Masoumeh Varedi
Volume 2, Issue 2 , June 2005, , Pages 67-77
Abstract
Interferons (IFNs) are a family of small regulatory glycoproteins that play a central role in the defense against viral infections. Although IFNs have been initially discovered as antiviral factors, today they are known as an integral part of the cytokine network that affect a wide range of biological ...
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Interferons (IFNs) are a family of small regulatory glycoproteins that play a central role in the defense against viral infections. Although IFNs have been initially discovered as antiviral factors, today they are known as an integral part of the cytokine network that affect a wide range of biological processes. IFNs exert their pleiotropic effects through their multisubunit cell surface receptors in a species specific manner that is believed to be controlled at the receptor and the post-receptor levels. Although IFN-mediated signaling and transcription activation of cellular gene expression is currently best understood in the context of the JAK-STAT signal transduction, additional IFNs signaling pathways may also act in certain conditions. The Janus family of tyrosine kinase (JAK) enzymes and two families of transcriptional regulators, signal transducer and activator of transcription (STATS) and IFN regulatory factors (IRFs), are the principal components of the JAK-STAT pathway. Overlapping subsets of JAKS are involved in signaling by type I (IFN- α/ß) and type II (IFN-γ IFNs, indicating that the receptor subunits confer specificity for activating particular JAK family members. A considerable cross talk can exist between separate signaling pathways. The emergence of new tools and approaches for study of IFNs signaling has been an exercise in coming to respect the level of complexity of IFNs system. For many years, IFNs have been satisfactorily used in many clinical trials. However, their serious side effects remain as the major concern in clinical use of IFNs. A better understanding of the exact mechanism involved in IFNs signaling pathways and the structure-function relationships of the IFNs system components will allow researchers to improve and expand the therapeutic potential of these naturally occurring molecules. IFNs actions are mediated through multiple signaling pathways. However, due to the space limitation, this review will focus primarily on the IFNs-mediated JAK-STAT pathway.
Magdy Mohamed Zedan; Amal Mohamed Osman; Wafaa Nabil Laimon; Mohamed Magdy Zedan; Nermin Youssef Abo-elkheir; Ahmed Zaki
Volume 13, Issue 2 , June 2016, , Pages 70-88
Abstract
Asthma is a heterogeneous disease, in which asthmatic patients present with different clinical phenotypes, variable endotypes, and different response to asthma medicines. Thus, we are faced with an asthma paradox; asthma is diagnosed subjectively by clinical history and treated with biologically active ...
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Asthma is a heterogeneous disease, in which asthmatic patients present with different clinical phenotypes, variable endotypes, and different response to asthma medicines. Thus, we are faced with an asthma paradox; asthma is diagnosed subjectively by clinical history and treated with biologically active drugs. To solve this paradox, we need objective airway biomarkers to tailor the proper medications to the proper patient. Biomarkers should have one or more of the following characteristics: 1) could differentiate poor symptoms perceivers from over-perceivers, 2) could predict disease activity and hence disease outcome, 3) could clarify asthma phenotype responders from non-responders, and finally 4) could characterize different clinical asthma phenotypes. Therefore, we have conducted a review of literature trying to apply those four parameters to different airway inflammatory biomarkers. We found that FeNO fulfilled the four proposed clinical parameters of airway inflammatory biomarkers whereas; serum periostin was the single best systemic biomarker of airway luminal and tissue eosinophilia in severe uncontrolled TH2 asthma phenotype. Thus, this may be considered a trial towards tailoring the proper medication to the proper patient. However, application of biomarkers in clinical practice requires easier and cheaper techniques together with standardized methods for sample collection and analysis.
Vijay Kumar; Bikash Medhi
Abstract
Normal pregnancy has been considered as a controlled state of inflammation at an early stage of blastocyst implantation that subsequently develops systemically. Till recent past most popular hypotheses regarding status of immune system in pregnancy were dominated by the Th1 and Th2 hypothesis, in which ...
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Normal pregnancy has been considered as a controlled state of inflammation at an early stage of blastocyst implantation that subsequently develops systemically. Till recent past most popular hypotheses regarding status of immune system in pregnancy were dominated by the Th1 and Th2 hypothesis, in which the fetus avoids maternal rejection through a bias towards T-helper (Th2) cytokine production. Recent findings have shown that predominant immune interactions in the human deciduas are between the placental trophoblast and maternal uterine natural killer (uNK) cells rather than the T cells. Thus NK cells are emerging as important players in the uterine immune response to invasive forms of placenta, as in cases of hemochorial placenta. In humans there is a lack of evidence for T-cell responses to trophoblast cells; therefore it was thought that uterine NK cells are the key factors by which the maternal immune system recognizes trophoblast cells. In this review we are trying to summarize the role of uNK cells in the maintenance of normal pregnancy in humans.
Soheila Rahgozar
Volume 9, Issue 2 , June 2012, , Pages 73-85
Abstract
Beta 2 glycoprotein I (β2GPI) is a single chain 50 kDa highly glycosylated glycoprotein at an approximate concentration of 4 μM in cells. The abundance of this protein in plasma and its high state of preservation indicate the important role of this protein in mammalian. In addition, β2GPI ...
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Beta 2 glycoprotein I (β2GPI) is a single chain 50 kDa highly glycosylated glycoprotein at an approximate concentration of 4 μM in cells. The abundance of this protein in plasma and its high state of preservation indicate the important role of this protein in mammalian. In addition, β2GPI has a particular structure in the fifth domain, and is categorized as the major antigen recognized by autoantibodies present in antiphospholipid syndrome. Beta 2 glycoprotein I has been usually studied in the context of antiphospholipid antibody production. Complexes of β2GPI/anti-β2GPI antibodies have been examined in different coagulation and cell activation pathways. However, the function of β2GPI, independent from the antibodies, has not been clearly determined. In this paper different features of β2GPI including its structure, plasma concentration and its proposed in vitro and in vivo functions in clot formation and fibrinolysis along with anti-β2GPI antibodies (Abs) are discussed. Their inhibitory or promotive effects are delineated in each facet.
Shamsi Noorpisheh Ghadimi; Shirin Farjadian; Gholam Reza Hatam; Mehdi Kalani; Bahador Sarkari
Abstract
Background: Toll like receptors play a major role in immune responses against Leishmania parasites. Objective: To evaluate the efficacy of vaccination with live attenuated L. major and TLR4 agonist in protection against L. major infection. Methods: Attenuated L. major was prepared by continuous sub-culturing ...
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Background: Toll like receptors play a major role in immune responses against Leishmania parasites. Objective: To evaluate the efficacy of vaccination with live attenuated L. major and TLR4 agonist in protection against L. major infection. Methods: Attenuated L. major was prepared by continuous sub-culturing of the parasite. A total of 90 mice were assigned to 9 groups including 6 groups of BALB/c (G1-6) and 3 groups (G7-9) of C57BL/6 mice. Group 1 was the control groups, group 2 received the wild-type L. major promastigotes, group 3 the attenuated line, group 4 the TLR4 agonist, group 5 the wild-type L. major and TLR4 agonist, and group 6 the attenuated line along with TLR4 agonist. Group 7 was control, group 8 received wild-type L. major and group 9 the wild-type along with TLR4 agonist. Vaccinated mice were then challenged with wild-type of L. major. Lesion size, parasite burden, and the expression levels of IL-4, IFN-γ, IL-2, 1L-17A, IL-10, TGF-β and TLR4 were evaluated before the challenge while parasite burden and lesion size were evaluated. Results: Vaccinated mice with a TLR4 agonist or attenuated L. major plus TLR4 agonist produced the highest levels of IFN-γ, IL-2, and IL-17A. Post-challenge analysis revealed that mice vaccinated with the attenuated line along with TLR4 agonist displayed the lowest lesion size and parasite load. These mice developed a predominant Th1 immune response. Conclusion: Vaccination with the attenuated L. major along with TLR4 agonist promotes a Th1-mediated immune response which leads to the protection of BALB/c mice against L. major infection.
Nasrollah Ghahramani
Volume 1, Issue 2 , September 2004, , Pages 78-96
Abstract
The subject of transplant immunosuppression has generated significant interest in recent years. Excellent immunosuppression, advances in surgical technique, post-transplantation care, and infection control have resulted in excellent outcomes. There is widespread support for the notion that the fundamental ...
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The subject of transplant immunosuppression has generated significant interest in recent years. Excellent immunosuppression, advances in surgical technique, post-transplantation care, and infection control have resulted in excellent outcomes. There is widespread support for the notion that the fundamental objective in transplant immunology should be the achievement of specific graft tolerance. However, until this objective evolves into reality, investigators are in search of the “ideal immunosuppressant”, which should target predominantly the immune system with minimal consequences for other tissues and minimal metabolic, cardiovascular and renal complications. While immunosuppressants have been associated with a tremendous trade-off in terms of morbidity, new agents have provided the investigators with the opportunity to formulate strategies that employ combination therapies with the goal of decreasing doses of individual agents and minimizing their toxicities. Multiple small studies have addressed the issue of minimizing immunosuppressants, but there is a need for well-designed clinical trials which should evaluate protocols that will reduce acute rejection, as well as chronic allograft nephropathy. They should address methods to identify subsets of patients who would maximally benefit from avoidance or withdrawal of steroids or calcineurin inhibitors. Other promising areas of research include tolerance studies among the sensitized recipients, and development of optimal immunosuppression based on genotype. In general, future trials must include a more diverse population of recipients, particularly the immunologically high risk groups.
Hadi Reihani; Maryam Rastin; Mahmoud Mahmoudi; Mohsen Ghoryani; Nafiseh Abdollahi; Nafiseh Sadat Tabasi; Shahrzad Zamani Taghizadeh Rabe; Maryam Sahebari
Volume 12, Issue 2 , June 2015, , Pages 82-93
Abstract
Background: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease. Emerging data suggests that T helper 17 (Th17) cells play a pathogenic role in SLE and the increased number of these cells correlates with disease activity. In recent years, 1α, 25-dihydroxyvitamin D3 (1,25VitD3) ...
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Background: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease. Emerging data suggests that T helper 17 (Th17) cells play a pathogenic role in SLE and the increased number of these cells correlates with disease activity. In recent years, 1α, 25-dihydroxyvitamin D3 (1,25VitD3) has been considered as an immunomodulatory factor. Objective: To investigate the effect of 1,25VitD3 on Th17 cells and on the expression of related cytokines in SLE patients. Method: Thirty SLE patients (newly diagnosed or in remission) were sampled for 10 ml whole blood to isolate peripheral blood mononuclear cells (PBMCs) using Ficoll-Hypaque density gradient centrifugation. Isolated cells were cultured in the presence and absence of 50 nM 1,25VitD3. After incubation, cells were harvested and stimulated for 4-5 hours with phorbol myristate acetate (PMA) and ionomycin in the presence of brefeldin A. IL-17 secreting cells were analyzed by flowcytometry. RNA was extracted from cultured cells, cDNA was synthesized, and the expression levels of IL-6, IL-17, IL-23 and TGF- β genes were assessed by real-time PCR. Results: The percentage of Th17 cells (CD3+ CD8- IL-17+ T cells) decreased significantly in 1,25VitD3-treated cells (3.67 ± 2.43%) compared to untreated cells (4.65 ± 2.75%) ( p=0.003). The expression of TGF- β up regulated (1.38-fold) and the expression of IL-6 (50%), IL-17 (27%) and IL-23 (64%) down regulated after 1,25VitD3 treatment. Conclusion: This study showed that 1,25VitD3 modulates Th17 related pathways in SLE patients and revealed the immunomodulatory effect of 1,25VitD3 on the Th17 mediated autoimmunity.
Gege Li; Jiahui Pan; Qiuling Tang; Xinchan Liu; Liuran Wang; Yang Meng; Weixian Yu
Abstract
Background: C5areceptor antagonistPMX205 is a synthetic hexapeptidecapable of blocking C5a-C5a receptor (C5aR) axis by simulating C5a active C-terminal amino acid residues. This hexapeptide presents good anti-inflammatory effects in a myriad inflammation models. The anti-inflammatory effect of PMX205 ...
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Background: C5areceptor antagonistPMX205 is a synthetic hexapeptidecapable of blocking C5a-C5a receptor (C5aR) axis by simulating C5a active C-terminal amino acid residues. This hexapeptide presents good anti-inflammatory effects in a myriad inflammation models. The anti-inflammatory effect of PMX205 on periodontitis is yet to be fully fathomed. Objective: To examine the anti-inflammatory effects of PMX205 on RAW264.7 murine macrophages exposed togingipain extracts and Porphyromonas gingivalis (P. gingivalis). Methods: MTT assay was carried out so as to specify the cytotoxicity of PMX205. RAW264.7 cells were co-cultured in vitro with gingipain extracts or P. gingivalis to simulate the periodontitis inflammatory milieu. Real-time quantitative PCR, ELISA and Griess assay were performed in order to detect tumor necrosis factor-α (TNF-α), IL-6, IL-23, nitric oxide (NO), IL-10, transforming growth factor-β1 (TGF-β1), andarginase-1 (Arg-1). Furthermore, phagocytosis assay was done to evaluate the phagocytic capacity of RAW 264.7 cells. Finally, western blot analysis was conducted to evaluate myeloid differentiation factor 88 (MyD88). Results: PMX205 increased the expression levels of bacteriostatic substances (NO and IL-23) and anti-inflammatory cytokines (TGF-β1, IL-10 and Arg-1); however, it reduced the expression levels of proinflammatory cytokines TNF-α and IL-6once RAW 264.7 macrophages were stimulated via gingipain extracts or P. gingivalis. In addition, PMX205 promoted the macrophage phagocytosis and down-regulated protein expression of MyD88. Conclusion: PMX205 has recognizable anti-inflammatory effects in RAW 264.7 cell inflammation model, a finding which probably opens doors to future investigations on new targets for the prevention and treatment of chronic periodontitis.
Junwei Chen; Meng Wu; Jinhua Yang; Jing Wang; Yue Qiao; Xiaofeng Li
Volume 14, Issue 2 , June 2017, , Pages 90-98
Asmaa M. Zahran; Asmaa S. Shaltout; Hussein Fakhry; Ola N. Abdel Fattah; Doaa F. Temerik; Salah M. Khalaf; Amal Rayan
Abstract
Background: It has been suggested that routine assessment and quantification of different lymphocyte subsets can provide clinically meaningful prognostic information in breast cancer (BC). Objective: To determine the relationship between peripheral blood lymphocyte subsets and pathological parameters ...
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Background: It has been suggested that routine assessment and quantification of different lymphocyte subsets can provide clinically meaningful prognostic information in breast cancer (BC). Objective: To determine the relationship between peripheral blood lymphocyte subsets and pathological parameters and response to therapy in patients with BC. Methods: Thirty patients with operable breast cancer treated surgically with either modified radical mastectomy or breast conservative surgery, and 20 healthy controls were included. For detection of lymphocyte subsets in peripheral blood; Fluorochrome-labeled monoclonal antibodies were used and cells were analyzed by flow cytometry. Patients were treated with chemotherapy, radiotherapy and hormonal treatment, and followed up to determine relapse and recurrence-free survival (RFS). Results: Significant differences were found in the frequencies of B, T, NK, NKT, and CD28‒T cells between patients with BC and controls. Moreover, a significant difference was found in the percentage of CD8+CD28‒ T cells between patients with different pathologic subtypes of BC and negative correlations were observed between the frequency of CD8+CD28‒T cells and memory B cells, and RFS. Also, a significant difference in the frequency of naïve B cells was found in patients with different tumor grades and a negative correlation was found between the frequencies of B cells and NKT cells. Conclusion: NK, NKT, lymphocytes, and CD28‒ T cells significantly differed between healthy controls and BC patients. Also, memory B cells were associated with good response to treatment while CD28‒ T cells were associated with shorter RFS.
Fatemeh Mashhadi-Abbas; Masoume Fayazi_Boroujeni; Akram Alizadeh; Mahshid Namdari; Seyed Abbas Mirzaei
Abstract
Background: The immune evasion of dysplastic cells plays an important role in suppressing the immune response and progression of malignancy. The role of the complement inhibitors in the development of oral epithelial dysplastic lesions and squamous cell carcinoma (SCC) is still unclear. Objective: This ...
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Background: The immune evasion of dysplastic cells plays an important role in suppressing the immune response and progression of malignancy. The role of the complement inhibitors in the development of oral epithelial dysplastic lesions and squamous cell carcinoma (SCC) is still unclear. Objective: This study aimed to assess the expression of C4 binding protein (C4BP) as a complement inhibitor in oral squamous cell carcinoma and leukoplakia. Methods: In this study, 94 samples were classified into four groups: leukoplakia with mild to moderate dysplasia, leukoplakia with severe dysplasia or carcinoma in situ, early invasive SCC, and invasive SCC. The expression of C4BP marker was evaluated by immunohistochemistry (IHC) and real-time PCR. The results were analyzed by the Kruskal-Wallis, Bonferroni adjusted Dunn’s multiple comparison, and one-way ANOVA tests. Results: The results of IHC revealed the expression patterns of C4BP in oral dysplasia and SCC, and indicated that the C4BP expression was not significantly different between different histopathological grades in epithelial cells and vessels (P=0.157 and P=0.123, respectively) but, it was significantly different in fibroblasts and lymphocytes (P=0.017 and P=0.043, respectively). The real-time PCR showed a significant correlation between the dysplasia grade and expression of C4BP (p <0.05). Conclusion: According to the results, C4BP is expressed in the cancerous tissue by the tumor cells and their surrounding stroma. In addition, upregulation of the C4BP gene as an inhibitor of the complement system is a possible strategy adopted by the tumor cells to evade the immune system.
Masutaka Furue; Dugarmaa Ulzii; Yen Vu; Gaku Tsuji; Makiko Kido-Nakahara; Takeshi Nakahara
Abstract
Atopic dermatitis (AD) is characterized by skin inflammation, barrier dysfunction and chronic pruritus. In this review, recent advances in the pathogenesis of AD are summarized. Clinical efficacy of the anti-IL-4 receptor antibody dupilumab implies that type 2 cytokines IL-4 and IL-13 have pivotal roles ...
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Atopic dermatitis (AD) is characterized by skin inflammation, barrier dysfunction and chronic pruritus. In this review, recent advances in the pathogenesis of AD are summarized. Clinical efficacy of the anti-IL-4 receptor antibody dupilumab implies that type 2 cytokines IL-4 and IL-13 have pivotal roles in atopic inflammation. The expression of IL-4 and IL-13 as well as type 2 chemokines such as CCL17, CCL22 and CCL26 is increased in the lesional skin of AD. In addition, IL-4 and IL-13 down-regulate the expression of filaggrin in keratinocytes and exacerbate epidermal barrier dysfunction. Keratinocytes in barrier-disrupted epidermis produce large amounts of thymic stromal lymphopoietin, IL-25 and IL-33, conducing to type 2 immune deviation via OX40L/OX40 signaling. IL-31, produced by type 2 T cells, is a cardinal pruritogenic cytokine. IL-4 and IL-13 also amplify the IL-31-mediated sensory nerve signal. These molecules are particularly important targets for future drug development for AD.
Samaneh Arab; Masoumeh Motamedi; Nematollah Khansari; Seied Mohammad Moazzeni; Zahra Gheflati; Jamshid Hadjati
Volume 3, Issue 3 , September 2006, , Pages 99-105
Abstract
Background: Bacterial DNA has immunostimulatory effects on different types of immune cells such as dendritic cells (DCs). Application of DCs as a cellular adjuvant represents a promising approach in the immunotherapy of infectious disease and cancers. Objectives: To investigate the effect of tumor antigen ...
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Background: Bacterial DNA has immunostimulatory effects on different types of immune cells such as dendritic cells (DCs). Application of DCs as a cellular adjuvant represents a promising approach in the immunotherapy of infectious disease and cancers. Objectives: To investigate the effect of tumor antigen pulsed DCs in the presence of CpG-1826 in treatment of a murine model of cancer. Methods: WEHI-164 cells (Balb/c derived fibrosarcoma cell line) were injected subcutaneously in the right flank of mice. Bone marrow cells were cultured in the presence of GM-CSF and IL- 4. After 5 days, tumor lysate, CpG-1826, and oligodeoxynucleosides, as control, were added to the culture media and incubated for 2 days. Cytokine production in DCs culture media was measured by ELISA. Then DCs were injected subcutaneously around the tumor site in the right flank of mice. Tumor growth rate was monitored in case and control groups. Two weeks after DCs immunotherapy, cytotoxic assay was conducted using various amounts of effector (splenic T cells) and target cells (WEHI-164 or CT26) for 6 h. Results: Immunotherapy with DCs treated with CpG led to a significant increase in the activity of cytotoxic T cells and decreased tumor growth in immunized mice. In the control group which received DCs without CpG treatment, no change in cytotoxic activity and tumor growth rate was detected. Conclusion: The current study suggests that specific anti tumor immune responses can be induced by DCs matured with CpG and proposes CpG usage in DCs targeted clinical strategies.
Marzieh Ebrahimi; Zuhair Mohammad Hassan; Jamshid Hadjati; Parisa Hayat; Seyed Mohammad Moazzeni
Volume 6, Issue 3 , September 2009, , Pages 107-118
Abstract
Background: Tumor necrosis factor alpha (TNF-α) is a primary mediator of immune regulation and might be required in the early stages of DC development from CD34+ cells. However, details of optimal timing of exposure to TNF-α in DC development process in monocytes or non-purified hematopoitic ...
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Background: Tumor necrosis factor alpha (TNF-α) is a primary mediator of immune regulation and might be required in the early stages of DC development from CD34+ cells. However, details of optimal timing of exposure to TNF-α in DC development process in monocytes or non-purified hematopoitic cells are still lacking and clear benefits of this approach to the development of DCs remain to be validated. Objective: To evaluate the effect of early and late exposure to TNF-α on DC devel-opment from non-purified cord blood mononuclear cells. Methods: To define the ef-fects of early exposure to TNF-α on cord blood mononuclear cells, we cultured UCB-MNC in the presence of SCF, Flt3L, GM-CSF and IL-4 for 14 days and matured them for an extra 4 days. TNF-α was added on day 0, 7 and 14 in TNF-α + group, and only on day 14 in TNF-α - group where it was used only as a maturation factor. Results: Immediate exposure to TNF-α was shown to: (1) enhance the survival of cells in the first week of culture; (2) produce mature DCs with higher maturation markers (CD80, CD83, CD86 and HLA-DR); and (3) increase secretion of IL-12 by mature DCs. In contrast, delayed exposure to TNF-α stimulate mature DCs with less purity producing a high level of IL-10 and a low level of IL-12. Conclusion: We developed a simple, easy and cost effective method to generate DCs from non-fractionating mononuclear cells in this study. Also we confirm the presence of a large number of functional DCs under inflammatory conditions, where local concentrations of TNF-α were high.
Sara Iranparast; Farhad Seif; Sanaz Tayebi; Farhad Abolnezhadian; Moosa Sharifat; Alireza Fazaeli; Neda Roshanravan; Azam Samei; Sholeh Khajoei
Abstract
Follicular helper T (TFH) cells are a subset of effector CD4+ T cells that support the differentiation of antigen-specific B cells in the germinal center. TFH cells are distinct from other established CD4+ T cell subsets and possess a list of transcription factors, including BCL6, IRF4, c-Maf, Batf, ...
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Follicular helper T (TFH) cells are a subset of effector CD4+ T cells that support the differentiation of antigen-specific B cells in the germinal center. TFH cells are distinct from other established CD4+ T cell subsets and possess a list of transcription factors, including BCL6, IRF4, c-Maf, Batf, NFAT1-2, and STAT3. The mentioned factors direct several activities such as cell differentiation, migration to the follicles, cell-to-cell interaction, as well as cell programming. Given that TFH cells are essential for the germinal center formation, affinity maturation and the development of most high-affinity antibodies. TFH cells may play crucial roles in different pathologic conditions, particularly autoimmune diseases. However, the mechanisms that cause functional differences of TFH cell responses are not exactly defined. In this review first the immunological profile of TFH cells will be discussed then attempts will be made to give a broad picture on the role of this key subset of T cells in autoimmune diseases.
Fatemeh Hajighasemi; Soheila Gharagozlou; Nasrin Moheghi; Roya Ghods; Jalal Khoshnoodi; Fazel Shokri
Volume 2, Issue 3 , September 2005, , Pages 125-133
Abstract
Background: There are two subclasses of human IgA (IgA1 and IgA2) that differ in antigenic properties and in chemical composition. The constant domains of α1 and α2 heavy chains have >95% sequence homology though major structural differences exist in the hinge region. Quantitation of IgA ...
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Background: There are two subclasses of human IgA (IgA1 and IgA2) that differ in antigenic properties and in chemical composition. The constant domains of α1 and α2 heavy chains have >95% sequence homology though major structural differences exist in the hinge region. Quantitation of IgA subclass levels depends on the availability of monoclonal antibodies (MAbs) specific for conserved conformational or linear epitopes restricted to each subclass. Objective: To produce, select and characterize monoclonal antibodies specific for human IgA2. Methods: Splenocytes from BALB/C mice immunized with a human IgA2 myeloma protein were fused with SP2/0 myeloma cells. Fused cells were grown in hypoxanthine, aminopterine and thymidine (HAT) selective medium and cloned by limiting dilution assay. Antibody (Ab) secreting cells were screened by enzyme-linked immunosorbent assay (ELISA) and the specificity of secreted MAbs was further analyzed, using a panel of purified myeloma proteins and some animal sera by ELISA and immunoblotting. The affinity constant (Kaff) was also determined by ELISA. Results: Four murine hybridoma clones designated 2F20G5, 2F20B5, 3F20E3 and 6F20H11 were obtained that secreted MAbs specific for the human IgA2. 2F20G5 and 6F20H11 MAbs react with linear epitope(s) while 2F20B5 and 3F20E3 react with conformational epitope(s) located to human IgA2 subclass. 2F20G5 MAb displays a weak cross-reactivity with monkey and rabbit sera and a strong cross-reactivity with cat and dog sera while the other three MAbs showed no cross-reactivity with the animal sera tested. Conclusion: These MAbs, especially 6F20H11 with high affinity constant (6.03 ×109 M-1) are useful tools for quantitation of human IgA2 subclass levels in various diseases. Cross-reactivity of 2F20G5 MAb with some animalsera suggests phylogenic conservation ofthe epitope recognized by this MAb.
Forough Golsaz Shirazi; Mohammad Mehdi Amiri; Hamed Mohammadi; Ali Ahmad Bayat; Azam Roohi; Jalal Khoshnoodi; Amir Hassan Zarnani; Mahmood Jeddi-Tehrani; Gholam Ali Kardar; Fazel Shokri
Volume 10, Issue 3 , September 2013, , Pages 127-138
Abstract
Background: The antibody response to hepatitis B surface antigen (HBsAg) controls hepatitis B virus infection. The "a" determinant of HBsAg is the most important target for protective antibody response, diagnosis and immunoprophylaxis. Mutations in this area may induce immune escape mutants and affect ...
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Background: The antibody response to hepatitis B surface antigen (HBsAg) controls hepatitis B virus infection. The "a" determinant of HBsAg is the most important target for protective antibody response, diagnosis and immunoprophylaxis. Mutations in this area may induce immune escape mutants and affect the performance of HBsAg assays. Objectives: To construct clinically relevant recombinant mutant forms of HBsAg and assessment of their reactivity with anti-HBs monoclonal antibodies (MAbs). Methods: Wild type (wt) and mutant (mt) HBsAg genes were constructed by site directed mutagenesis and SEOing PCR. The amplified genes were inserted into pCMV6-neo plasmid and transfected in CHO cell line. The expression of wt- and mtHBsAg was assessed by commercial ELISA assays and stable cells were established and cloned by limiting dilution. The recombinant mutants were further characterized using a panel of anti-HBs monoclonal antibodies (MAbs) and the pattern of their reactivity was assessed by ELISA. Results: Ten HBsAg mutants having single mutation within the "a" determinant including P120E, T123N, Q129H, M133L, K141E, P142S, D144A, G145R, N146S and C147S together with a wt form were successfully constructed and expressed in CHO cells. Reactivity of anti-HBs MAbs with mtHBsAgs displayed different patterns. The effect of mutations on antibody binding differed depending on the amino acid involved and its location within the ‘‘a’’ determinant. Mutation at amino acids 123 and 145 resulted in either complete loss or significant reduction of binding to all anti-HBs MAbs. Conclusion: Our panel of mtHBsAgs is a valuable tool for assessment of the antibody response to HBV escape mutants and may have substantial implications in HBV immunological diagnostics.
Abbas Ghaderi
Volume 8, Issue 3 , September 2011, , Pages 127-149
Abstract
Gene association studies are less appealing in cancer compared to autoimmune diseases. Complexity, heterogeneity, variation in histological types, age at onset, short survival, and acute versus chronic conditions are cancer related factors which are different from an organ specific autoimmune disease, ...
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Gene association studies are less appealing in cancer compared to autoimmune diseases. Complexity, heterogeneity, variation in histological types, age at onset, short survival, and acute versus chronic conditions are cancer related factors which are different from an organ specific autoimmune disease, such as Grave’s disease, on which a large body of multicentre data is accumulated. For years the focus of attention was on diversity and polymorphism of major histocompatibility complex in respect to human diseases specially the autoimmune diseases, but in recent years, access to other human gene sequences prompted investigators to focus on genes encoding the immune regulatory proteins such as the co-stimulatory, adhesion molecules, cytokines and chemokines and their receptors. Among them, CTLA4 (CD152) has been in the centre of attention for its pivotal role in autoimmunity and cancer. Although not fully understood, CTLA4 with no doubt plays an important role in the maintenance of the immune response by its expression on activated and regulatory T cells. CTLA4 (Gene ID:1493, MIM number:123890) has many variants and polymorphic forms, some present in regulatory positions, some in 3' UTR and the most important one in the leader sequence (+49 A/G). As a pivotal regulatory element of the immune responses magnitude, CTLA4 could be considered as a two-blade knife, for which only the optimal expression ensures an effective, but at the same time, safe immune response. It can accordingly be speculated that CTLA4 alleles associated with extraordinary expression could make a person more susceptible to tumor growth and/or progression. On the other hand, alleles associated with a compromised CTLA4 expression/function may accelerate the formation and/or manifestation of inflammatory autoimmune disorder. I hypothesized a spectrum of the functional dichotomy of CTLA4 SNPs diverging from autoimmunity to cancer. To examine these hypotheses, results from previously published investigations on CTLA4 polymorphisms together with the work done by our own group are discussed in details. Because the most published data are about the polymorphism at position +49, I concentrated on this position; however the data regarding other SNPs are also included for comparison. To support the significance of CTLA4 gene variation in these two major human diseases evidences from organ transplantation are also included. As will be discussed in the manuscript, our work and reports by others from a normal population perspective support the hypothesis that individuals inheriting a GG genotype at position +49, for which lower CTLA4 expression has been extensively suggested, are more susceptible for developing autoimmune disorders and those with AA genotype, with an existence of a state of self-tolerance, may have a higher chance of developing cancer. CTLA4 SNPs may accordingly be considered as a crucial element, along with other known or yet unknown mechanisms, in keeping the immune balance in predisposed individuals to cancer and autoimmunity. Although an spectrum line can be drawn between autoimmunity and cancer by considering published data regarding CTLA4 +49 polymorphism, the extreme functional dichotomy of this SNP appears to be more complex and difficult to understand, but there is no doubt that the future investigations will resolve most ambiguities.
Ahmad Jalili
Volume 4, Issue 3 , December 2007, , Pages 127-144
Abstract
Dendritic cells (DCs) are antigen presenting cells with unique capability to take up and process antigens in the peripheral blood and tissues. They subsequently migrate to draining lymph nodes where they present these antigens and stimulate naive T lympho-cytes. During their life cycle, DCs go through ...
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Dendritic cells (DCs) are antigen presenting cells with unique capability to take up and process antigens in the peripheral blood and tissues. They subsequently migrate to draining lymph nodes where they present these antigens and stimulate naive T lympho-cytes. During their life cycle, DCs go through two maturation stages and are referred to as immature and mature cells, respectively. While immature DCs are very good at cap-turing antigens, mature DCs are suitably equipped to present antigens to T cells and to initiate an immune response. DCs with different phenotypes serve as sentinels in nearly all tissues including the peripheral blood, where they are continuously exposed to anti-gens. Very small numbers of activated DCs are extremely efficient at generating im-mune response against viruses, other pathogens and in experimental models of tumors. Protection against infectious microorganisms and probably against tumors is provided by complex interactions of the innate and adaptive immune systems. For the initiation to occur, pathogens must first be recognized as a “danger”. DC possesses specific recep-tors to detect such danger signals. The unique immune-stimulating properties of DC and the feasibility of manipulating their function arouse much enthusiasm and hold great promise for the treatment of cancer. Early clinical trials showed that DC can induce immune responses in cancer patients. Nonetheless, cancer treatments based on DC ad-ministration require further studies that will optimize this promising treatment modality.
Esra Kazak; Sergio Costa Oliveria; Güher Goral; Halis Akalin; Emel Yilmaz; Yasemin Heper; Haluk Barbaros Oral
Volume 7, Issue 3 , September 2010, , Pages 132-141
Abstract
Background: Because of high morbidity of the brucellosis in humans and the potential use of the microorganism as an agent of biologic warfare, protection of effective vaccines and specific diagnostic reagents become necessary to eradicate brucellosis. Objective: In this study we aimed to investigate ...
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Background: Because of high morbidity of the brucellosis in humans and the potential use of the microorganism as an agent of biologic warfare, protection of effective vaccines and specific diagnostic reagents become necessary to eradicate brucellosis. Objective: In this study we aimed to investigate the cytokine responses and changes in peripheral blood lymphocyte subgroups of acute brucellosis patients in response to L7/L12 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) recombinant proteins derived from Brucella abortus. Methods: levels of IFN-γ, IL-4 and IL-10 secreted from PBMCs of 25 acute brucellosis patients and 15 healthy controls, stimulated with Phytohemagglutinin (PHA), L7/L12 or GAPDH were measured by ELISA. Furthermore alterations in lymphocyte subgroups in response to these Brucella antigens were determined by flow cytometry. Results: Extracellular IFN-γ levels were found to be elevated after stimulation with L7/L12 in patients with acute brucellosis, whereas no significant changes were found in IL-4 and IL-10 levels. Similar data was also obtained with GAPDH, but the stimulation of IFN-γ production was not observed in all patients and was not as strong as that observed for L7/L12. Moreover, when the distribution of lymphocytes subgroups (CD3+, CD3+CD4+, CD3+CD8+, CD4+CD25+, CD3+CD69+ and CD3+CD152+) was evaluated, it was found that the stimulation with L7/L12 and GAPDH only led to an increase in the percentage of CD3+CD69+ lymphocytes. Conclusion: These data indicate that Brucella abortus L7/L12 or GAPDH induce a Th1 type immune response in acute brucellosis patients. Additionally, these recombinant proteins, especially L7/L12, may be used in new vaccine preparations and diagnostic tests.
Sara Assadiasl; Pedram Ahmadpoor; Mohsen Nafar; Mahboob Lessan Pezeshki; Fateme Pourrezagholi; Mahmoud Parvin; Abtin Shahlaee; Adel Sepanjnia; Mohammad Hossein Nicknam; Aliakbar Amirzargar
Volume 11, Issue 3 , September 2014, , Pages 139-152
Abstract
Background: Regulatory T cells have been suggested to have a protective role against acute rejection in allograft recipients. However, there is little information available about their contribution to chronic rejection process. The role of transforming growth factor-beta 1 (TGF- β1) as a profibrogenic ...
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Background: Regulatory T cells have been suggested to have a protective role against acute rejection in allograft recipients. However, there is little information available about their contribution to chronic rejection process. The role of transforming growth factor-beta 1 (TGF- β1) as a profibrogenic and/or immunoregulatory cytokine in renal allografts is also controversial. Objectives: To evaluate the frequency of CD4+CD25+CD127- and CD3+CD8+CD28- regulatory T cells in chronic allograft dysfunction (CAD) and to investigate the expression of TGF- β1 in renal allografts. Methods: Thirty biopsy-proven CAD patients were pair-matched with 30 stable graft function patients and a third group of healthy volunteers. Flowcytometry was performed on PBMCs to determine the frequency of CD3+CD8+CD28- and CD4+CD25+CD127- regulatory T cells in lymphocyt population. TGF- β1 gene expression was assessed by Real Time PCR. Results: The percentage of CD3+CD8+CD28- Tregs among renal allograft recipients was higher than healthy controls (p<0.001) since stable graft patients showed the most rates. The frequency of CD4+CD25+CD127- Tregs was lower in CAD patients than stable recipients (p=0.024) and healthy group (p=0.015). TGF- β1 gene expression was greater in CAD patients compared to healthy group (p=0.03) but there was no significant difference between gene expression of stable graft patients and healthy volunteers. Conclusion: The negative association between the frequency of regulatory T cell subtypes and chronic allograft dysfunction proposes these cells as probable candidates for promoting allograft survival. Moreover, despite the immunoregulatory capacity of TGF- β1, it is likely to be implicated in chronic damages of allograft tissue.
Amir Hassan Zarnani; Pouneh Dokouhaki; Mahmood Jeddi-Tehrani
Volume 1, Issue 3 , December 2004, , Pages 143-153
Abstract
Indoleamine 2,3-dioxygenase (IDO), an enzyme involved in the catabolism of tryptophan, is expressed by a variety of cells and tissues such as macrophages, dendritic cells, cells of the endocrine system and by the placenta. IFN- γ is the main inducer of this enzyme. IDO acts as an important defense ...
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Indoleamine 2,3-dioxygenase (IDO), an enzyme involved in the catabolism of tryptophan, is expressed by a variety of cells and tissues such as macrophages, dendritic cells, cells of the endocrine system and by the placenta. IFN- γ is the main inducer of this enzyme. IDO acts as an important defense mechanism of innate immunity against pathogens. It also has tumor suppressive activity and prolongs the survival of allograft. One of the interesting functions of IDO is prevention of the allogenic fetus rejection during pregnancy by inhibiting alloreactive T cells. It was shown that inhibition of IDO activity by IDO inhibitor, 1-methyl tryptophan, during mouse pregnancy causes fetal rejection. The main mechanism by which IDO protects fetus is through reducing the tryptophan level and suppressing the T cell activity in the feto-maternal interface. In this review the biological functions of IDO with emphasis on its role in allogeneic fetus protection have been discussed.
Wenjie Zhang; Shan Liu; Lin Zhao; Juncheng Wang; Meng Liu; Fengge Wang; Yuekang Xu
Abstract
Background: The functions of dendritic cells (DCs) are influenced by their intracellular metabolism, in which liver kinase B1 (LKB1) plays an important role. However, due to the difficulty in isolating the DCs, the roles of LKB1 in DC maturation and functions in tumor settings have been poorly characterized.Objective: ...
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Background: The functions of dendritic cells (DCs) are influenced by their intracellular metabolism, in which liver kinase B1 (LKB1) plays an important role. However, due to the difficulty in isolating the DCs, the roles of LKB1 in DC maturation and functions in tumor settings have been poorly characterized.Objective: To investigate the roles of LKB1 in DC functions including phagocytosis and presentation of antigens, activation, T cell differentiation, and ultimately tumor eradication.Methods: Genetic modification of Lkb1 in the DCs was made by lentiviral transduction, and their impacts on T cell proliferation, differentiation, activity, or B16 melanoma metastasis were examined by flow cytometry, qPCR, or lung tumor nodule counting.Results: LKB1 did not affect antigen uptake and presentation by the DCs, but facilitated the stimulation of T cell proliferation. Interestingly, following T cell activation, Foxp3-expressing regulatory T cells (Treg) were increased (P=0.0267) or decreased (P=0.0195) in mice injected with Lkb1 knockdown DCs or overexpressing DCs, respectively. Further exploration revealed that LKB1 inhibited OX40L (P=0.0385) and CD86 (P=0.0111) expression, and these co-stimulatory molecules enhanced Treg proliferation, and downregulated immune suppressive cytokine IL-10 (P=0.0315). Moreover, we found that the injection of the DCs with limited LKB1 expression before tumor inoculation could reduce their production of granzyme B (P<0.0001) and perforin (P=0.0042) from CD8+T cells, thereby impairing their cytotoxicity and promoting tumor growth.Conclusion: Our data suggest that LKB1 can enhance DC-mediated T cell immunity by restraining Treg development and thereby suppressing tumor growth.
Volume 5, Issue 3 , September 2008, , Pages 148-148
Abdolkarim Sheikhi; Abdollah Jafarzadeh; Parviz Kokhaei; Mohammad Hojjat-Farsangi
Volume 13, Issue 3 , September 2016, , Pages 148-166
Abstract
Cancer immunotherapy (passive or active) involves treatments which promote the ability of the immune system to fight tumor cells. Several types of immunotherapeutic agents, such as monoclonal antibodies, immune checkpoint inhibitors, non-specific immunomodulatory agents, and cancer vaccines are currently ...
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Cancer immunotherapy (passive or active) involves treatments which promote the ability of the immune system to fight tumor cells. Several types of immunotherapeutic agents, such as monoclonal antibodies, immune checkpoint inhibitors, non-specific immunomodulatory agents, and cancer vaccines are currently under intensive investigation in preclinical and clinical trials. Cancer vaccines induce permanent activation of the immune system and may be considered the most promising method for cancer treatment, especially in combination with other agents of passive immunotherapy. Among various approaches to cancer vaccines, whole tumor cell vaccines have been attracting attention for several years. Despite their low to moderate clinical effects, these vaccines have numerous advantages. Their ability to generate immune responses against tumor-associated antigens reduces the possibility for tumor cells to escape and facilitates the development of “off-the-shelf” allogeneic tumor vaccines. Understanding the reciprocal interactions between tumor cells and leukocytes is a key to harness the full potential of whole cell vaccination. Cytokines are considered as potent immunomodulatory molecules which behave as adjuvants in whole tumor cell vaccines. Improved mechanistic understanding of key cytokines in tumor immunity will serve as a resource for rational design of whole cell cancer vaccines. Although there are several reports about the use of different immunostimulatory cytokines as adjuvants, interleukin (IL)-12 appears to have superior effects compared to other cytokines. This review describes the effects of IL-12 compared to other immunomodulatory cytokines, such as IL-2 and IL-15, and highlights its application in whole cell tumor vaccination.