Publications by authors named "Gholamreza Daryabor"

8 Publications

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In vitro-derived insulin-producing cells modulate Th1 immune responses and induce IL-10 in streptozotocin-induced mouse model of pancreatic insulitis.

Hepatobiliary Pancreat Dis Int 2021 Apr 4. Epub 2021 Apr 4.

Autoimmune Diseases Research Center, Medical School, Shiraz University of Medical Sciences, Shiraz 71345-1798, Iran; Department of Immunology, Medical School, Shiraz University of Medical Sciences, Shiraz 71345-1798, Iran. Electronic address:

Background: insulitis is defined by the presence of immune cells infiltrating in the pancreatic islets that might progress into the complete β-cell loss. The immunomodulatory properties of bone marrow-derived mesenchymal stem cells (BM-MSCs) have attracted much attention. This study aimed to evaluate the possible immunomodulatory effects of rat BM-MSCs and MSCs-derived insulin-producing cells (IPCs) in a mouse model of pancreatic insulitis.

Methods: insulitis was induced in BALB/c mice using five consecutive doses of streptozotocin. MSCs or IPCs were directly injected into the pancreas of mice and their effects on the expression of Th subsets-related genes were evaluated.

Results: both BM-MSCs and IPCs significantly reduced the expression of pancreatic Th1-related IFN-γ (P < 0.001 and P < 0.05, respectively) and T-bet genes (both P < 0.001). Moreover, the expression of IL-10 gene was significantly increased in IPC-treated compared to BM-MSC- or PBS-treated mice (P < 0.001 both comparisons).

Conclusions: BM-MSCs and IPCs could successfully suppress pathologic Th1 immune responses in the mouse model of insulitis. However, the marked increase in IL-10 gene expression by IPCs compared to BM-MSCs suggests that their simultaneous use at the initial phase of autoimmune diabetes might be a better option to reduce inflammation but these results need to be verified by further experiments.
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http://dx.doi.org/10.1016/j.hbpd.2021.03.008DOI Listing
April 2021

Interleukin-27 gene variant rs153109 is associated with enhanced cytokine serum levels and susceptibility to Behçet's disease in the Iranian population.

Eur Cytokine Netw 2020 Dec;31(4):140-146

Autoimmune Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran, Department of Immunology, Shiraz University of Medical Sciences, Shiraz, Iran.

Behcet's disease (BD) is a systemic vasculitis, characterized by recurrent oral aphthous, genital ulcers, ocular lesions, and other organ involvement. Interleukin (IL)-27 with its pro- and anti-inflammatory effects might be an important effective cytokine in this disease. The aim of this study was to investigate the association of IL-27 serum concentration and a single-nucleotide polymorphism (SNP) rs153109 (-964 A > G) with the risk and clinical features of the patients with BD. IL-27 Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and the IL-27 serum levels were measured using enzyme-linked immunosorbent assay (ELISA). It is shown that AG, GG, and AG + GG genotypes, as well as G allele of rs153109, can significantly increase the risk of BD in total and in male individuals. Significantly higher frequencies of AG and GG genotypes and G allele were observed in total and male patients with an active form of BD. AG and GG genotypes were associated with joint (p = 0.046) and vascular (p = 0.02) involvement. The frequency of the G allele was higher in all patients, as well as in female patients with vascular involvement (p = 0.02). Serum cytokine analysis indicated an increased level of IL-27 in BD patients compared to healthy subjects (p = 0.038). Additionally, a higher level of IL-27 was detected in patients carrying the rs153109 GG genotype (p = 0.04) and those with renal (p = 0.009) and skin (p = 0.05) involvement. In conclusion, this study underscores the involvement of IL-27 rs153109 variants and increased serum level in BD susceptibility and pathogenesis.
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http://dx.doi.org/10.1684/ecn.2020.0458DOI Listing
December 2020

The Effects of Type 2 Diabetes Mellitus on Organ Metabolism and the Immune System.

Front Immunol 2020 22;11:1582. Epub 2020 Jul 22.

Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.

Metabolic abnormalities such as dyslipidemia, hyperinsulinemia, or insulin resistance and obesity play key roles in the induction and progression of type 2 diabetes mellitus (T2DM). The field of immunometabolism implies a bidirectional link between the immune system and metabolism, in which inflammation plays an essential role in the promotion of metabolic abnormalities (e.g., obesity and T2DM), and metabolic factors, in turn, regulate immune cell functions. Obesity as the main inducer of a systemic low-level inflammation is a main susceptibility factor for T2DM. Obesity-related immune cell infiltration, inflammation, and increased oxidative stress promote metabolic impairments in the insulin-sensitive tissues and finally, insulin resistance, organ failure, and premature aging occur. Hyperglycemia and the subsequent inflammation are the main causes of micro- and macroangiopathies in the circulatory system. They also promote the gut microbiota dysbiosis, increased intestinal permeability, and fatty liver disease. The impaired immune system together with metabolic imbalance also increases the susceptibility of patients to several pathogenic agents such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Thus, the need for a proper immunization protocol among such patients is granted. The focus of the current review is to explore metabolic and immunological abnormalities affecting several organs of T2DM patients and explain the mechanisms, whereby diabetic patients become more susceptible to infectious diseases.
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http://dx.doi.org/10.3389/fimmu.2020.01582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387426PMC
August 2020

A simple method for the generation of insulin producing cells from bone marrow mesenchymal stem cells.

In Vitro Cell Dev Biol Anim 2019 Jun 20;55(6):462-471. Epub 2019 May 20.

Department of Immunology, Shiraz Medical School, Shiraz University of Medical Sciences, Po Box 71345-1798, Shiraz, Iran.

To produce insulin-producing cells (IPCs) from bone marrow mesenchymal stem cells (BM-MSCs) using a simple and cost effective method. During the initial 7 days of three-dimensional (3D) culture, BM-MSCs were cultured on 1% agar or agarose to form multicellular spheroids. Spheroids and spheroid-derived single cells (SS and SSC, respectively) were cultured in the absence of any proteinaceous growth factor in a simple specific medium for a further 7 d. The insulin content of the differentiated cells was evaluated at the mRNA and protein levels. Furthermore, the expression of pancreatic beta cells-related genes other than INS as well as the in vitro responses of IPCs to different glucose concentrations were investigated. Cellular clusters generated on agar and SS conditions (agar+SS-IPCs) stained better with beta cell specific stains and were more reactive to serum-containing insulin reactive antibodies compared with agarose-SS-IPCs. Gene expression analysis revealed that in comparison to agarose + SS-IPCs, agar+SS-IPCs expressed significantly higher levels of INS-1, INS-2, PDX-1, NKX6.1, and XBP-1. Of interest, agar+SS-IPCs expressed 2215.3 ± 120.8-fold more INS-1 gene compared to BM-MSCs. The expression of β-cell associated genes was also higher in agar+SS-IPCs compared to the agar+SSC-IPCs. Moreover, the expression of INS-1 gene was significantly higher in agar+SS-IPCs compared with agar+SSC-IPCs after culture in media with high concentration of glucose. Compared to the most expensive and time-consuming protocols, 3D culture of MSCs on agar followed by 2D culture of cellular clusters in a minimally supplemented high glucose media produced highly potent IPCs which may pay the way to the treatment of diabetic patients.
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http://dx.doi.org/10.1007/s11626-019-00358-zDOI Listing
June 2019

Pyrin and Hematopoietic Interferon-Inducible Nuclear Protein Domain Proteins: Innate Immune Sensors for Cytosolic and Nuclear DNA.

Crit Rev Immunol 2019;39(4):275-288

Department of Immunology, Medical School, Shiraz University of Medical Sciences, Shiraz, Iran.

The innate immune system is the first line of defense against microbial pathogens. The response of innate immunity is initiated by molecules known as pattern recognition receptors (PRRs). Such responses are often triggered by nucleic acids that are delivered to the cytoplasm or nucleus of cells. The ability to recognize foreign nucleic acids in these two locations is an important defense mechanism of the human innate immune system. Several PRRs are located in the cytosol or nucleus and detect foreign DNAs. The pyrin and hematopoietic interferon-inducible nuclear (PYHIN) domain protein is a family of PRRs that includes interferon-inducible protein 16, absent in melanoma 2, PYHIN 1 (or interferon-inducible protein X, as it is also known), myeloid cell nuclear differentiation antigen, and pyrin domain only protein 3. These nuclear and cytosolic sensors play an essential part in host defense of intracellular pathogens. In addition, members of the PYHIN family are critical regulators of immune response, apoptosis, cell growth, differentiation, and transcription. In this review, we summarize important characteristics of these innate immune sensors and their roles in several diseases. A better understanding of the role of DNA sensors in the nucleus and cytoplasm will lead to the development of novel therapeutic approaches to control infections and associated diseases.
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http://dx.doi.org/10.1615/CritRevImmunol.2020033114DOI Listing
August 2020

An update on immune dysregulation in obesity-related insulin resistance.

Scand J Immunol 2019 Apr 29;89(4):e12747. Epub 2019 Jan 29.

Department of Immunology, Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, Iran.

Obesity is associated with chronic low-grade inflammation of the adipose tissue (AT) that might develop into systemic inflammation, insulin resistance (IR) and an increased risk of type 2 diabetes mellitus (T2DM) in severe obese rodents and humans. In the lean state, small normal adipocytes and AT macrophages interact with each other to maintain metabolic homeostasis but during obesity, enlarged adipocytes secrete inflammatory mediators and express immune receptors to recruit immune cells and aggravate the inflammation. The better understanding of the obesity-related inflammatory milieu and the sequential events leading to IR could be helpful in designing new preventive and therapeutic strategies. The present review will discuss the cellular and molecular abnormalities participating in the pathogenesis of obesity in obese individuals as well as high-fat diet (HFD)-fed mice, a mouse model of obesity.
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http://dx.doi.org/10.1111/sji.12747DOI Listing
April 2019

Gender-Specific Association of Leptin and Adiponectin Genes With Multiple Sclerosis.

Am J Med Sci 2018 08 6;356(2):159-167. Epub 2018 Mar 6.

Neurology Department, Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Immunology, Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, Iran; Autoimmune Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address:

Background: Adipocytokines such as leptin (LEP) and adiponectin (ADIPOQ) represent a link between metabolism, nutritional status and immune responses. The present study aimed to determine the possible association between single nucleotide polymorphisms of LEP and ADIPOQ genes with multiple sclerosis (MS).

Materials And Methods: Single nucleotide polymorphisms in LEP (rs2167270 or 19G > A and rs7799039 or -2,548G > A) and ADIPOQ (rs1501299 or +276G > T and rs266729 or -11,377C > G) were genotyped in 305 patients and 255 healthy individuals using polymerase chain reaction-restriction fragment length polymorphism. Sera levels of leptin and adiponectin were measured using enzyme-linked immunosorbent assay.

Results: The frequencies of low leptin producer rs2167270GG genotype and rs2167270G allele were significantly lower in patients with MS compared to those of controls (for GG genotype: 39.7% and 49.8%, respectively; P = 0.01; for G allele: 63.3% and 68.8%, respectively; P = 0.05). Both polymorphisms in ADIPOQ did not show any significant association with disease susceptibility, though after gender categorization the frequency of high adiponectin producer rs1501299TT genotype and rs1501299T allele were significantly higher in male controls compared to male patients (TT genotype: P = 0.006; T allele: P = 0.006). Additionally, rs1501299TT genotype in ADIPOQ was associated with susceptibility to primary progressive multiple sclerosis (PP-MS) (P = 0.02). Moreover, while the sera levels of leptin were only different between male patients and controls (P = 0.05), adiponectin levels were significantly higher in total and female healthy controls (P < 0.001, P = 0.002, respectively).

Conclusions: Our findings provide evidence to support the hypothesis that functional ADIPOQ and LEP gene polymorphisms are associated with susceptibility to MS and its clinical forms.
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http://dx.doi.org/10.1016/j.amjms.2018.03.008DOI Listing
August 2018

Determination of IL-23 receptor gene polymorphism in Iranian patients with ankylosing spondylitis.

Eur Cytokine Netw 2014 Mar;25(1):24-9

Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Introduction: The result of recent genome-wide association studies revealed that, in addition to HLA-B27, a few non-HLA genes are associated with susceptibility to ankylosing spondylitis (AS) in Caucasian populations. According to these studies, IL-23R is one of the genes that is associated with AS. In this study, we evaluated five important single nucleotide polymorphisms (SNPs) of the IL-23R gene which confers susceptibility to AS, and its effects on the severity of the disease in HLA-B27 positive and negative patients and several subtypes of HLA-B27.

Materials And Methods: The study population consisted of 294 AS patients and 352 age-, sex-, and ethnicity-matched healthy controls. All patients were examined by rheumatologists, and met modified, New York criteria for the disease. Five SNPs (rs1004819, rs11209032, rs1495965, rs11465804, and rs1004819) of the IL-23R gene were genotyped using the Real-Time PCR TaqMan genotyping method.

Results: We found that only rs1004819 has a significant association with AS, and that the remaining four SNP alleles are not associated with AS. Also, there was no association between these five polymorphisms and BASDAI, BASFI, and BASMI indices. Two haplotypes, ACGAT and ACGAG, were found to be associated with the heritability of AS. In addition, two significant, protective diplotypes (D8, GCGAG/GTGGG ; and D9, ACGAG/GCGAG) were discovered.

Conclusion: This study supported our previous findings regarding the differences between the genetic patterns of AS in Iranian patients compared with those in other parts of the world.
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http://dx.doi.org/10.1684/ecn.2014.0350DOI Listing
March 2014