Predictors of the Therapeutic Response to Intralesional Bivalent HPV Vaccine in Wart Immunotherapy

Variable intralesional immunotherapies have recently been proposed as a means of achieving a successful eradication of recurrent and recalcitrant human papillomavirus (HPV)-induced cutaneous and anogenital warts. The bivalent HPV vaccine is one of the newly proposed immunotherapeutic agents. We investigated the role of interleukin-4 (IL-4) and interferon-gamma (IFN-γ) as ex vivo immunologic predictors to estimate the response to the bivalent HPV vaccine as a potential immunotherapy for cutaneous and anogenital warts. Heparinized blood samples were withdrawn from forty patients with multiple recurrent recalcitrant cutaneous and anogenital warts and forty matched healthy control subjects. Whole blood cultures were prepared with and without bivalent HPV vaccine stimulation. Culture supernatants were harvested and stored for IL-4 and IFN-γ measurements using an enzyme-linked immunosorbent assay. A comparative analysis of IL-4 and IFN-γ levels in culture supernatants revealed a non-significant change between the patient and control groups. The bivalent HPV vaccine stimulated cultures exhibited a non-significant reduction in IL-4 levels within both groups. IFN-γ was markedly induced in both groups in response to bivalent HPV vaccine stimulation. The bivalent HPV vaccine can give a sensitive IFN-γ immune response ex vivo, superior to IL-4 and sufficient to predict both the successful eradication of HPV infection and the ultimate clearance of cutaneous and anogenital warts when the bivalent HPV vaccine immunotherapy is applied.

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NSP4 as Adjuvant for Immunogenicity and Design of Effective Therapeutic HPV16 E6/E7/L1 DNA Vaccine in Tumoric and Healthy C57BL/6 Mice

10.21203/rs.3.rs-1176705/v1 ◽

2021 ◽

Author(s):

Sahar Sadr-Momtaz ◽

Maryam Aftabi ◽

Emad Behboudi ◽

Malihe Naderi ◽

Anahita Hashemzadeh-Omran ◽

...

Keyword(s):

Immune Responses ◽

Dna Vaccine ◽

Therapeutic Vaccine ◽

Hpv Infection ◽

Interleukin 4 ◽

Spleen Cells ◽

Hpv16 E6 ◽

Hpv Dna ◽

Healthy Control ◽

Ifn Γ

Abstract Introduction: In humans, approximately 5% of all cancers are attributable to HPV infection. Prophylactic vaccines can inhibit viral migration and persistence. However, requirement to develop therapeutic treatments prevails. To achieve this goal, we designed a therapeutic HPV DNA vaccine encoding a construct of E6/E7/L1 and used NSP4 antigen as adjuvant to assess efficiency of this construct in generating antigen-specific antitumor immune responses.Material and Methods: Sixty female C57BL/6 mice (6–8 weeks old) were purchased from Institute Pasteur of Iran. 30 of them became cancerous, but 30 of them were healthy control. To amplify E6/E7/L1-pcDNA3, NSP4-pcDNA3, expression vector of DH5α and TC-1 cell line were used to generate a tumor. Mice were immunized with HPV DNA vaccine. Cell proliferation was assessed by MTT assay. Finally, we assessed cytokine responses (IL-2, IL-4, INF- γ), in the serum of mice spleen cells.Result: Mice receiving the NSP4/E6-E7-L1 vaccine had the highest stimulatory index compared to other groups but it was not significant. Interleukin 4/12 and INF-γ production were significantly higher in E6-E7-L1 / NSP4 group and E6-E7-L1 group compared to other groups (P <0.05). Among different groups, E6/E7/L1 + NSP4 group was able to slow down the tumor growth process, but it was not significant (p>0.05). Among the cytokines mentioned, IFN-γ and IL-12 are among the cytokines that stimulate the Th1 pathway and IL-4 cytokine stimulates the Th2 pathway and B lymphocytes.Conclusion: Our data suggest that present vaccine can stimulate innate and acquired immunity response, and can be a therapeutic vaccine in the tumoric mice.

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Dichotomy of Cytokine Profiles in Patients and High-Risk Healthy Subjects Exposed to Tuberculosis

Infection and Immunity ◽

10.1128/iai.67.11.5597-5603.1999 ◽

1999 ◽

Vol 67 (11) ◽

pp. 5597-5603 ◽

Cited By ~ 46

Author(s):

S. Bhattacharyya ◽

R. Singla ◽

A. B. Dey ◽

H. K. Prasad

Keyword(s):

T Cells ◽

High Risk ◽

Healthy Subjects ◽

Ex Vivo ◽

Close Contact ◽

Interleukin 4 ◽

Enzyme Linked Immunosorbent Assay ◽

Mycobacterial Antigen ◽

Ifn Γ

ABSTRACT To better understand the role of cytokines in susceptible and resistant subjects exposed to Mycobacterium tuberculosisinfection, intracellular gamma interferon (IFN-γ) and interleukin-4 (IL-4) in ex vivo peripheral blood-derived CD4+ T cells were examined by flow cytometry. Of the 37 individuals examined, 20 had clinical evidence of pulmonary tuberculosis and showed acid-fast bacilli in the sputum. Other individuals in close contact with these patients showed no evidence of disease. Patients had a higher number of CD4+ T cells expressing IFN-γ and IL-4 in unstimulated cultures compared to healthy subjects. Despite this, the ratio of IFN-γ+ to IL-4+ CD4+ T cells was similar in both groups. The Th1 response seen in CD4+ T cells in patients was also observed in the overall pattern of IFN-γ and IL-4 detected in control culture supernatants by enzyme-linked immunosorbent assay (ELISA). However, after in vitro stimulation of PBMC with heat-killed M. tuberculosis there was a significant reduction in the percentage of IFN-γ+CD4+ T cells (P < 0.001) in patients. This trend was reflected in the IFN-γ ELISA assay with supernatants derived from stimulated cultures. However, the accumulated levels of IFN-γ were higher than those for IL-4. The reduction of IFN-γ+ CD4+ T cells resulted in the dominance of IL-4+ CD4+ T cells in 13 patients (P < 0.05). The elevated levels of IL-4+CD4+ T cells seen in patients may contribute to the downregulation of IFN-γ expression and the crucial effector function of CD4 T cells, leading to the persistence of disease and the immunopathology characteristically seen in patients. Preliminary data on the indicators of apoptosis in antigen-stimulated cultures in PBMC derived from patients are presented. Of the 17 high-risk healthy individuals examined, 11 differed in that, after mycobacterial-antigen stimulation, there was an enhancement in IFN-γ+CD4+ T cells.

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A narrative review on HPV vaccination among boys and men

Global Journal of Medical Research ◽

10.34257/gjmrfvol20is4pg9 ◽

2020 ◽

pp. 9-12

Author(s):

Vinod K Ramani ◽

Radheshyam Naik

Keyword(s):

Hpv Vaccine ◽

Hpv Vaccination ◽

Herd Immunity ◽

Population Level ◽

Hpv Infection ◽

Level Control ◽

Anogenital Warts ◽

Indian Context ◽

Present Generation ◽

The Cost

Apart from cervical cancer, Human papillomavirus (HPV) infection is associated with head and neck as well as other anogenital cancers such as vulva, vagina, anus, and penis. HPV vaccine provides specific protection against the disease and its subsequent manifestations.Vaccination programs for men tend to improve population-level control of HPV infection and directly prevent HPV related disease such as anogenital warts and oropharyngeal cancers in males. HPV vaccine does not treat existing infection or lesions/cancer and is intended for individuals before initiation fo sexual activity or any other form of exposure to HPV.Many programs across the globe do not include vaccination for boys because of the cost and little recognition of the emerging epidemic of HPV associated cancers in men. In the Indian context, as screening is not feasible for non-cervical HPV associated cancers, its incidence mostly among men will continue to rise until the present generation of vaccinated adolescents reaches their middle-age.Vaccination will reduce transmission rates and increase herd immunity. This in-turn, will prevent not just cervical cancers but also other HPV-associated malignancies among men and women.

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An Ex Vivo Study of T Lymphocytes Recovered from the Lungs of I/St Mice Infected with and Susceptible toMycobacterium tuberculosis

Infection and Immunity ◽

10.1128/iai.66.10.4981-4988.1998 ◽

1998 ◽

Vol 66 (10) ◽

pp. 4981-4988 ◽

Cited By ~ 33

Author(s):

Irina Lyadova ◽

Vladimir Yeremeev ◽

Konstantin Majorov ◽

Boris Nikonenko ◽

Sergei Khaidukov ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Ex Vivo ◽

Antimycobacterial Activity ◽

Enzymatic Digestion ◽

Interleukin 4 ◽

T Cell Clones ◽

Cell Clones ◽

Ifn Γ

ABSTRACT I/St mice, previously characterized as susceptible toMycobacterium tuberculosis H37Rv, were given 103 or 105 CFU intravenously. At two time points postinoculation, the cell suspensions that resulted from enzymatic digestion of lungs were enumerated and further characterized phenotypically and functionally. Regarding the T-cell populations recovered at 2 and 5 weeks postinfection, two main results were obtained: (i) the population of CD44− CD45RB+cells disappeared within 2 weeks postinfection, while the number of CD44+ CD45RB−/low cells slowly increased between weeks 2 and 5; (ii) when cocultured with irradiated syngeneic splenocytes, these lung T cells proliferated in the presence of H37Rv sonicate. Using H37Rv sonicate and irradiated syngeneic splenocytes to reactivate lung T cells, we selected five CD3+CD4+ CD8− T-cell clones. In addition to the H37Rv sonicate, the five clones react to both a short-term culture filtrate and an affinity-purified 15- to 18-kDa mycobacterial molecule as assessed by the proliferative assay. However, there was a clear difference between T-cell clones with respect to cytokine (gamma interferon [IFN-γ] and interleukin-4 [IL-4] and IL-10) profiles: besides one Th1-like (IFN-γ+ IL-4−) clone and one Th0-like (IFN-γ+ IL-4+IL-10+) clone, three clones produced predominantly IL-10, with only marginal or no IL-4 and IFN-γ responses. Inhibition of mycobacterial growth by macrophages in the presence of T cells was studied in a coculture in vitro system. It was found that the capacity to enhance antimycobacterial activity of macrophages fully correlated with INF-γ production by individual T-cell clones following genetically restricted recognition of infected macrophages. The possible functional significance of cytokine diversity among T-cell clones is discussed.

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Effect of Ninjin-Youei-To on Th1/Th2 Type Cytokine Production in Different Mouse Strains

The American Journal of Chinese Medicine ◽

10.1142/s0192415x0200034x ◽

2002 ◽

Vol 30 (02n03) ◽

pp. 215-223 ◽

Cited By ~ 11

Author(s):

Tsutomu Nakada ◽

Kenji Watanabe ◽

Guang-Bi Jin ◽

Kazuo Toriizuka ◽

Toshihiko Hanawa

Keyword(s):

Oral Administration ◽

Cytokine Production ◽

Interferon Γ ◽

Interleukin 4 ◽

Mouse Strains ◽

Enzyme Linked Immunosorbent Assay ◽

Herbal Formula ◽

Beneficial Effects ◽

Ifn Γ ◽

Th1 And Th2

Ninjin-Youei-To (NYT; Ren-Shen-Yang-Rong-Tang in Chinese) is a traditional herbal formula, which is widely used in Japan, Korea and China to modulate physiological immunity. The effects of oral administration of NYT on cytokine production from splenocytes were investigated in both C57BL/6 and BALB/c mice in which Th1 and Th2 were dominant, respectively. Splenocytes from C57BL/6 and BALB/c mice, which took NYT orally for four weeks, were cultured with anti-mouse CD3 mAb, and the supernatant was examined for cytokine production using enzyme-linked immunosorbent assay (ELISA). Administration of NYT to C57BL/6 mice, increased the production of interleukin-4 (IL-4) significantly, and slightly decreased interferon-γ (IFN-γ) production from splenocytes. In contrast, the same treatment significantly increased IFN-γ secretion from splenocytes of BALB/c mice. No remarkable changes of IL-12 production from splenocytes were observed in either strain of mice. These results suggest that oral administration of NYT ameliorates the excessive inclination of Th1 and Th2 type cytokine production, and NYT may provide a beneficial effects for the treatment of diseases caused by a skewed Th1-Th2 balance in the immune system.

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Changes in interleukin-27 levels in patients with acute coronary syndrome and their clinical significance

PeerJ ◽

10.7717/peerj.5652 ◽

2019 ◽

Vol 7 ◽

pp. e5652 ◽

Cited By ~ 1

Author(s):

Lin Zhang ◽

Junfeng Zhang ◽

Shaohong Su ◽

Suyan Luo

Keyword(s):

Acute Coronary Syndrome ◽

Angina Pectoris ◽

Th17 Cells ◽

Serum Levels ◽

Enzyme Linked Immunosorbent Assay ◽

Control Groups ◽

Coronary Syndrome ◽

Significant Difference ◽

Ifn Γ ◽

And Control

Background This study evaluated changes in interleukin (IL)-27 levels in patients with acute coronary syndrome (ACS) and their influence on Th1, Th2, and Th17 cells. Methods Serum levels of IL-27, IL-4, IL-17, and interferon (IFN)-γ in healthy subjects as well as patients with ACS, including stable angina pectoris (SA), unstable angina pectoris (UA), and acute myocardial infarction (AMI), were determined using an enzyme-linked immunosorbent assay. The proportions of Th1, Th2, and Th17 cells among peripheral blood mononuclear cells (PBMCs), were measured using flow cytometry, after incubation with phorbol myristate acetate (PMA) for 4 h. The proportions of Th1 and Th17 cells among PBMCs in AMI and UA were detected after stimulation with IL-27 or PMA + IL-27 for 4, 8, and 12 h. Results Serum levels of IL-27 in patients with AMI and UA were significantly lower than those in SA and control groups, while serum levels of IL-17 and IFN-γ in AMI and UA groups were dramatically increased compared to those in SA and healthy control groups. However, there were no statistically significant differences in serum IL-4. The proportions of Th1 and Th17 cells among PBMCs were statistically significantly higher in the AMI and UA groups than those in the SA and control groups, while there was no statistically significant difference in the proportion of Th2 cells among different groups. For patients with AMI and UA, the effect of co-stimulation of PBMCs with PMA and IL-27 was not significantly different from that of PMA single stimulation, while PMA + IL-27 co-stimulation lowered the Th17 cell proportion significantly compared to PMA single stimulation. Discussion Compared to SA patients and healthy controls, patients with ACS (AMI + UA) had lower serum levels of IL-27 and higher proportions of PBMC Th1 and Th17 cells, which could be attributed to the inhibitory effects of IL-27 on the proliferation of Th17 cells. These results indicated that IL-27 could be a novel therapeutic target in ACS patients.

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Flow Cytometric Determination of Cellular Sources and Frequencies of Key Cytokine-Producing Lymphocytes Directed against Recombinant LACK and Soluble Leishmania Antigen in Human Cutaneous Leishmaniasis

Infection and Immunity ◽

10.1128/iai.69.5.3232-3239.2001 ◽

2001 ◽

Vol 69 (5) ◽

pp. 3232-3239 ◽

Cited By ~ 88

Author(s):

R. L. A. Bottrel ◽

W. O. Dutra ◽

F. A. Martins ◽

B. Gontijo ◽

E. Carvalho ◽

...

Keyword(s):

T Lymphocytes ◽

Cutaneous Leishmaniasis ◽

Ex Vivo ◽

Protozoan Parasite ◽

Recombinant Antigen ◽

Interleukin 4 ◽

Leishmania Braziliensis ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Ifn Γ

ABSTRACT Leishmaniasis, caused by infection with the protozoan parasiteLeishmania, affects millions of individuals worldwide, causing serious morbidity and mortality. This study directly determined the frequency of cells producing key immunoregulatory cytokines in response to the recombinant antigen Leishmania homolog of receptors for activated kinase C (LACK) and soluble leishmania antigen (SLA), and it determined relative contributions of these antigens to the overall cytokine profile in individuals infected for the first time with Leishmania braziliensis. All individuals presented with the cutaneous clinical form of leishmaniasis and were analyzed for proliferative responses to LACK antigen and SLA, frequency of lymphocyte subpopulations (analyzed ex vivo), and antigen-induced (LACK and SLA) cytokine production at the single-cell level (determined by flow cytometry). The following were determined. (i) The Th1-type response previously seen in patients with cutaneous leishmaniasis is due to gamma interferon (IFN-γ) production by several different sources, listed in order of contribution: CD4+ T lymphocytes, CD4−, CD8− lymphocytes, and CD8+ T lymphocytes. (ii) SLA induced a higher frequency of lymphocytes producing IFN-γ and tumor necrosis factor alpha (TNF-α) than did LACK. (iii) LACK induced an activation of monocyte populations as reflected by an increased percentage of CD14-positive cells. (iv) Neither SLA nor LACK induced detectable frequencies of cells producing interleukin-4 (IL-4) or IL-5. These data demonstrated a multifaceted immune response to SLA in human leishmaniasis involving Th1 CD4+ T lymphocytes (IFN-γ+ and IL-10−/IL-4−), Tc1 CD8+ T cells (IFN-γ+, and IL-10−/IL-4−), and a high frequency of TNF-α-producing lymphocytes. Moreover, it was determined that the recombinant antigen LACK acts as a weak inducer of Th1-type lymphocyte responses compared to SLA.

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Serum Interleukin-6 Level in Children With Attention-Deficit Hyperactivity Disorder (ADHD)

Journal of Child Neurology ◽

10.1177/0883073818809831 ◽

2018 ◽

Vol 34 (2) ◽

pp. 61-67 ◽

Cited By ~ 11

Author(s):

Amira Hamed Darwish ◽

Tarek Mohamed Elgohary ◽

Nahla A. Nosair

Keyword(s):

Attention Deficit Hyperactivity Disorder ◽

Attention Deficit ◽

Interleukin 6 ◽

Rating Scale ◽

Enzyme Linked Immunosorbent Assay ◽

Parent Rating ◽

Hyperactivity Disorder ◽

Diagnostic And Statistical Manual ◽

Healthy Control ◽

And Control

Introduction: Attention-deficit hyperactivity disorder (ADHD) is a common neurobehavioral disorder in children, but its specific etiology and pathophysiology are still incompletely understood. Objectives: This case-control study aimed to measure the level of serum interleukin-6 (IL-6) as a predictor of the immunologic status in children with ADHD, and to study its correlation with severity of symptoms. Subjects and Methods: 60 ADHD children who met the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, criteria for ADHD and 60 control children were subjected to complete history taking, clinical examination, and psychometric tests. Serum interleukin-6 of ADHD patients and control children was measured by enzyme-linked immunosorbent assay. Results: The mean serum level of IL-6 was 22.35 (95% confidence interval [CI], 17.68-26.99) in ADHD patients, and it was 5.44 (95% CI, 4.81-6.06) in controls. A significantly higher level of IL-6 was reported in ADHD patients compared with controls ( P = .001). No significant correlation was found between serum IL-6 level and either the Intelligence Quotient (IQ) or the Conners’ Parent Rating Scale score. Conclusion: Serum IL-6 values were significantly higher in ADHD patients compared to healthy control children. Increased production of IL-6 may play a role in the pathogenesis of ADHD.

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Listeria monocytogenes as a Short-Lived Delivery System for the Induction of Type 1 Cell-Mediated Immunity against the p36/LACK Antigen of Leishmania major

Infection and Immunity ◽

10.1128/iai.68.3.1498-1506.2000 ◽

2000 ◽

Vol 68 (3) ◽

pp. 1498-1506 ◽

Cited By ~ 35

Author(s):

Neirouz Soussi ◽

Geneviève Milon ◽

Jean-Hervé Colle ◽

Evelyne Mougneau ◽

Nicolas Glaichenhaus ◽

...

Keyword(s):

T Cells ◽

Listeria Monocytogenes ◽

Cd4 T Cells ◽

Leishmania Major ◽

Ex Vivo ◽

Experimental Models ◽

Interleukin 4 ◽

Cell Mediated Immunity ◽

Th1 Cells ◽

Ifn Γ

ABSTRACT Listeria monocytogenes has been used as an experimental live vector for the induction of CD8-mediated immune responses in various viral and tumoral experimental models. Susceptibility of BALB/c mice to Leishmania major infection has been correlated to the preferential development of Th2 CD4 T cells through an early production of interleukin 4 (IL-4) by a restricted population of CD4 T cells which react to a single parasite antigen, LACK (stands forLeishmania homologue of receptors for activated C kinase). Experimental vaccination with LACK can redirect the differentiation of CD4+ T cells towards the Th1 pathway if LACK is coadministrated with IL-12. As IL-12 is known to be induced by L. monocytogenes, we have tested the ability of a recombinant attenuated actA mutant L. monocytogenes strain expressing LACK to induce the development of LACK-specific Th1 cells in both B10.D2 and BALB/c mice, which are resistant and susceptible toL. major, respectively. After a single injection of LACK-expressing L. monocytogenes, IL-12/p40 transcripts showed a rapid burst, and peaks of gamma interferon (IFN-γ)-secreting LACK-specific Th1 cells were detected around day 5 in the spleens and livers of mice of both strains. These primed IFN-γ-secreting LACK-reactive T cells were not detected ex vivo after day 7 of immunization but could be recruited and detected 15 days later in the draining lymph node after an L. major footpad challenge. Although immunization of BALB/c mice with LACK-expressing L. monocytogenes did not change the course of the infection withL. major, immunized B10.D2 mice exhibited significantly smaller lesions than nonimmunized controls. Thus, our results demonstrate that, in addition of its recognized use for the induction of effector CD8 T cells, L. monocytogenes can also be used as a live recombinant vector to favor the development of potentially protective IFN-γ-secreting Th1 CD4 T lymphocytes.

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The effects of BAFF and BAFF-R-Fc fusion protein in immune thrombocytopenia

Blood ◽

10.1182/blood-2009-05-217513 ◽

2009 ◽

Vol 114 (26) ◽

pp. 5362-5367 ◽

Cited By ~ 57

Author(s):

Xiao-juan Zhu ◽

Yan Shi ◽

Jun Peng ◽

Cheng-shan Guo ◽

Ning-ning Shan ◽

...

Keyword(s):

Fusion Protein ◽

Immune Thrombocytopenia ◽

Interleukin 4 ◽

In Vitro Assays ◽

Enzyme Linked Immunosorbent Assay ◽

Cd8 Cells ◽

Promising Therapeutic Approach ◽

Fc Fusion Protein ◽

Ifn Γ

Abstract Elevated level of B-cell activating factor (BAFF) has been implicated in the pathogenesis of some autoimmune diseases. Blockade of receptor and ligand binding by decoy receptor has demonstrated a clinical benefit in both oncologic and immunologic diseases. In this report, we have detected plasma BAFF and BAFF mRNA expression in immune thrombocytopenia (ITP) patients by enzyme-linked immunosorbent assay (ELISA) and real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR). The effects of recombinant human BAFF (rhBAFF) and BAFF-R-Fc fusion protein (BR3-Fc) on B cells, T cells, platelets, secretion of interferon γ (IFNγ), and interleukin-4 (IL-4) were measured by flow cytometry and ELISA. Patients with active disease had higher levels of plasma BAFF and BAFF mRNA than patients in remission and controls. In in vitro assays, rhBAFF promoted the survival of CD19+ and CD8+ cells, and increased the apoptosis of platelets and the secretion of IFN-γ. BR3-Fc successfully corrected the effects of rhBAFF on lymphocytes, platelets, and cytokines. These findings suggest that BAFF may play a pathogenic role in ITP by promoting the survival of CD19+ and CD8+ cells, and increasing the apoptosis of platelets and the secretion of IFN-γ. Blockade of BAFF by BR3-Fc might be a promising therapeutic approach for ITP.

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