing established lymphoma. These results may pave the way to evaluate this combination in the clinical ground.


Assuntos
Vacinas Anticâncer/administração & dosagem , Células Dendríticas/imunologia , Sinergismo Farmacológico , Fatores Imunológicos/imunologia , Interferon-alfa/imunologia , Lenalidomida/farmacologia , Linfoma Folicular/terapia , Animais , Terapia Combinada , Feminino , Humanos , Fatores Imunológicos/farmacologia , Linfoma Folicular/imunologia , Linfoma Folicular/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID
3.
Magy Onkol ; 63(3): 165-171, 2019 Sep 18.
Artigo em Húngaro | MEDLINE | ID: mdl-31533135

RESUMO

In the immune defense against cancer, cell-mediated adaptive immune response is considered of primary importance, in which T lymphocytes play a key role. Activation, expansion and function of antigen-specific T cells is a multistep process and its outcome depends on the balance of positive and negative regulatory mechanisms controlling each step. Many factors can hamper the development of an efficient antitumor immune response, such as insufficient expression of tumor antigens or of molecules necessary for their processing, inhibitory molecular interactions (e.g. immune checkpoints), immune suppressive factors or suppressor cells. Various therapeutic strategies have been developed in order to increase the efficiency of antitumor immune defense, of which the application of immune checkpoint inhibitors, antibodies blocking the brakes of immune response, is the most widespread. These immunomodulatory antibodies had more favorable effect than traditional treatment modalities on a widening spectrum of tumor types, still the majority of patients do not or only transiently respond. Therefore, great efforts are made to develop rational combinations of immune and other therapies, and to identify resistance mechanisms and biomarkers predicting therapy outcome.


Assuntos
Imunoterapia , Neoplasias/imunologia , Neoplasias/terapia , Linfócitos T/imunologia , Antígenos de Neoplasias/imunologia , Humanos , Fatores Imunológicos/imunologia
4.
Magy Onkol ; 63(3): 217-223, 2019 Sep 18.
Artigo em Húngaro | MEDLINE | ID: mdl-31533142

RESUMO

Despite the spectacular development of clinical immunotherapy (IT) in the last decade, the regular treatment approaches for the most common central nervous system (CNS) tumors, the malignant gliomas (MGs) has not changed yet. The most important pitfalls of the routine application of immunotherapy can be imputed to the special and originally immunosuppressed microenvironment and the extreme heterogeneity of MGs, however the defensive role of the blood-brain barrier, the general usage of steroids and the difficulties in the evaluation of brain images can also play a role in these types of difficulties. Additionally, in the case of MGs, well-accepted IT biomarker assays (PDL1 positivity, mismatch repair deficiencies, tumor mutation burden, etc.) generally reveal only minimal levels of immunogen activities. Nevertheless, there are some promising results with the utilization of checkpoint inhibitors and other IT modalities (such as virus-based therapies, tumor vaccines, adoptive T cell therapies) and with the combination of conventional oncotherapy methods in case of CNS malignancies, as well. In conclusion, although the CNS is not any more considered as an "immunological sanctuary" and despite some encouraging experimental and clinical results in CNS oncotherapy, the routine application of IT in case of MGs is still awaited.


Assuntos
Neoplasias Encefálicas/terapia , Glioma/terapia , Imunoterapia , Neoplasias Encefálicas/imunologia , Glioma/imunologia , Humanos , Fatores Imunológicos/imunologia , Microambiente Tumoral/imunologia
5.
Immunopharmacol Immunotoxicol ; 41(4): 463-468, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31339393

RESUMO

Context: CD4+ T lymphocytes are able to differentiate into distinct subtypes according to several immunological scenarios, including T helper (Th)1, Th2, Th17 and regulatory T (Treg) cells. CD4+ T cells are phenotypically flexible and have specific ion channels, such as the nicotinic acetylcholine receptors (nAChR) that could be modulated by peptides produced by marine snails, known as conotoxins. Their effect on T lymphocytes has not been explored and emerging evidence suggests that these peptides may have immunomodulatory activities. Objective: This study investigated the effect of two Californiconus californicus-derived synthetic conotoxins on the proliferation and differentiation of T lymphocyte subpopulations Th1, Th2, Th17 and Treg. Methods: Cells from lymph nodes of BALB/c mice were cultured in the presence of conotoxins cal14.1b and cal14.2c (5.5 µM), during 96 h. Cell proliferation and intracellular cytokine production (IFN-γ, IL-4, IL-17 and IL-10) were analyzed by flow cytometry. Results and Discussion: cal14.1b and cal14.2c increased intracellular IL-10 production in Treg (CD3+CD4+Foxp3+) cells and decreased intracellular IL-17 production (CD3+CD4+) after 72 h of culture. Conotoxins did not show any effect on T cell proliferation nor Th1/Th2 balance. Conclusion: These results suggest that synthetic conotoxins exert immunomodulatory activity, especially by regulating specific functions on T lymphocytes.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Conotoxinas/imunologia , Fatores de Transcrição Forkhead/imunologia , Fatores Imunológicos/imunologia , Interleucina-10/imunologia , Peptídeos/imunologia , Linfócitos T Reguladores/imunologia , Animais , Organismos Aquáticos/imunologia , Diferenciação Celular/imunologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citocinas/imunologia , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C
6.
Arch Pharm Res ; 42(7): 560-566, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31147902

RESUMO

Over the past decade, immune checkpoint inhibitor (ICI) therapy has demonstrated improved therapeutic efficacy in a wide range of cancers. However, the benefits are restricted to a small population of patients. Therefore, studies on understanding the mechanisms resistant to ICI therapy and for finding predictive biomarkers for ICI therapy are being actively conducted. Recent studies have demonstrated that myeloid-derived suppressor cells (MDSC) inhibit ICI therapy by various mechanisms, and that the response to ICI therapy can be improved by blocking MDSC activity. Moreover, low level of MDSC in patients with cancer has been shown to be correlated with their good prognosis after ICI treatment, thereby suggesting MDSC as a predictive biomarker in this regard. This review focuses on the roles of MDSC in ICI therapy and their relevant applications.


Assuntos
Fatores Imunológicos/imunologia , Imunoterapia , Células Supressoras Mieloides/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Animais , Humanos
7.
PLoS Negl Trop Dis ; 13(6): e0007431, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31206512

RESUMO

Antivenoms from hyperimmune animal plasma are the only specific pharmaceuticals against snakebites. The improvement of downstream processing strategies is of great interest, not only in terms of purity profile, but also from yield-to-cost perspective and rational use of plasma of animal origin. We report on development of an efficient refinement strategy for F(ab')2-based antivenom preparation. Process design was driven by the imperative to keep the active principle constantly in solution as a precautionary measure to preserve stability of its conformation (precipitation of active principle or its adsorption to chromatographic stationary phase has been completely avoided). IgG was extracted from hyperimmune horse plasma by 2% (V/V) caprylic acid, depleted from traces of precipitating agent and digested by pepsin. Balance between incomplete IgG fraction breakdown, F(ab')2 over-digestion and loss of the active principle's protective efficacy was achieved by adjusting pepsin to substrate ratio at the value of 4:300 (w/w), setting pH to 3.2 and incubation period to 1.5 h. Final polishing was accomplished by a combination of diafiltration and flow-through chromatography. Developed manufacturing strategy gave 100% pure and aggregate-free F(ab')2 preparation, as shown by size-exclusion HPLC and confirmed by MS/MS. The overall yield of 75% or higher compares favorably to others so far reported. This optimised procedure looks also promising for large-scale production of therapeutic antivenoms, since high yield of the active drug and fulfillment of the regulatory demand considering purity was achieved. The recovery of the active substance was precisely determined in each purification step enabling accurate estimation of the process cost-effectiveness.


Assuntos
Antivenenos/imunologia , Antivenenos/isolamento & purificação , Fragmentos Fab das Imunoglobulinas/imunologia , Fragmentos Fab das Imunoglobulinas/isolamento & purificação , Fatores Imunológicos/imunologia , Fatores Imunológicos/isolamento & purificação , Tecnologia Farmacêutica/métodos , Animais , Cavalos
8.
Neuroscience ; 410: 264-273, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31128159

RESUMO

Neurobrucellosis, which is the most morbid form of brucellosis disease, presents with inflammatory signs and symptoms. Recent experimental evidence clearly indicates that deregulation of astrocytes and microglia caused by Brucella infection creates a microenvironment in the central nervous system (CNS) in which secretion of pro-inflammatory mediators lead to destabilization of the glial structure, the damage of the blood brain barrier (BBB) and neuronal demise. This review of Brucella interactions with cells of the CNS and the BBB is intended to present recent immunological findings that can explain, at least in part, the basis for the inflammatory pathogenesis of the nervous system that takes place upon Brucella infection.


Assuntos
Barreira Hematoencefálica/imunologia , Brucelose/imunologia , Sistema Nervoso Central/imunologia , Imunidade Inata/fisiologia , Fatores Imunológicos/imunologia , Animais , Barreira Hematoencefálica/metabolismo , Brucelose/metabolismo , Sistema Nervoso Central/metabolismo , Humanos , Fatores Imunológicos/metabolismo
9.
Biomed Res Int ; 2019: 8086257, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31016198

RESUMO

Αlpha-lipoic acid is a naturally occurring antioxidant in human body and has been widely used as an antioxidant clinically. Accumulating evidences suggested that α-lipoic acid might have immunomodulatory effects on both adaptive and innate immune systems. This review focuses on the evidences and potential targets involved in the immunomodulatory effects of α-lipoic acid. It highlights the fact that α-lipoic acid may have beneficial effects in autoimmune diseases once the immunomodulatory effects can be confirmed by further investigation.


Assuntos
Doenças Autoimunes/imunologia , Fatores Imunológicos/imunologia , Ácido Tióctico/imunologia , Animais , Antioxidantes/farmacologia , Humanos , Fatores Imunológicos/farmacologia , Ácido Tióctico/farmacologia
10.
APMIS ; 127(7): 529-537, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31017317

RESUMO

Chronic immune activation and inflammation are constant findings in people living with HIV (PLWH) and contribute to the risk of non-AIDS-related morbidities, including cardiovascular diseases (CVD). Type 2 diabetes (T2D) is also characterized by immune activation and inflammation. We aimed to investigate the impact of concurrent HIV infection and T2D on T-cell subsets. The study included PLWH with T2D (HIV+T2D+, N = 25) and without T2D (HIV+T2D-, N = 25) and HIV-negative controls with T2D (HIV-T2D+, N = 22) and without T2D (HIV-T2D-, N = 28). All PLWH in the study were receiving combination antiretroviral therapy. We examined T-cell homeostasis by determining T-cell subsets (immune maturation, immune regulation and immune activation) using flow cytometry. HIV+T2D- had lower proportion of Tc17 cells and higher proportion of apoptotic cells than HIV-T2D-. When comparing HIV+T2D+ and HIV+T2D- a lower proportion of CD4+ recent thymic emigrants (RTE) was found (p = 0.028). Furthermore, HIV+T2D+ had a higher proportion of non-suppressive CD4+ Tregs compared to HIV+T2D- (p = 0.010). In conclusion, even in the setting of treated HIV infection, distinct immunological alterations are found. In PLWH with concomitant T2D, most alterations in T-cell subsets were related to HIV and only few differences were found between PLWH with and without diabetes.


Assuntos
Diabetes Mellitus Tipo 2/imunologia , Infecções por HIV/imunologia , HIV/imunologia , Antirretrovirais/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Feminino , HIV/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Humanos , Fatores Imunológicos/imunologia , Pessoa de Meia-Idade
11.
Curr Protein Pept Sci ; 20(6): 505-524, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30950347

RESUMO

α1-acid glycoprotein (orosomucoid, AGP) is an Acute Phase Protein produced by liver and peripheral tissues in response to systemic reaction to inflammation. AGP functions have been studied mostly in human, cattle and fish, although the protein has been also found in many mammalian species and birds. AGP fulfils at least two set of functions, which are apparently different from each other but in fact intimately linked. On one hand, AGP is an immunomodulatory protein. On the other hand, AGP is one of the most important binding proteins in plasma and, beside modulating pharmacokinetics and pharmacodynamics of many drugs, it is also able to bind and transport several endogen ligands related to inflammation. The focus of this review is the immunomodulatory activity of AGP. This protein regulates every single event related to inflammation, including binding of pathogens and modulating white blood cells activity throughout the entire leukocyte attacking sequence. The regulation of AGP activity is complex: the inflammation induces not only an increase in AGP serum concentration, but also a qualitative change in its carbohydrate moiety, generating a multitude of glycoforms, each of them with different, and sometimes opposite and contradictory, activities. We also present the most recent findings about the relationship between AGP and adipose tissue: AGP interacts with leptin receptor and, given its immunomodulatory function, it may be included among the potential players in the field of immunometabolism.


Assuntos
Fatores Imunológicos/imunologia , Orosomucoide/imunologia , Proteínas da Fase Aguda/metabolismo , Tecido Adiposo/imunologia , Animais , Quimiotaxia , Citocinas/biossíntese , Humanos , Fatores Imunológicos/metabolismo , Imunomodulação , Inflamação/imunologia , Inflamação/metabolismo , Orosomucoide/química , Orosomucoide/metabolismo , Conformação Proteica , Processamento de Proteína Pós-Traducional , Receptores para Leptina/metabolismo
12.
Fish Shellfish Immunol ; 88: 480-488, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30877062

RESUMO

As one of the most important neuropeptides identified only in invertebrates of Mollusca, Annelida and Arthropoda, FMRFamide (Phe-Met-Arg-Phe-NH2) involves in multiple physiological processes, such as mediating cardiac frequency and contraction of somatic and visceral muscles. However, its modulatory role in the immune defense has not been well understood. In the present study, an FMRFamide precursor (designed as CgFMRFamide) was identified in oyster Crassostrea gigas, which could be processed into nineteen FMRFamide peptides. Phylogenetic analysis revealed that CgFMRFamide shared high similarity with other identified FMRFamides in mollusks. The mRNA of CgFMRFamide was mainly concentrated in the tissues of visceral ganglia, hepatopancreas and hemocytes, and a consistent distribution of FMRFamide peptide was confirmed by immunohistochemistry and immunocytochemistry assays. The mRNA expression level of CgFMRFamide in hemocytes was significantly up-regulated after immune stimulation with lipopolysaccharide (LPS). After the concentration of FMRFamide was increased by exogenous injection, the in vivo expressions of pro-inflammatory cytokine CgIL17-5, as well as the apoptosis-related CgCaspase-1 and CgCaspase-3 in hemocytes were promptly increased (p < 0.05), but the concentration of signal molecule nitric oxide (NO) was significantly down-regulated (p < 0.05). Meanwhile, an increased phosphorylation of p38 MAP kinase in hemocytes was also detected after the FMRFamide injection. These results collectively demonstrated that the conserved FMRFamide could not only respond to immune stimulation, but also regulate the expression of immune effectors and apoptosis-related genes, which might be mediated by p38 MAP kinase pathway, thereby effectively involved in clearing pathogens and maintaining homeostasis in oysters.


Assuntos
Crassostrea/imunologia , FMRFamida/imunologia , Fatores Imunológicos/imunologia , Animais , Apoptose , Caspases/metabolismo , Citocinas/metabolismo , FMRFamida/administração & dosagem , FMRFamida/genética , Hemócitos/efeitos dos fármacos , Hemócitos/imunologia , Imunidade Inata , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/genética , Lipopolissacarídeos , Óxido Nítrico/metabolismo , Fosforilação/efeitos dos fármacos , Filogenia , RNA Mensageiro , Regulação para Cima
13.
Fish Shellfish Immunol ; 88: 587-594, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30885741

RESUMO

Antimicrobial peptides (AMPs) are amphipathic peptides, which play an important role in innate defence. These peptides are gene-encoded and either constitutively expressed and/or upregulated during an infection. NK-lysins are AMPs with a three-dimensional globular structure. They are larger molecules, which comprise 74-78 amino acid residues and six conserved cysteine residues forming three disulphide bonds. Cathelicidins are a family of antimicrobial peptides that act as important components of the innate immune system with a broad spectrum of antimicrobial activity and immunomodulatory properties. Although they are widely studied in mammals, little is known about their immunomodulatory function. In the present study, we identified and characterized for the first time four NK-lysin-like transcripts from Atlantic salmon (Salmo salar) based on EST reported sequences. In vitro, NK-lysin derived peptides were able to induce the expression of IL-1ß and IL-8 in Salmo salar head kidney leukocytes. We also tested Salmo salar cathelicidin 1 derived peptide in a similar assay, showing its ability to induce the expression of IFN-γ. These results indicate that NK-lysin and cathelicidin 1 derived peptides are able to modulated immune response, suggesting their potential use to enhance immune response in fish.


Assuntos
Catelicidinas/genética , Proteínas de Peixes/imunologia , Fatores Imunológicos/imunologia , Proteolipídeos/genética , Salmo salar/imunologia , Animais , Catelicidinas/imunologia , Doenças dos Peixes/imunologia , Rim Cefálico/citologia , Rim Cefálico/imunologia , Imunidade Inata , Interferon gama/imunologia , Leucócitos/imunologia , Proteolipídeos/imunologia
14.
Isr Med Assoc J ; 21(3): 158-162, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30905098

RESUMO

BACKGROUND: The hygiene theory represents one of the environmental facets that modulate the risk for developing autoimmune diseases. There is a reverse correlation between the presence of helminthes and flares of autoimmune diseases, which explains the rise in incidence of certain autoimmune diseases in developed countries. The protective properties of certain helminthes are attributed to their secretory compounds which immunomodulate the host immune network in order to survive. Thus, the helminthes use an array of mechanisms. One of the major mechanisms enabling manipulation of the host-helminth interaction is by targeting the pattern recognition receptors (PRRs)-dependent and -independent mechanisms, which include toll-like receptors, C-type lectin receptors, and the inflammasome. The current review provides a glimpse of numerous helminth secreted products which have a role in the immunomodulation of the host immune network, focusing on bifunctional tuftsin-phosphorylcholine (TPC). TPC is a natural compound based on phosphorylcholine of helminth origin that was used in the past to cover stents and tuftsin, a self-peptide derived from the spleen. TPC was proven to be efficient in three murine experimental models (lupus, colitis, and arthritis) and ex vivo in giant cell arteritis.


Assuntos
Doenças Autoimunes/prevenção & controle , Helmintíase/imunologia , Helmintos/imunologia , Fatores Imunológicos/imunologia , Fatores Imunológicos/farmacologia , Imunomodulação/imunologia , Fosforilcolina/imunologia , Fosforilcolina/farmacologia , Tuftsina/imunologia , Tuftsina/farmacologia , Animais , Modelos Animais de Doenças , Humanos , Camundongos
15.
Nat Commun ; 10(1): 1052, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30837455

RESUMO

Mouth ulcers are the most common ulcerative condition and encompass several clinical diagnoses, including recurrent aphthous stomatitis (RAS). Despite previous evidence for heritability, it is not clear which specific genetic loci are implicated in RAS. In this genome-wide association study (n = 461,106) heritability is estimated at 8.2% (95% CI: 6.4%, 9.9%). This study finds 97 variants which alter the odds of developing non-specific mouth ulcers and replicate these in an independent cohort (n = 355,744) (lead variant after meta-analysis: rs76830965, near IL12A, OR 0.72 (95% CI: 0.71, 0.73); P = 4.4e-483). Additional effect estimates from three independent cohorts with more specific phenotyping and specific study characteristics support many of these findings. In silico functional analyses provide evidence for a role of T cell regulation in the aetiology of mouth ulcers. These results provide novel insight into the pathogenesis of a common, important condition.


Assuntos
Loci Gênicos/imunologia , Predisposição Genética para Doença , Fatores Imunológicos/genética , Úlceras Orais/genética , Estomatite Aftosa/genética , Adulto , Idoso , Estudos de Coortes , Simulação por Computador , Feminino , Estudo de Associação Genômica Ampla , Humanos , Fatores Imunológicos/imunologia , Masculino , Pessoa de Meia-Idade , Úlceras Orais/imunologia , Estomatite Aftosa/imunologia , Linfócitos T/imunologia
16.
Acta Trop ; 193: 113-123, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30831113

RESUMO

The genus Porthidium includes nine pitviper species inhabiting Mexico, Central America, and northern South America. Porthidium porrasi is a species endemic to the Southwest of Costa Rica, for which no information on its venom was available. In this study, the proteomic composition and functional activities of P. porrasi venom are described. The most abundant venom proteins were identified as metalloproteinases (36.5%). In descending order of abundance, proteins belonging to the disintegrin, phospholipase A2, serine proteinase, C-type lectin/lectin-like, vascular endothelial growth factor, Cysteine-rich secretory protein, L-amino acid oxidase, phospholipase B, and phosphodiesterase families were also identified. P. porrasi venom showed a weak lethal potency in mice (10 µg/g body weight by intraperitoneal route), induced marked hemorrhage and edema, and weak myotoxic effect. These in vivo activities, as well as those assayed in vitro (proteolytic and phospholipase A2 activities) correlated with compositional data. A comparison of P. porrasi venom with those of three other Porthidium species studied to date reveals a generally conserved compositional and functional pattern in this pitviper genus. Importantly, the lethal effect of P. porrasi venom in mice was adequately cross-neutralized by a heterospecific polyvalent antivenom, supporting its use in the treatment of eventual envenomings by this species.


Assuntos
Antivenenos/imunologia , Venenos de Crotalídeos/enzimologia , Venenos de Crotalídeos/imunologia , Crotalinae , Fatores Imunológicos/imunologia , Animais , Antivenenos/uso terapêutico , Costa Rica , Fatores Imunológicos/uso terapêutico , Metaloproteases/análise , Camundongos , Proteômica
17.
Nat Commun ; 10(1): 1012, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30833557

RESUMO

Amphiphilicity in ɑ-helical antimicrobial peptides (AMPs) is recognized as a signature of potential membrane activity. Some AMPs are also strongly immunomodulatory: LL37-DNA complexes potently amplify Toll-like receptor 9 (TLR9) activation in immune cells and exacerbate autoimmune diseases. The rules governing this proinflammatory activity of AMPs are unknown. Here we examine the supramolecular structures formed between DNA and three prototypical AMPs using small angle X-ray scattering and molecular modeling. We correlate these structures to their ability to activate TLR9 and show that a key criterion is the AMP's ability to assemble into superhelical protofibril scaffolds. These structures enforce spatially-periodic DNA organization in nanocrystalline immunocomplexes that trigger strong recognition by TLR9, which is conventionally known to bind single DNA ligands. We demonstrate that we can "knock in" this ability for TLR9 amplification in membrane-active AMP mutants, which suggests the existence of tradeoffs between membrane permeating activity and immunomodulatory activity in AMP sequences.


Assuntos
Anti-Infecciosos/química , Anti-Infecciosos/imunologia , Peptídeos Catiônicos Antimicrobianos/química , DNA/química , Receptor Toll-Like 9/química , Anti-Infecciosos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Morte Celular/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Simulação por Computador , DNA/imunologia , Humanos , Fatores Imunológicos/química , Fatores Imunológicos/imunologia , Ligantes , Macrófagos/efeitos dos fármacos , Modelos Moleculares , Conformação Proteica em alfa-Hélice/fisiologia , Espalhamento de Radiação , Receptor Toll-Like 9/imunologia , Difração de Raios X
19.
Nat Rev Cancer ; 19(3): 133-150, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30755690

RESUMO

Checkpoint inhibitor-based immunotherapies that target cytotoxic T lymphocyte antigen 4 (CTLA4) or the programmed cell death 1 (PD1) pathway have achieved impressive success in the treatment of different cancer types. Yet, only a subset of patients derive clinical benefit. It is thus critical to understand the determinants driving response, resistance and adverse effects. In this Review, we discuss recent work demonstrating that immune checkpoint inhibitor efficacy is affected by a combination of factors involving tumour genomics, host germline genetics, PD1 ligand 1 (PDL1) levels and other features of the tumour microenvironment, as well as the gut microbiome. We focus on recently identified molecular and cellular determinants of response. A better understanding of how these variables cooperate to affect tumour-host interactions is needed to optimize the implementation of precision immunotherapy.


Assuntos
Neoplasias/imunologia , Neoplasias/terapia , Animais , Antígeno B7-H1/imunologia , Antígeno CTLA-4/imunologia , Humanos , Fatores Imunológicos/imunologia , Imunoterapia/métodos , Microambiente Tumoral/imunologia
20.
Crit Rev Food Sci Nutr ; 59(6): 992-1007, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30795687

RESUMO

Cancer is considered a fetal disease caused by uncontrolled proliferation and progression of abnormal cells. The most efficient cancer therapies suppress tumor growth, prevent progression and metastasis, and are minimally toxic to normal cells. Natural compounds have shown a variety of chemo-protective effects alone or in combination with standard cancer therapies. Along with better understanding of the dynamic interactions between our immune system and cancer development, nutritional immunology-the use of natural compounds as immunomodulators in cancer patients-has begun to emerge. Cancer cells evolve strategies that target many aspects of the immune system to escape or even edit immune surveillance. Therefore, the immunesuppressive tumor microenvironment is a major obstacle in the development of cancer therapies. Because interaction between the tumor microenvironment and the immune system is a complex topic, this review focuses mainly on human clinical trials and animal studies, and it highlights specific immune cells and their cytokines that have been modulated by natural compounds, including carotenoids, curcumin, resveratrol, EGCG, and ß-glucans. These natural compounds have shown promising immune-modulating effects, such as inhibiting myeloid-derived suppressor cells and enhancing natural killer and cytolytic T cells, in tumor-bearing animal models, but their efficacy in cancer patients remains to be determined.


Assuntos
Fatores Imunológicos/imunologia , Fatores Imunológicos/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Animais , Carotenoides/farmacologia , Catequina/análogos & derivados , Catequina/farmacologia , Curcumina/farmacologia , Humanos , Sistema Imunitário , Células Matadoras Naturais/efeitos dos fármacos , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Resveratrol/farmacologia , Linfócitos T/efeitos dos fármacos , Tretinoína/farmacologia , beta-Glucanas/farmacologia
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