Publications by authors named "Fatemeh Faraji"

12 Publications

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Remote controlling of CAR-T cells and toxicity management: Molecular switches and next generation CARs.

Transl Oncol 2021 Mar 28;14(6):101070. Epub 2021 Mar 28.

Cancer Research Center, Cancer Institute of Iran, Tehran University of Medical Science, Tehran, Iran; Breast Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Cell-based immunotherapies have been selected for the front-line cancer treatment approaches. Among them, CAR-T cells have shown extraordinary effects in hematologic diseases including chemotherapy-resistant acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma (NHL). In this approach, autologous T cells isolated from the patient's body genetically engineered to express a tumor specific synthetic receptor against a tumor antigen, then these cells expanded ex vivo and re-infusion back to the patient body. Recently, significant clinical response and high rates of complete remission of CAR T cell therapy in B-cell malignancies led to the approval of Kymriah and Yescarta (CD19-directed CAR-T cells) were by FDA for treatment of acute lymphoblastic leukemia and diffuse large B-cell lymphoma. Despite promising therapeutic outcomes, CAR T cells also can elicit the immune-pathologic effects, such as Cytokine Release Syndrome (CRS), Tumor Lysis Syndrome (TLS), and on-target off-tumor toxicity, that hampered its application. Ineffective control of these highly potent synthetic cells causes discussed potentially life-threatening toxicities, so researchers have developed several mechanisms to remote control CAR T cells. In this paper, we briefly review the introduced toxicities of CAR-T cells, then describe currently existing control approaches and review their procedure, pros, and cons.
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http://dx.doi.org/10.1016/j.tranon.2021.101070DOI Listing
March 2021

Cytotoxicity Assessment and Apoptosis-related Gene Profiling of Antibody Treated Acute Myeloid Leukemia (AML) and Acute Lymphocytic Leukemia (ALL) Cancerous Cell Lines.

Iran J Allergy Asthma Immunol 2019 Oct 30;18(6):679-687. Epub 2019 Oct 30.

National Cell Bank of Iran, Pasteur Institute of Iran, Tehran, Iran.

Acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) are common acute leukemia in adults and children, respectively. In these malignancies, chemotherapy is the main treatment strategy that fails in many cases and is usually associated with adverse effects on healthy cells. In this regard, the development of new therapies is essential. Monoclonal antibodies directed to the cell surface markers of leukemic blasts may have promising consequences with minimal toxic effects on normal cells. Since cluster of differentiation 45Ra (CD45Ra) and CD123 antigens, two considered surface markers of leukemic blasts in AML and ALL respectively, are overexpressed on AML and ALL blasts, CD34+ leukemic progenitors, and AML-LSCs in comparison with normal hematopoietic stem cells (HSCs), they were selected to be targeted; using specific monoclonal antibodies. In this project, CD45Ra+ cells and CD123+ cells were targeted by anti-CD45Ra and/or anti-CD123 monoclonal antibodies. Cytotoxicity effect and cell death induction was determined by 3-(4,5-dimethylthiazol-2-yl)-2-5-diphenyltetrazolium bromide (MTT) assay and flow cytometry. Changes in the expression profile of MCL1, cMyc, Survivin, Id1, and PIM1 genes were assessed by real-time PCR. Statistical analysis of the results showed effective antibody-mediated cytotoxicity and induction of apoptosis in KG1α (CD45Ra+) and Nalm6 (CD123+) cell lines. Also, a significant change in the expression level of some of the apoptosis-related genes was observed. According to the results of this study, it can be concluded that an effective targeting of AML and ALL cancerous cell lines can be performed by anti-CD45Ra and anti-CD123 monoclonal antibodies through their effector functions and apoptosis induction.
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http://dx.doi.org/10.18502/ijaai.v18i6.2181DOI Listing
October 2019

Protective responses of an engineered PspA recombinant antigen against .

Biotechnol Rep (Amst) 2019 Dec 30;24:e00385. Epub 2019 Oct 30.

National Cell Bank of Iran, Pasteur Institute of Iran, Tehran, Iran.

is a major pathogen in human respiratory tract which causes significant morbidity and mortality across from the world. Currently available vaccines are not completely effective and cannot cover all pathogenic strains so there is an important need to develop an alternative cost-effective vaccine, based on conserved protein antigens. Pneumococcal surface protein A (PspA) is one of interesting candidates for development of a serotype-independent vaccine against pneumococcal infections. PspA is grouped into two major families with five clades, and broad-reacting PspA-based vaccines should contain at least one functional fragment from each of the two families. In this study, we developed two immunogenic antigens based on recombinant PspA proteins that including the different antigenic regions of PspA from both two families. The cross-reactivity of antibodies elicited against two PspA proteins PspAB1-5 and PspAABC and their role in complement deposition with three strains of pneumococci were tested. The protective effects of developed anti-PspA antibodies in mice in intranasal and intraperitoneal challenges were evaluated using a strain from clade 2. Sera from immunized mice with PspAB in comparison with PspAABC was able to deposit more C3 complement component on surface of pneumococci bearing diverse PspA from both families 1 and 2, and immunized mice with the PspAB showed a higher protection than PspAABC in pneumococcal challenges. The obtained results from this study indicate that a PspA-based antigen composed of B region from all clades in addition to conserved domains, can provide a significant protection against multiple strains of . and may overcome the limitation of polysaccharide vaccines.
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http://dx.doi.org/10.1016/j.btre.2019.e00385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864353PMC
December 2019

An antibody fragment against human delta-like ligand-4 for inhibition of cell proliferation and neovascularization.

Immunopharmacol Immunotoxicol 2018 Oct 5;40(5):368-374. Epub 2018 Sep 5.

d National Cell Bank of Iran, Pasteur Institute of Iran , Tehran , Iran.

Objectives: Angiogenesis targeting is an attractive approach for cancer treatment. Delta-like ligand 4 (DLL4) plays a pivotal role in neovascular development and its inhibitors have recently entered clinical trials for solid tumors. The aim of this study was to evaluate the possibilities of using anti-DLL4 antibody fragment as an angiogenesis maturation inhibitor.

Materials And Methods: In this study, a DLL4-specific Nanobody, named 3Nb3, was selected and assessed by western blotting and internalization assays. Functional assessments included MTT, apoptosis, and chicken chorioallantoic membrane (CAM) assays.

Results: Based on the results, 3Nb3 specifically binds to DLL4 and internalizes into MKN cell. Furthermore, 3Nb3 significantly inhibited the proliferation of cells and also neovascularization in the CAM.

Conclusions: These data demonstrated the potential of Nanobody for application in targeting DLL4. Our findings may provide a basis for the development of novel therapeutic techniques to inhibit growth and neovascularization of tumors.
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http://dx.doi.org/10.1080/08923973.2018.1505907DOI Listing
October 2018

Challenges related to the immunogenicity of parenteral recombinant proteins: Underlying mechanisms and new approaches to overcome it.

Int Rev Immunol 2018 31;37(6):301-315. Epub 2018 May 31.

a Immunology Research Center , Iran University of Medical Sciences (IUMS) , Tehran , Iran.

Immune response elicited by therapeutic proteins is an important safety and efficacy issue for regulatory agencies, drug manufacturers, clinicians, and patients. Administration of therapeutic proteins can potentially induce the production of anti-drug antibodies or cell-mediated immune responses. At first, it was speculated that the immunogenicity is related to the non-human origin of these proteins. Later on, it was confirmed that the human proteins may also show immunogenicity. In this review article, we will focus on a number of factors, which play crucial roles in the human protein immunogenicity. These factors are related to the patient's status (or intrinsic properties) and molecular characteristics of the therapeutic protein's (or extrinsic properties). Furthermore, we will discuss available in silico, in vitro, and in vivo methods for the prediction of sequences, which may generate an immune response following parenteral administration of these proteins. In summary, nowadays, it is possible for drug manufacturers to evaluate the risk of immunogenicity of therapeutic proteins and implement a management plan to overcome the problems prior to proceeding to human clinical trials.
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http://dx.doi.org/10.1080/08830185.2018.1471139DOI Listing
June 2019

Development and characterization of a camelid single-domain antibody directed to human CD22 biomarker.

Biotechnol Appl Biochem 2018 Sep 6;65(5):718-725. Epub 2018 Apr 6.

National Cell Bank of Iran, Pasteur Institute of Iran, Tehran, Iran.

CD22 is a B-cell-specific trans-membrane glycoprotein, which is found on the surface of the most B cells and modulates their function, survival, and apoptosis. Recently, targeting this cell surface biomarker in B-cell malignancies and disorders has attracted a lot of attention. The variable domain of camelid single-chain antibodies (VHH, nanobody) is a form of antibodies with novel properties including small size (15-17 kDa), thermal and chemical stability, high affinity and homology to human antibody sequences. In this study, a novel anti-CD22-specific VHH (Nb) has been developed and characterized by the screening of an immunized phage display library and its binding to CD22 B cells is evaluated. Produced anti-CD22 VHH had a single protein band about 17 kDa of molecular size in Western blotting and its binding affinity was approximately 9 × 10  M. Also, this product had high specificity and it was able to recognize the natural CD22 antigen in CD22+ cell lysate as well as on the cell surface (93%). This anti-CD22 VHH with both high affinity and specificity recognizes CD22 antigen well and can be used in diagnosis and treatment of B cell disorders and malignancies.
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http://dx.doi.org/10.1002/bab.1654DOI Listing
September 2018

Human adipose tissue-derived mesenchymal stem cells in rheumatoid arthritis: Regulatory effects on peripheral blood mononuclear cells activation.

Int Immunopharmacol 2017 Jun 30;47:59-69. Epub 2017 Mar 30.

Department of Immunology and Microbiology, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran.

Background And Objectives: Mesenchymal stem cells (MSCs) are multipotent adult stem cells with immunomodulatory properties. The mechanisms by which MSCs inhibit the proliferation of pro-inflammatory T cells have not been fully elucidated yet. It is assumed that pro-inflammatory T-cells play an important role in the development of autoimmune diseases. We investigated the potential therapeutic effects of human adipose tissue derived (Ad)-MSCs on the peripheral blood mononuclear cells (PBMCs) of rheumatoid arthritis (RA) patients and healthy individuals, with a particular focus on Th17-associated cytokines.

Materials And Methods: PBMCs from RA patients and healthy donors were co-cultured with Ad-MSCs and HeLa with or without Phytohemagglutinin (PHA). Finally, IL-6, IL-17, IL-21, IL-23 and TGF-β levels were determined by ELISA and quantitative real-time RT-PCR on co-culture supernatants and PBMCs, respectively.

Results: In co-culture interaction, Ad-MSCs inhibited IL-17 secretion by PBMCs compared to unstimulated PBMCs cultured alone. In addition, IL-21 expressions in PBMCs of the patient group, and IL-17 and IL-21 in healthy group were inhibited by Ad-MSCs compared to PBMCs cultured alone. TGF-β expression in healthy individuals remarkably increased in both MSC-treated groups with and without PHA in comparison to PHA-stimulated and -unstimulated PBMCs.

Conclusions: This study demonstrates that human Ad-MSCs act as key regulators of immune tolerance by inhibiting the inflammation. Therefore, they can be attractive candidates for immunomodulatory cell-based therapy in RA.
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http://dx.doi.org/10.1016/j.intimp.2017.03.016DOI Listing
June 2017

Elevated Levels of T-helper 17-associated Cytokines in Diabetes Type I Patients: Indicators for Following the Course of Disease.

Immunol Invest 2016 Oct 9;45(7):641-51. Epub 2016 Sep 9.

d Department of Student Research Committee, School of Medicine , Jahrom University of Medical Sciences , Jahrom , Iran.

Background: Type 1 diabetes (T1D) is thought to involve chronic inflammation, which is manifested by the activation and expression of different inflammatory mediators. Th1- and Th17-associated cytokines are factors that have been shown to exert profound pro-inflammatory activities and have been implicated in the pathogenesis of T1D in mice and humans.

Objectives: Therefore, the aim of this case control study was to determine the serum level of IL-17, IL-21, IL-27, transforming growth factor beta (TGF-β), and IFN-γ and their reciprocal relationship in Iranian T1D patients.

Patients And Methods: Blood samples were collected from 48 T1D patients and 49 healthy individuals with no history of malignancies or autoimmune disorders based on simple sampling. The serum levels of IL-17, IL-21, IL-27, TGF-β, and IFN-γ were measured by the enzyme linked immunosorbent assay (ELISA).

Results: The serum levels of IL-17 and IL-21 were significantly higher in T1D patients compared to the healthy individuals (p = 0.005 and 0.01, respectively), but interestingly, the opposite was the case for IL-27 (p < 0.0001). However, there were no significant differences in TGF-β and IFN-γ between both groups. In addition, IL-17/IFN-γ and IL-17/IL-27 ratios were higher in patients compared to the control group.

Conclusions: Our results indicated dominant Th17-associated IL-17, suggesting a shift from the Treg and Th1 phenotypes toward the Th17 phenotype. Therefore, it can promote inflammation in β cells in T1D. In addition, it suggests the role of Th17 and Th17/Th1 ratios as a potential contributor to β cells destruction and the Th17/Th1 response ratio may provide a novel biomarker for rapid T1D diagnosis before the destruction of β cells and progression of the disease to the clinical end stages.
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http://dx.doi.org/10.1080/08820139.2016.1197243DOI Listing
October 2016

Molecular detection of virulence genes in Pseudomonas aeruginosa isolated from children with Cystic Fibrosis and burn wounds in Iran.

Microb Pathog 2016 Oct 25;99:1-4. Epub 2016 Jul 25.

Pediatric Infections Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Pseudomonas aeruginosa possesses various virulence factors which contribute to the bacterial invasion and toxicity. Moreover, children suffered from Cystic Fibrosis (CF) and burn wounds are at a high risk of various bacterial infections. The aim of this study was to determine the prevalence of virulent genes in P. aeruginosa isolated from children with CF and burn wounds and comparing their virulence genes to figure out the role of every virulent factor in the infections. P. aeruginosa were isolated from sputum, oropharyngeal swabs, and broncho-alveolar lavage (BAL) specimens from CF and burn wounds between June 2013 and June 2014 in Tehran's hospitals. Bacterial genomic DNAs were extracted and uniplex, duplex and multiplex PCR were performed for detection of toxA, algD and plcN, exoS, lasB, plcH genes, respectively. The prevalence rate of virulence genes in P. aeruginosa isolated from CF was; toxA (63.1%), algD (64.6%), plcH (87.7%), plcN (60%), lasB (95.4%) and exoS (70.8%) and virulence genes in P. aeruginosa from burn patients were: toxA (36.9%), algD (70.1%), plcH (79%), plcN (63.1%), lasB (82%) and exoS (21.1%). The prevalence of three virulent genes in P. aeruginosa was higher in CF comparing to burn wound infections. We found that the number of toxA, lasB and exoS were significantly higher in the bacteria which were isolated from children with CF. This finding shows that these virulence factors play an important role in CF infections by P. aeroginosa.
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http://dx.doi.org/10.1016/j.micpath.2016.07.013DOI Listing
October 2016

Effects of 1,25-dihydroxyvitamin D3 on IL-17/IL-23 axis, IFN-γ and IL-4 expression in systemic lupus erythematosus induced mice model.

Iran J Basic Med Sci 2016 Apr;19(4):374-80

Immunology Research Center, BuAli Research Institute, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Objectives: Systemic lupus erythematosus (SLE) is a multi-factorial autoimmune disease which may be characterized by T lymphocytes dysfunctions. Th17 cells have been identified as new effector cells, which play an important role in the pathogenesis. In recent years, immunomodulatory effect of vitamin D3 has been noticed. In the present experiment, the effect of vitamin D3 on the expression of IL-17, IL-23, IL-4 and IFN-γ were assessed in activated chromatin-induced mouse model for SLE.

Materials And Methods: Five groups of mice were included in this study; Group one received active chromatin +CFA + PBS; Group 2 received vitamin D3 starting 2 weeks before disease induction; Group 3 received vitamin D3 (50 ng/day) starting with the disease establishment; Group 4 received non active chromatin +CFA + PBS; Group 5 received CFA + PBS. On day 56 splenocytes were isolated and gene expression of interleukin IL-17, IL-23, IL-4 and IFN-γ were analyzed by Real-Time PCR method. Proteinuria and serum anti-dsDNA and Th17 levels were measured using commercial kits.

Results: The results showed that IL-17, IL-23, and IFN-γ mRNA expression, and IL-17 titers were decreased remarkably and that of IL-4 increased in mice which received vitamin D3 before SLE induction. Administration of vitamin D3 after the establishment of SLE failed to affect the IL-17 or IL-23 mRNA levels. Lastly, pre-treatment of mice with vitamin D3 decreased the anti-ds DNA antibody titer.

Conclusion: Our findings showed that vitamin D3 supplementation in lupus induced mice through modulating the expression rate of some inflammatory cytokines diminished the inflammatory conditions in SLE.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887709PMC
April 2016

HLA-DRB1 alleles of susceptibility and protection in Iranians with autoimmune hepatitis.

Hum Immunol 2016 Apr 11;77(4):330-5. Epub 2016 Jan 11.

Immunology Research Center (IRC), Iran University of Medical Sciences, Tehran, Iran. Electronic address:

Autoimmune hepatitis (AIH) is an uncommon autoimmune liver disease of unknown etiology. The aim of this study was to determine the frequency of HLA-DRB1 alleles in Iranian patients with AIH and investigate the association between HLA alleles and the different types of the disease. Fifty-four AIH patients and 100 age- and sex-matched healthy controls were subjected to low resolution HLA-DRB typing performed by polymerase chain reaction-sequence-specific primers (PCR-SSP) technique. The results revealed higher frequencies of HLA-DRB1(∗)03, and DRB1(∗)13 alleles in patients with AIH compared to controls. However, DRB1(∗)11 was less frequent in AIH patients. In type I AIH patients HLA-DRB1(∗)03, HLA-DRB1(∗)04, HLA-DRB1(∗)08, and HLA-DRB1(∗)13 were the most frequent alleles. While in type II, the most frequent alleles were HLA-DRB1(∗)07 and HLA-DRB1(∗)13. The seronegative patients showed more frequency of HLA-DRB1(∗)03 and HLA-DRB3. In contrary, the frequency of HLA-DRB1(∗)11, HLA-DRB1(∗)15 and HLA-DRB5 in type 1 was less than healthy individuals. These findings indicate the role of HLA-DRB haplotypes in AIH susceptibility and protection, in the Iranian population.
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http://dx.doi.org/10.1016/j.humimm.2016.01.007DOI Listing
April 2016

Assessment of 1,25-dihydroxyvitamin D3 effects on Treg cells in a mouse model of systemic lupus erythematosus.

Immunopharmacol Immunotoxicol 2015 Feb 16;37(1):12-8. Epub 2014 Oct 16.

Immunology Research Center, School of Medicine, Bu-Ali Research Institute, Mashhad University of Medical Sciences , Mashhad , Iran.

Context: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease which is characterized by the presence of auto-reactive T cell and anti-ds DNA antibodies. Treg cells are crucial for maintaining immunologic self-tolerance and are shown to be reduced in SLE patients. 1,25-Dihydroxyvitamin D3 has immunomedulatory effects on the immune system and has recently received substantial attention.

Objective: In this study we evaluated the effects of 1,25-dihydroxyvitamin D3 on Treg cells and related cytokines in lupus-like induced mice model.

Materials And Methods: Female Balb/c mice were divided into four groups: Group one: injected with PBS and Freund's adjuvant; Group two: injected with non-activated chromatin; Group three: Lupus-like disease was induced with activated chromatin; Group four: Mice were initially treated for two weeks with 1,25-dihydroxyvitamin D3 and then lupus-like disease was induced. Group five: Four mice from group one were treated with 1,25-dihydroxyvitamin D3 for two weeks after disease establishment. Ten weeks after the last injection the mice were killed and spleens were studied for Treg percentages and expression of cytokine genes.

Results: We found that treatment with 1,25-dihydroxyvitamin D3 reduces IL-6 and IL-10 mRNA expression and increases TGF-β and Foxp3 mRNA expression levels, and also enhances spleen Treg percentage.

Conclusions: The remarkable reduction of IL-6 and IL-10 gene expressions, significant enhancement of TGF-β and Foxp3 gene expressions, along with an increase in Treg cell population after oral 1,25-dihydroxyvitamin D3 administration suggest a possible role for this vitamin as a prophylactic supplement in SLE.
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http://dx.doi.org/10.3109/08923973.2014.968255DOI Listing
February 2015