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1.
Article in English | WPRIM | ID: wpr-880368

ABSTRACT

BACKGROUND@#Asbestos fibers possess tumorigenicity and are thought to cause mesothelioma. We have previously reported that exposure to asbestos fibers causes a reduction in antitumor immunity. Asbestos exposure in the mixed lymphocyte reaction (MLR) showed suppressed induction of cytotoxic T lymphocytes (CTLs), accompanied by a decrease in proliferation of CD8@*METHODS@#For MLR, human peripheral blood mononuclear cells (PBMCs) were cultured with irradiated allogenic PBMCs upon exposure to chrysotile B asbestos at 5 μg/ml for 7 days. After 2 days of culture, IL-15 was added at 1 ng/ml. After 7 days of MLR, PBMCs were collected and analyzed for phenotypic and functional markers of CD8@*RESULTS@#IL-15 addition partially reversed the decrease in CD3@*CONCLUSION@#These findings indicate that CTLs induced upon exposure to asbestos possess dysfunctional machinery that can be partly compensated by IL-15 supplementation, and that IL-15 is more effective in the recovery of proliferation and granzyme B levels from asbestos-induced suppression of CTL induction compared with IL-2.


Subject(s)
Asbestos/adverse effects , CD8-Positive T-Lymphocytes/metabolism , Humans , Interleukin-15/pharmacology , Lymphocyte Activation/immunology , T-Lymphocytes, Cytotoxic/metabolism
2.
Chinese Journal of Biotechnology ; (12): 2924-2935, 2021.
Article in Chinese | WPRIM | ID: wpr-887854

ABSTRACT

The β2m (Beta-2-microglobin) gene encodes a non-glycosylated protein that functions as an important component of major histocompatibility complexⅠ(MHCⅠ) for antigen presentation. To evade immune mediated clearance, human tumors and pathogens have adopted different strategies, including loss of MHCⅠexpression. Appropriate animal models are essential for understanding the mechanisms underpinning the clinical treatment of tumor and other human diseases. We constructed β2m knockout mice using CRISPR/Cas9 gene editing tool through embryo microinjection. Subsequently, genotyping and phenotyping of knockout mice were performed by PCR, qPCR, and flow cytometry. Mice genotyping showed that the coding region of the target gene was absent in the knockout mice. Real time PCR showed that mRNA level of β2m was significantly downregulated. Flow cytometry showed that the proportions of CD8+ killer T cells was significantly reduced in a variety of tissues and organs of the immune system. Taken together, we have successfully constructed a strain of β2m knockout mice, which will facilitate subsequent in vivo study on the function and mechanism of the β2m gene.


Subject(s)
Animals , Histocompatibility Antigens Class I , Mice , Mice, Inbred C57BL , Mice, Knockout , T-Lymphocytes, Cytotoxic , beta 2-Microglobulin/genetics
3.
Article in English | WPRIM | ID: wpr-878349

ABSTRACT

Objective@#To evaluate the safety and effectiveness of a vaccine based on latent membrane protein 2 (LMP2) modified dendritic cells (DCs) that boosts specific responses of cytotoxic T lymphocytes (CTLs) to LMP2 before and after intradermal injection in patients with nasopharyngeal carcinoma (NPC).@*Methods@#DCs were derived from peripheral blood monocytes of patients with NPC. We prepared LMP2-DCs infected by recombinant adenovirus vector expressing LMP2 (rAd-LMP2). NPC patients were immunized with 2 × 10 @*Results@#We demonstrated that DCs derived from monocytes displayed typical DC morphologies; the expression of LMP2 in the LMP2-DCs vaccine was confirmed by immunocytochemical assay. Twenty-nine patients with NPC were enrolled in this clinical trial. The LMP2-DCs vaccine was well tolerated in all of the patients. Boosted responses to LMP2 peptide sub-pools were observed in 18 of the 29 patients with NPC. The follow-up data of 29 immunized patients from April, 2010 to April 2015 indicated a five-year survival rate of 94.4% in responders and 45.5% in non-responders.@*Conclusion@#In this pilot study, we demonstrated that the LMP2-DCs vaccine is safe and effective in patients with NPC. Specific CTLs responses to LMP2 play a certain role in controlling and preventing the recurrence and metastasis of NPC, which warrants further clinical testing.


Subject(s)
Adult , Aged , Cancer Vaccines/therapeutic use , China , Dendritic Cells/immunology , Female , Humans , Immunotherapy/methods , Injections, Intradermal , Male , Middle Aged , Nasopharyngeal Carcinoma/therapy , Nasopharyngeal Neoplasms/therapy , T-Lymphocytes, Cytotoxic/immunology , Viral Matrix Proteins/therapeutic use , Young Adult
4.
Iatreia ; 32(4): 311-320, oct.-dic. 2019. tab, graf
Article in Spanish | LILACS | ID: biblio-1056311

ABSTRACT

RESUMEN La linfohistiocitosis hemofagocítica (LHH) posterior al trasplante renal hace referencia a un estado hiperinflamatorio grave, asociado a la activación no controlada de los linfocitos T citotóxicos y macrófagos por causa infecciosas y/o secundaria al tratamiento inmunosupresor. Las causas más prevalentes dentro de las infecciones son la histoplasmosis, la tuberculosis y las infecciones por virus herpes. Se caracteriza por fiebre, organomegalias, citopenias, hiperferritinemia, hipertrigliceridemia y/o hipofibrinogenemia; puede acompañarse con hemofagocitosis documentada en la médula ósea, el hígado u otros órganos. Su curso puede ser fulminante con progresión a falla multisistémica y la muerte. El tratamiento va enfocado a controlar tempranamente la causa desencadenante, reducir la inmunosupresión y controlar la inflamación. En pocos casos es necesario el uso de otros inmunosupresores, quimioterapia o, en situaciones muy seleccionadas, se puede requerir el trasplante de médula ósea.


SUMMARY Hemophagocytic lymphohistiocytosis (HLH) in renal transplant recipients is a life-threatening hyper-inflammatory syndrome; associated with uncontrolled activation of cytotoxic T-lymphocytes and macrophages due to infections or immunosuppressive therapy. Histoplasmosis, tuberculosis and herpes virus infection are among the leading infectious causes. It is characterized by fever, organomegaly, cytopenia, hyperferritinemia, hypertrigiceridemia and/or hypofibrinogenemia; which may be accompanied by hemophagocytosis in bone marrow, liver or other organs. HLH can follow a rapidly fatal course, with progression to multisystemic failure and death. The treatment is based on early control of the triggering cause, reducing immunosuppression and stop the inflammatory process. In some cases, is necessary to use other immunosuppressant, chemotherapy and in a very few cases, a bone marrow transplant may be required.


Subject(s)
Humans , T-Lymphocytes, Cytotoxic , Kidney Transplantation , Lymphohistiocytosis, Hemophagocytic
5.
Article in English | WPRIM | ID: wpr-719487

ABSTRACT

PURPOSE: The influenza B virus diverges into two antigenically distinct lineages: B/Yamagata and B/Victoria. Influenza B is the dominant circulating virus during some influenza seasons, and recent data demonstrated that influenza A and B infection similarly cause severe clinical symptoms in hospitalized patients. Nucleoprotein (NP) is a good target for a universal influenza vaccine. This study investigated whether NP epitope variation within two lineages affects the dominant cytotoxic T lymphocyte (CTL) responses induced by vaccination and the resultant protective immunity. MATERIALS AND METHODS: The NP of B/Yamagata/16/1988, the representative strain of the Yamagata lineage, includes a dominant CTL epitope, FSPIRITFL, while B/Shangdong/7/1997 from the Victoria lineage has one amino acid difference in this sequence, FSPIRVTFL. Two recombinant replication-deficient adenovirus (rAd)-vectored vaccines expressing either NP were prepared (rAd/B-NP(I) and rAd/B-NP(V), respectively) and administered to BALB/c mice intranasally. To examine the efficacy of vaccination, antibody responses, CTL responses, and morbidity/mortality after challenge were measured. RESULTS: Both vaccines induce similar antibody and CD8 T-cell responses cross-reacting to both epitopes, and also confer cross-protection against both lineages regardless of amino acid difference. CONCLUSION: The rAd-vectored vaccine expressing the NP could be developed as universal influenza B vaccine which provides broader protection.


Subject(s)
Adenoviridae , Animals , Antibody Formation , Epitopes , Humans , Influenza B virus , Influenza Vaccines , Influenza, Human , Lymphocytes , Mice , Nucleoproteins , Seasons , T-Lymphocytes , T-Lymphocytes, Cytotoxic , Vaccination , Vaccines , Victoria
6.
São Paulo; s.n; 2019. 99 p. ilust, tabelas.
Thesis in Portuguese | LILACS, Inca | ID: biblio-1179933

ABSTRACT

O linfoma de Hodgkin é uma neoplasia singular, caracterizada pela escassez de células tumorais, imersas em abundante microambiente inflamatório. Com base nas diferenças histológicas e no fenótipo das células tumorais, divide-se em duas entidades: o linfoma de Hodgkin clássico e o linfoma de Hodgkin predominância linfocitária nodular. A incidência do linfoma de Hodgkin varia de acordo com idade, nível socioeconômico e associação com o vírus EBV. Existem estudos que associam a composição do microambiente tumoral do linfoma de Hodgkin com prognóstico, particularmente o alto índice de macrófagos no microambiente tumoral a pior prognóstico. No Brasil, os estudos publicados foram discordantes com os demais estudos. O presente estudo propõe avaliar a interação entre o linfoma de Hodgkin e seu microambiente, em busca de marcadores prognósticos no infiltrado inflamatório peritumoral, bem como avaliar as diferenças entre a região Sudeste, de melhor nível socioeconômico e a região Nordeste, que tem índice socioeconômico mais baixo. Para tanto, foram identificados retrospectivamente 176 pacientes com diagnóstico de linfoma de Hodgkin clássico, entre 2003 e 2013, provenientes de dois centros oncológicos de referência: o AC Camargo Cancer Center (região Sudeste) e Hospital Haroldo Juaçaba (região Nordeste). A média de idade foi 35±16 anos, sendo 39±15 nos pacientes do A.C.Camargo Cancer Center e 30±17 nos pacientes do HHJ (p<0,001). O LHEN foi o subtipo mais frequente, correspondendo a 89,9% dos casos do A.C.Camargo Cancer Center e 63,2% dos casos do HHJ. Positividade para EBV foi vista em 9,2% dos pacientes do A.C.Camargo Cancer Center e em 35,6% dos pacientes do HHJ. Os pacientes do HHJ apresentaram um microambiente tumoral com maior número células expressando CD 3, CD 4 e CD 8. Para ambas as populações, os linfomas associados a positividade para EBV apresentaram maior número de células CD 8 no microambiente. Para os pacientes do A.C.Camargo Cancer Center o microambiente não influenciou SLE. Para os pacientes do HHJ, na análise univariada um maior percentual de células expressando CD 20 no microambiente mostrou associação com maior SLE. Na análise multivariada, alta expressão de CD 20 mostrou ser fator independente associado a maior SLE. Macrófagos associados ao tumor não mostraram associação com pior prognóstico, quando avaliados por CD68


Hodgkin's lymphoma (HL) is a unique neoplasm, characterized by the scarcity of tumor cells which are immersed in an abundant inflammatory microenvironment. Based on histologic and phenotypic differences in tumor cells, HL is divided in two entities: classic Hodgkin's lymphoma (cHL) and nodular lymphocyte predominant Hodgkin lymphoma. HL incidence varies upon age, socioeconomic level and EBV association. In addition, some studies have associated tumor microenvironment (TME) features in HL with prognosis, specially a high number of tumor associated macrophages as an adverse prognosis marker. In Brazil, the published studies are not in accordance to the international data. In this study, we evaluated HL interaction with TME and we compared populations from two different geographic regions: Brazilian Southeast, with higher socioeconomic level, and Northeast Brazil with lower socioeconomic level. 176 patients previously diagnosed with cHL from 2003 to 2013 from two referral oncologic centers (A. C. Camargo Cancer Center (AC) ­ Southeast Brazil and Hospital Haroldo Juaçaba (HHJ) ­ Northeast Brazil) were included in this study. The global median age was 35±16, which comprises a median of 30±17 for HHJ patients and 39±15 for AC patients (p<0.001). Nodular scleroris HL was the most frequent subtype, comprising 89.9% and 63.2% of AC and HHJ cases, respectively. EBV positivity was detected in 9.2% of AC patients and in 35.6% of HHJ patients. Patients from the HHJ presented a higher expression of CD3, CD4 and CD8 in the TME. In both populations, EBV-associated lymphoma were associated to a higher CD8 detection in the TME. Event-free survival (EFS) was not influenced by TME constitution in the AC patients. On the other hand, considering HHJ patients, univariate analysis showed an association between a longer EFS to high CD20 expression. In multivariate analysis, high CD20 expression showed to be an independent prognostic factor related to a longer EFS. Tumor associated macrophages showed no association to prognosis when evaluated by CD68 expression


Subject(s)
Humans , Male , Female , Adolescent , Adult , Hodgkin Disease , B-Lymphocytes , T-Lymphocytes, Cytotoxic , Epstein-Barr Virus Infections , Tumor Microenvironment
7.
Article in English | WPRIM | ID: wpr-715521

ABSTRACT

Thyroid diseases, including autoimmune thyroid diseases and thyroid cancer, are known to have high heritability. Family and twin studies have indicated that genetics plays a major role in the development of thyroid diseases. Thyroid function, represented by thyroid stimulating hormone (TSH) and free thyroxine (T4), is also known to be partly genetically determined. Before the era of genome-wide association studies (GWAS), the ability to identify genes responsible for susceptibility to thyroid disease was limited. Over the past decade, GWAS have been used to identify genes involved in many complex diseases, including various phenotypes of the thyroid gland. In GWAS of autoimmune thyroid diseases, many susceptibility loci associated with autoimmunity (human leukocyte antigen [HLA], protein tyrosine phosphatase, non-receptor type 22 [PTPN22], cytotoxic T-lymphocyte associated protein 4 [CTLA4], and interleukin 2 receptor subunit alpha [IL2RA]) or thyroid-specific genes (thyroid stimulating hormone receptor [TSHR] and forkhead box E1 [FOXE1]) have been identified. Regarding thyroid function, many susceptibility loci for levels of TSH and free T4 have been identified through genome-wide analyses. In GWAS of differentiated thyroid cancer, associations at FOXE1, MAP3K12 binding inhibitory protein 1 (MBIP)-NK2 homeobox 1 (NKX2-1), disrupted in renal carcinoma 3 (DIRC3), neuregulin 1 (NRG1), and pecanex-like 2 (PCNXL2) have been commonly identified in people of European and Korean ancestry, and many other susceptibility loci have been found in specific populations. Through GWAS of various thyroid-related phenotypes, many susceptibility loci have been found, providing insights into the pathogenesis of thyroid diseases and disease co-clustering within families and individuals.


Subject(s)
Autoimmunity , Genes, Homeobox , Genetics , Genome-Wide Association Study , Graves Disease , Hashimoto Disease , Humans , Leukocytes , Neuregulin-1 , Phenotype , Protein Tyrosine Phosphatase, Non-Receptor Type 22 , Receptors, Interleukin-2 , T-Lymphocytes, Cytotoxic , Thyroid Diseases , Thyroid Gland , Thyroid Neoplasms , Thyrotropin , Thyroxine
8.
Article in English | WPRIM | ID: wpr-758865

ABSTRACT

The bursa of Fabricius (BF) is a central humoral immune organ unique to birds. Four bursal peptides (BP-I, BP-II, BP-III, and BP-IV) have been isolated and identified from the BF. In this study, the immunoadjuvant activities of BPs I to IV were examined in mice immunized with H9N2 avian influenza virus (AIV) vaccine. The results suggested that BP-I effectively enhanced cell-mediated immune responses, increased the secretion of Th1 (interferon gamma)- and Th2 (interleukin-4)-type cytokines, and induced an improved cytotoxic T-lymphocyte (CTL) response to the H9N2 virus. BP-II mainly elevated specific antibody production, especially neutralizing antibodies, and increased Th1- and Th2-type cytokine secretion. BP-III had no significant effect on antibody production or cell-mediated immune responses compared to those in the control group. A strong immune response at both the humoral and cellular levels was induced by BP-IV. Furthermore, a virus challenge experiment followed by H&E staining revealed that BP-I and BP-II promoted removal of the virus and conferred protection in mouse lungs. BP-IV significantly reduced viral titers and histopathological changes and contributed to protection against H9N2 AIV challenge in mouse lungs. This study further elucidated the immunoadjuvant activities of BPs I to IV, providing a novel insight into immunoadjuvants for use in vaccine design.


Subject(s)
Adjuvants, Immunologic , Animals , Antibodies, Neutralizing , Antibody Formation , Birds , Bursa of Fabricius , Cytokines , Immunity, Cellular , Immunity, Humoral , Influenza A Virus, H9N2 Subtype , Influenza in Birds , Lung , Mice , Peptides , T-Lymphocytes, Cytotoxic
9.
Protein & Cell ; (12): 121-129, 2018.
Article in English | WPRIM | ID: wpr-756967

ABSTRACT

Novel biologics that redirect cytotoxic T lymphocytes (CTLs) to kill tumor cells bearing a tumor associated antigen hold great promise in the clinic. However, the ability to safely and potently target CD3 on CTL toward tumor associated antigens (TAA) expressed on tumor cells remains a challenge of both technology and biology. Herein we describe the use of a Half DVD-Ig format that can redirect CTL to kill tumor cells. Notably, Half DVD-Ig molecules that are monovalent for each specificity demonstrated reduced non-specific CTL activation and conditional CTL activation upon binding to TAA compared to intact tetravalent DVD-Ig molecules that are bivalent for each specificity, while maintaining good drug like properties and appropriate PK properties.


Subject(s)
Animals , Antibodies, Bispecific , Allergy and Immunology , Antibodies, Monoclonal , Allergy and Immunology , Pharmacokinetics , CD3 Complex , Metabolism , Cell Line, Tumor , Cytotoxicity, Immunologic , ErbB Receptors , Metabolism , Female , Humans , Lymphocyte Activation , Allergy and Immunology , Mice, SCID , Neoplasms , Allergy and Immunology , Pathology , Rats, Sprague-Dawley , T-Lymphocytes, Cytotoxic , Allergy and Immunology
10.
Journal of Liver Cancer ; : 67-74, 2018.
Article in Korean | WPRIM | ID: wpr-765677

ABSTRACT

Hepatocellular carcinoma (HCC) has extremely poor prognosis. Immunotherapy has emerged as a new treatment for a number of cancers. Adoptive immunotherapy is one of the important cancer immunotherapy, which relies on the various lymphocytes including cytotoxic T lymphocytes, natural killer (NK) and cytokine induced killer cells. Also, there has been advance in techniques of NK cell activation to more effectively kill the cancer cells. Of note, recently the blocking antibodies targeting programmed cell death protein 1 (PD-1) have shown promising results in diverse cancers including HCC. We report our recent experience of a patient accompanying advanced HCC with extrahepatic metastases. Disease progression had occurred after sorafenib administration, while the patient showed local tumor control and tumor marker decrease by NK cell immunotherapy combined with PD-1 inhibitor therapy. Though, there was no definite survival advantage due to impaired liver function, which might be caused by treatment related toxicities as well as cancer progression.


Subject(s)
Antibodies, Blocking , Carcinoma, Hepatocellular , Cell Death , Cytokine-Induced Killer Cells , Disease Progression , Humans , Immunotherapy , Immunotherapy, Adoptive , Killer Cells, Natural , Liver , Lymphocytes , Neoplasm Metastasis , Prognosis , Programmed Cell Death 1 Receptor , T-Lymphocytes, Cytotoxic
11.
Mem. Inst. Oswaldo Cruz ; 112(11): 733-740, Nov. 2017. tab, graf
Article in English | LILACS | ID: biblio-894850

ABSTRACT

Cutaneous leishmaniasis (CL) is a chronic disease caused by species of the protozoan Leishmania and characterised by the presence of ulcerated skin lesions. Both parasite and host factors affect the clinical presentation of the disease. The development of skin ulcers in CL is associated with an inflammatory response mediated by cells that control parasite growth but also contribute to pathogenesis. CD8+ T cells contribute to deleterious inflammatory responses in patients with CL through cytotoxic mechanisms. In addition, natural killer cells also limit Leishmania infections by production of interferon-γ and cytotoxicity. In this review, we focus on studies of cytotoxicity in CL and its contribution to the pathogenesis of this disease.


Subject(s)
Humans , Animals , Killer Cells, Natural/drug effects , Killer Cells, Natural/parasitology , T-Lymphocytes, Cytotoxic/immunology , Leishmaniasis, Cutaneous/immunology , Leishmaniasis, Cutaneous/pathology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/parasitology , Cytotoxicity, Immunologic/immunology , Disease Models, Animal
12.
Int. braz. j. urol ; 43(4): 615-627, July-Aug. 2017. tab, graf
Article in English | LILACS | ID: biblio-892856

ABSTRACT

ABSTRACT Background In order to induce a potent cytotoxic T lymphocyte (CTL) response in dendritic cell (DC)-based immunotherapy for bladder cancer, various tumor antigens can be loaded onto DCs. Objective The aim of this study was to establish a method of immunotherapy for male patients with non-muscle invasive bladder cancer (NMIBC), using bladder cancer-specific CTLs generated in vitro by DCs. Materials and Methods Monocyte-derived DCs from bladder cancer patients were induced to mature in a standard cytokine cocktail (IL-1β, TNF-α, IL-6, and PGE2: standard DCs, sDCs) or anα-type 1-polarized DC (αDC1) cocktail (IL-1β, TNF-α, IFN-α, IFN-γ, and polyinosinic:polycytidylic acid) and loaded with the UVB-irradiated bladder cancer cell line, T24. Antigen-loaded αDC1s were evaluated by morphological and functional assays, and the bladder cancer-specific CTL response was analyzed by cytotoxic assay. Results The αDC1s significantly increased the expression of several molecules pertaining to DC maturation, regardless of whether or not the αDC1s were loaded with tumor antigens, relative to sDCs. The αDC1s demonstrated increased production of interleukin-12 both during maturation and after subsequent stimulation with CD40L that was not significantly affected by loading with tumor antigens as compared to that of sDCs. Bladder cancer-specific CTLs targeting autologous bladder cancer cells were successfully induced by αDC1s loaded with dying T24 cells. Conclusion Autologous αDC1s loaded with an allogeneic bladder cancer cell line resulted in increased bladder cancer-specific CTL responses as compared to that with sDCs, and therefore, may provide a novel source of DC-based vaccines that canbe used in immunotherapy for male patients with NMIBC.


Subject(s)
Humans , Male , Aged , Urinary Bladder Neoplasms/therapy , Dendritic Cells/immunology , T-Lymphocytes, Cytotoxic/immunology , Cytokines/therapeutic use , Immunotherapy/methods , Urinary Bladder Neoplasms/immunology , Cell Differentiation/immunology , Treatment Outcome , Cell Line, Tumor , Immunotherapy/adverse effects , Middle Aged
13.
Article in English | WPRIM | ID: wpr-208836

ABSTRACT

Over the past five years immune-checkpoint inhibitors have dramatically changed the therapeutic landscape of advanced solid and hematologic malignancies. The currently approved immune-checkpoint inhibitors include antibodies to cytotoxic T-lymphocyte antigen-4, programmed cell death (PD-1), and programmed cell death ligand (PD-L1 and PD-L2). Response to immune-checkpoint inhibitors is evaluated on imaging using the immune-related response criteria. Activation of immune system results in a unique toxicity profile termed immune-related adverse events. This article will review the molecular mechanism, clinical applications, imaging of immune-related response patterns and adverse events associated with immune-checkpoint inhibitors.


Subject(s)
Antibodies , Cell Death , Hematologic Neoplasms , Immune System , Precision Medicine , T-Lymphocytes, Cytotoxic
14.
Yonsei Medical Journal ; : 43-50, 2017.
Article in English | WPRIM | ID: wpr-65064

ABSTRACT

PURPOSE: To identify new immunogenic HLA-A*33;03-restricted epitopes from the human papillomavirus (HPV) 16 E7 protein for immunotherapy against cervical cancer. MATERIALS AND METHODS: We synthesized fourteen overlapping 15-amino acid peptides and measured intracellular interferon-γ (IFN-γ) production in PBMC and CD8+ cytotoxic T lymphocytes (CTLs) after sensitization with these peptides using flow cytometry and ELISpot assay. The immunogenicity of epitopes was verified using a ⁵¹Cr release assay with SNU1299 cells. RESULTS: Among the fourteen 15-amino acid peptides, E7₄₉₋₆₃ (RAHYNIVTFCCKCDS) demonstrated the highest IFN-γ production from peripheral blood mononuclear cells (PBMCs), and CD8+ CTLs sensitized with E7₄₉₋₆₃ showed higher cytotoxic effect against SNU1299 cells than did CD8+ CTLs sensitized with other peptides or a negative control group. Thirteen 9- or 10-amino acid overlapping peptides spanning E7₄₉₋₆₃, E7₅₀₋₅₉ (AHYNIVTFCC), and E7₅₂₋₆₁ (YNIVTFCCKC) induced significantly higher IFN-γ production and cytotoxic effects against SNU1299 cells than the other peptides and negative controls, and the cytotoxicity of E7₅₀₋₅₉- and E7₅₂₋₆₁-sensitized PBMCs was induced via the cytolytic effect of CD8+ CTLs. CONCLUSION: We identified E7₅₀₋₅₉ and E7₅₂₋₆₁ as novel HPV 16 E7 epitopes for HLA-A*33;03. CD8+ CTL sensitized with these peptides result in an antitumor effect against cervical cancer cells. These epitopes could be useful for immune monitoring and immunotherapy for cervical cancer and HPV 16-related diseases including anal cancer and oropharyngeal cancer.


Subject(s)
Amino Acid Sequence , CD8-Positive T-Lymphocytes/immunology , Epitopes/immunology , Female , HLA-A Antigens , Human papillomavirus 16/immunology , Humans , Immunotherapy , Interferon-gamma/analysis , Leukocytes, Mononuclear/immunology , T-Lymphocytes, Cytotoxic/immunology , Uterine Cervical Neoplasms/therapy
15.
Article in English | WPRIM | ID: wpr-174856

ABSTRACT

German cockroaches are major household allergens that can trigger allergic airway inflammatory diseases with sensitive T-cell responses. Although the use of immune modulatory biologics, such as antibodies, to mediate allergic responses has recently been examined, only systemic administration is available because of the size limitations on intranasal administration. Here we utilized a cell-permeable peptide, dNP2, to deliver the cytoplasmic domain of cytotoxic T-lymphocyte antigen-4 (ctCTLA-4) through the airway epithelium to modulate Th2 responses in a German cockroach extract (GCE)-induced allergic airway inflammation model. The intranasal delivery efficiency of the dNP2-dTomato protein to the lungs was higher in GCE-induced asthmatic lung parenchymal cells compared to the sham cells. Intranasal administration of the dNP2-ctCTLA-4 protein inhibited airway hyper-responsiveness and reduced airway inflammation and remodeling, including goblet cell metaplasia and collagen deposition around the bronchi. The number of infiltrated cells, including eosinophils, and the levels of IL-4, IL-5, IL-13 and IFN-γ in the lungs were significantly reduced, presumably owing to inhibition of Th2 differentiation. However, intranasal administration of CTLA4-Ig did not inhibit airway inflammation. These results collectively suggest that dNP2-ctCTLA-4 is an efficient intranasally applicable candidate biologic for treating allergic asthma.


Subject(s)
Abatacept , Administration, Intranasal , Allergens , Antibodies , Asthma , Biological Products , Blattellidae , Bronchi , Collagen , Cytoplasm , Eosinophils , Epithelium , Family Characteristics , Goblet Cells , Inflammation , Interleukin-13 , Interleukin-4 , Interleukin-5 , Lung , Metaplasia , Respiratory Hypersensitivity , T-Lymphocytes , T-Lymphocytes, Cytotoxic
16.
Article in Chinese | WPRIM | ID: wpr-328267

ABSTRACT

<p><b>OBJECTIVE</b>To explore the effect of Telbivudine (LDT) Tablet combined with Jianpi Bushen Recipe (JBR) on serum hepatitis B virus (HBV) specific cytotoxic T lymphocyte (CTL) and HBeAg seroconversion in chronic hepatitis B (CHB) patients.</p><p><b>METHODS</b>Totally 90 HBeAg-positive and human leukocyte antigen (HLA)-A2 positive CHB patients were randomly assigned to the treatment group and the control group, 45 cases in each group. Patients in the treatment group took LDT Tablet (600 mg, once per day) combined with JBR granule (twice per day), while those in the control group took LDT Tablet alone. The therapeutic course for all was one year. HBV DNA negative conversion rate, HBeAg seroconversion rate, and level of HBV specific CTL were compared after 1 year treatment; liver function, drug resistance mutations, and adverse reactions were also compared between the two groups.</p><p><b>RESULTS</b>After 1 year treatment, HBV DNA negative conversion rate and HBeAg seroconversion rate were 88.89% (40/45) and 40.00% (18/45) in the treatment group, higher than those of the control group [68.89% (31/45) and 20.00% (9/45)], with statistical difference (P < 0.05). Level of HBV specific CTL in the treatment group was 0.78% +/- 0.09% after treatment, higher than that of the control group after 1 year treatment (0.54% +/- 0.11%) and that before treatment (0.36% +/- 0.07%), with statistical difference (P < 0.01). Level of HBV specific CTL in 27 patients with HBeAg seroconversion was 0.81% 0.10%, higher than that of 63 patients without HBeAg seroconversion (0.60% +/- 0.09%), with statistical difference (P < 0.01). ALT returned to normal in 44 cases of the treatment group (97.78%), while it was 42 cases (93.33%) of the control group, with no statistical difference between the two groups (P > 0.05). Total bilirubin (TBil) in the two groups all turned to normal. rtM204I variation occurred in 1 case (2.22%) of the treatment group and 2 cases (4.44%) in the control group. No obvious adverse reaction occurred in the two groups.</p><p><b>CONCLUSION</b>LDT Tablet combined with JBR could elevate levels of HBV specific CTL and HBeAg seroconversion in CHB patients.</p>


Subject(s)
Drug Therapy, Combination , Drugs, Chinese Herbal , Therapeutic Uses , Hepatitis B e Antigens , Blood , Hepatitis B virus , Hepatitis B, Chronic , Drug Therapy , Humans , Seroconversion , T-Lymphocytes, Cytotoxic , Allergy and Immunology , Tablets , Thymidine , Therapeutic Uses
17.
Article in Chinese | WPRIM | ID: wpr-360037

ABSTRACT

Human cytomegalovirus (HCMV) infection, a common complication, remains a major risk factor related with patient death after hematopoietic stem cell transplantation (HSCT). Cytotoxic T lymphocytes (CTL) which is crucial to control HCMV infection, can prevent or treat HCMV infection safely and effectively after adoptive infusion. Many studies have been focussed on exploring different methods for preparation of CTL. The method of using antigen presenting cells to stimulate peripheral blood mononuclear cells is simple to operate, easy to conduct large-scale clinical trials. Isolation of CTL from donor-derived PBMC by peptide-tetramer or INF-γ antibody requires a large volume of peripheral blood and high cost for preparation. Third-party CTL can provide an "off-the-shelf" product, but the problem of HLA-mismatch still would be solved. In addition, the clinical efficacy and safety of different methods also vary. This article reviews and compares the current methods to generate CTL and efficacy of the cells after infusions.


Subject(s)
Adoptive Transfer , Antigen-Presenting Cells , Cell Biology , Cytomegalovirus , Cytomegalovirus Infections , Therapeutics , Hematopoietic Stem Cell Transplantation , Humans , Leukocytes, Mononuclear , Cell Biology , T-Lymphocytes, Cytotoxic , Cell Biology
18.
Radiation Oncology Journal ; : 250-259, 2016.
Article in English | WPRIM | ID: wpr-33377

ABSTRACT

Immune checkpoint blockades including monoclonal antibodies (mAbs) of cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and programmed death-ligand 1 (PD-L1) have been emerged as a promising anticancer therapy. Several immune checkpoint blockades have been approved by US Food and Drug Administration (FDA), and have shown notable success in clinical trials for patients with advanced melanoma and non-small cell lung cancer. Radiotherapy is a promising combination partner of immune checkpoint blockades due to its potent pro-immune effect. This review will cover the current issue and the future perspectives for combined with radiotherapy and immune checkpoint blockades based upon the available preclinical and clinical data.


Subject(s)
Antibodies, Monoclonal , Carcinoma, Non-Small-Cell Lung , Humans , Melanoma , Programmed Cell Death 1 Receptor , Radiotherapy , T-Lymphocytes, Cytotoxic , United States Food and Drug Administration
19.
Yonsei Medical Journal ; : 652-657, 2016.
Article in English | WPRIM | ID: wpr-21849

ABSTRACT

PURPOSE: Acute hepatitis A (AHA) and acute hepatitis B (AHB) are caused by an acute infection of the hepatitis A virus and the hepatitis B virus, respectively. In both AHA and AHB, liver injury is known to be mediated by immune cells and cytokines. In this study, we measured serum levels of various cytokines and T-cell cytotoxic proteins in patients with AHA or AHB to identify liver injury-associated cytokines. MATERIALS AND METHODS: Forty-six patients with AHA, 16 patients with AHB, and 14 healthy adults were enrolled in the study. Serum levels of 17 cytokines and T-cell cytotoxic proteins were measured by enzyme-linked immunosorbent assays or cytometric bead arrays and analyzed for correlation with serum alanine aminotransferase (ALT) levels. RESULTS: Interleukin (IL)-18, IL-8, CXCL9, and CXCL10 were significantly elevated in both AHA and AHB. IL-6, IL-22, granzyme B, and soluble Fas ligand (sFasL) were elevated in AHA but not in AHB. In both AHA and AHB, the serum level of CXCL10 significantly correlated with the peak ALT level. Additionally, the serum level of granzyme B in AHA and the serum level of sFasL in AHB correlated with the peak ALT level. CONCLUSION: We identified cytokines and T-cell cytotoxic proteins associated with liver injury in AHA and AHB. These findings deepen the existing understanding of immunological mechanisms responsible for liver injury in acute viral hepatitis.


Subject(s)
Acute Disease , Adult , Alanine Transaminase/blood , Biomarkers/blood , Cytokines/blood , Enzyme-Linked Immunosorbent Assay , Fas Ligand Protein/blood , Female , Hepatitis A/blood , Hepatitis A virus/genetics , Hepatitis B/blood , Hepatitis B virus/genetics , Humans , Interleukin-6/blood , Interleukin-8/blood , Interleukins/blood , Liver Failure/immunology , Male , Middle Aged , T-Lymphocytes, Cytotoxic/immunology
20.
Article in Chinese | WPRIM | ID: wpr-246853

ABSTRACT

<p><b>OBJECTIVE</b>To find and identify HLA-A*0201 restricted cytotoxic T lymphocyte (CTL) epitopes from epidermal growth factor pathway substrate number 8 (Eps8) for specific immunotherapy based on Eps8-derived epitopes in clinic.</p><p><b>METHODS</b>Online biological softwares involved C-proteasomal cleavage, MHC class I binding affinity and TAP transport efficiency were used for prediction of HLA-A*0201 restricted epitopes from Eps8. Then, T2-binding assays and peptide/MHC complex stability tests were used to further verify the predicted epitopes. Specific secretion of IFN-γ from human CTL was assayed using the IFN-γ ELISPOT kit, and cytolytic activity was measured by a 4-h lactate dehydrogenase (LDH) release assay. Finally, the functional effects in vivo were measured in HLA-A*0201/Kb transgenic (Tg) mice.</p><p><b>RESULTS</b>Four natural epitopes were designed through online biological softwares. Of the four epitopes selected, p360-368 was found to have the high binding affinity to HLA-A*0201, while p101-109 and p276-284 showed moderate affinities. DC50 of peptide/MHC complexes of the natural epitopes mentioned were all longer than 8 h. In functional assays with human PBMNC in vitro and in HLA-A*0201/Kb transgenic mice in vivo, CTLs primed by each epitope (p101-109, p276-284 and p360-368) secreted IFN-γ and were toxic to cancer cells from a variety of tissue types in an HLA-A*0201-restricted and Eps8-specific manner.</p><p><b>CONCLUSION</b>Natural epitopes (p101-109, p276-284 and p360-368) may be the HLA-A*0201 restricted epitope derived from Eps8.</p>


Subject(s)
Adaptor Proteins, Signal Transducing , Allergy and Immunology , Animals , Epitopes, T-Lymphocyte , Metabolism , HLA-A2 Antigen , Metabolism , Humans , Mice , Mice, Transgenic , T-Lymphocytes, Cytotoxic
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