Majid Ahmadi

Immunomodulatory characteristics of mesenchymal stem cells and their role in the treatment of Multiple Sclerosis

Multiple Sclerosis (MS) is a chronic inflammatory neurodegenerative disease of central nervous system (CNS). Although the main cause of MS is not clear, studies suggest that MS is an autoimmune disease which attacks myelin sheath of neurons. There are different therapeutic regimens for MS patients including interferon (IFN)-β, glatiramer acetate (GA), and natalizumab. However, such therapies are not quite effective and are associated with some side effects. So which, there is no complete therapeutic method for MS patients. Regarding the potent immunomodulatory effects of mesenchymal stem cells (MSCs) and their ameliorative effects in experimental autoimmune encephalopathy (EAE), it seems that MSCs may be a new therapeutic method in MS therapy. MSC transplantation is an approach to regulate the immune system in the region of CNS lesions. In this review, we have tried to discuss about the immunomodulatory properties of MSCs and their therapeutic mechanisms in MS patients.

Utilization of nanoparticle technology in rheumatoid arthritis treatment

Rheumatoid arthritis (RA) is one of the common and severe autoimmune diseases related to joints. This chronic autoimmune inflammatory disease, leads to functional limitation and reduced quality of life, since as there is bone and cartilage destruction, joint swelling and pain. Current advances and new treatment approaches have considerably postponed disease progression and improved the quality of life for many patients. In spite of major advances in therapeutic options, restrictions on the routes of administration and the necessity for frequent and long-term dosing often result in systemic adverse effects and patient non-compliance. Unlike usual drugs, nanoparticle systems are planned to deliver therapeutic agents especially to inflamed synovium, so avoiding systemic and unpleasant effects. The present review discusses about some of the most successful drugs in RA therapy and their side effects and also focuses on key design parameters of RA-targeted nanotechnology-based strategies for improving RA therapies.

Effects of HMGA2 siRNA and doxorubicin dual delivery by chitosan nanoparticles on cytotoxicity and gene expression of HT-29 colorectal cancer cell line.

Over‐expressions of HMGA2, vimentin and MMP‐9 and downregulation of E‐cadherin occur on colorectal cancer cells followed by a reduction in let‐7 as a regulatory factor. In this study, we first used carboxymethyl dextran (CMD)–chitosan nanoparticles (ChNPs) platform to encapsulate HMGA2 siRNA and doxorubicin (DOX), and then, we evaluated the efficacy of the simultaneous delivery of siRNA/drug on viability and gene expression of HT‐29 cell lines.

Epigenetic Modifications and Therapy in Multiple Sclerosis

Breakthroughs in genetic studies, like whole human genome sequencing and genome-wide association studies (GWAS), have richened our knowledge of etiopathology of autoimmune diseases (AID) through discovery of genetic patterns. Nonetheless, the precise etiology of autoimmune diseases remains largely unknown. The lack of complete concordance of autoimmune disease in identical twins suggests that non-genetic factors also play a major role in determining disease susceptibility. Although there is no certain definition, epigenetics has been known as heritable alterations in gene function without changes in the nucleotide sequence. DNA methylation, histone modifications, and microRNA-associated gene expression suppression are the central mechanisms for epigenetic regulations. Multiple sclerosis (MS) is a disorder of the central nervous system (CNS), characterized by both inflammatory and neurodegenerative features. Although studies on epigenetic alterations in MS only began in the past decade, a mounting number of surveys suggest that epigenetic changes may be involved in the initiation and development of MS, probably through bridging the effects of environmental risk factors to genetics. Arming with clear understanding of epigenetic dysregulations underpins development of epigenetic therapies. Identifying agents inhibiting the enzymes controlling epigenetic modifications, particularly DNA methyltransferases and histone deacetylases, will be promising therapeutic tool toward MS. In the article underway, it is aimed to go through the recent progresses, attempting to disclose how epigenetics associates with the pathogenesis of MS and how can be used as therapeutic approach.

Immune regulatory network in successful pregnancy and reproductive failures

Maternal immune system must tolerate semiallogenic fetus to establish and maintain a successful pregnancy. Despite the existence of several strategies of trophoblast to avoid recognition by maternal leukocytes, maternal immune system may react against paternal alloantigenes. Leukocytes are important components in decidua. Not only T helper (Th)1/Th2 balance, but also regulatory T (Treg) cells play an important role in pregnancy. Although the frequency of Tregs is elevated during normal pregnancies, their frequency and function are reduced in reproductive defects such as recurrent miscarriage and preeclampsia. Tregs are not the sole population of suppressive cells in the decidua. It has recently been shown that regulatory B10 (Breg) cells participate in pregnancy through secretion of IL-10 cytokine. Myeloid derived suppressor cells (MDSCs) are immature developing precursors of innate myeloid cells that are increased in pregnant women, implying their possible function in pregnancy. Natural killer T (NKT) cells are also detected in mouse and human decidua. They can also affect the fetomaternal tolerance. In this review, we will discuss on the role of different immune regulatory cells including Treg, γd T cell, Breg, MDSC, and NKT cells in pregnancy outcome.

Epigenetic modifications and epigenetic based medication implementations of autoimmune diseases

Recent genome-wide association studies have documented a number of genetic variants to explain mechanisms underlying autoimmune diseases. However, the precise etiology of autoimmune diseases remains largely unknown. Epigenetic mechanisms like alterations in the post-translational modification of histones and DNA methylation may potentially cause a breakdown of immune tolerance and the perpetuation of autoreactive responses. Recently, several studies both in experimental models and clinical settings proposed that the epigenome may hold the key to a better understanding of autoimmunity initiation and perpetuation. More specifically, data support the impact of epigenetic changes in autoimmune diseases, in some cases based on mechanistical observations. Epigenetic therapy already being employed in hematopoietic malignancies may also be associated with beneficial effects in autoimmune diseases. In this review, we will discuss on what we know and expect about the treatment of autoimmune disease based on epigenetic aberrations.

Nanocurcumin restores aberrant miRNA expression profile in multiple sclerosis, randomized, double-blind, placebo-controlled trial

In the current study, we aimed to identify nanocurcumin effects on microRNAs (miRNAs) in the peripheral blood of patients with relapsing‐remitting multiple sclerosis (RRMS). We intended to investigate the expression pattern of these miRNAs in experimental settings in vivo. The expression levels of the selected 27 miRNAs known to be involved in the regulation of immune responses were analyzed in 50 RRMS patients and 35 healthy controls. The miRNA expression profiles were investigated by quantitative PCR (qPCR) at baseline and after 6 months of nanocurcumin therapy. Our data revealed that the expression of a number of microRNAs including miR‐16, miR‐17‐92, miR‐27, miR‐29b, miR‐126, miR‐128, miR‐132, miR‐155, miR‐326, miR‐550, miR‐15a, miR‐19b, miR‐106b, miR‐320a, miR‐363, miR‐31, miR‐150, and miR‐340 is regulated by nanocurcumin. The results of the current work indicate that nanocurcumin is able to restore the expression pattern of dysregulated miRNAs in MS patients. We discovered that some miRNAs are deregulated in untreated patients compared with healthy controls and nanocurcumin‐treated patients. This is a new finding that might represent the potential contribution of these miRNAs to MS pathogenesis. Taken together, these data provide novel insights into miRNA‐dependent regulation of the function of B and T cells in MS disease and enrich our understanding of the effects mediated by a therapeutic approach that targets B and T cells.

Effect of Intravenous immunoglobulin on Th1 and Th2 lymphocytes and improvement of pregnancy outcome in recurrent pregnancy loss (RPL)

BACKGROUND Women with elevated natural killer (NK) cell frequency and function during pregnancy, suffer from recurrent pregnancy loss (RPL). In the present study, the possible effect of intravenous immunoglobulin (IVIG) administration on Th1 and Th2 cell frequency, cytokine secretion, and expression of transcription factors is compared between RPL patients and control group. MATERIALS AND METHODS Totally, 44 women with a history of RPL (32 women as treated group and 12 as control group) were enrolled in the study. The frequency of Th1 and Th2 lymphocytes, the expression of transcription factors related to these cells and the serum levels of associated cytokines were assessed by flowcytometry, real-time PCR and ELISA, respectively. All, assessments were performed both before and after treatment with IVIG. RESULTS A significant reduction in Th1 lymphocyte frequency, transcription factor expression and cytokine levels were observed in IVIG-treated group, while all the above parameters indicated a significant increase for Th2 lymphocytes. Th1/Th2 ratio decreased significantly (p value<0.0001) at the end of treatment and 28 out of 32 (87.5%) women in IVIG-treated group had live birth in comparison with 5 out of 12 (41.6%) in untreated group. CONCLUSION IVIG administration proves to be an efficient therapeutic strategy which is able to enhance the success rate of pregnancy through a shift in Th2 responses. Furthermore, IVIG presents efficacy for the treatment of reproduction failures especially in subjects with immune cell abnormalities and increased NK cell level and function.

Intravenous immunoglobulin (IVIG) treatment modulates peripheral blood Th17 and regulatory T cells in recurrent miscarriage patients: Non randomized, open-label clinical trial

BACKGROUND Th17 cells and Treg cells have been proposed as new risk factors for recurrent miscarriage (RM). In this study, we investigated the effect of Intravenous immunoglobulin G (IVIG) on the levels and function of Th17 and Treg cells and pregnancy outcome in women with RM. MATERIALS AND METHODS 94 pregnant women with RM were enrolled in this study. Blood was drawn at the time of positive pregnancy. On the same day, IVIG 400mg/kg was administered intravenously for 44 patients. 50 other RM patients were included as no IVIG interfering control group. Following the first administration, IVIG was given every 4 weeks through 32 weeks of gestation. Peripheral blood was drawn after the last administration (32 weeks after pregnancy). RESULTS IVIG down-regulated Th17 cells population and function and up-regulated Treg cells population and function were significant in the treated group. Pregnancy outcome in IVIG treated subjects was successful in 38 out of 44 RM women (86.3%). However, pregnancy outcome was successful in 21 out of 50 untreated RM women (42%). CONCLUSION Administration of IVIG in RM women with cellular immune cells abnormalities during pregnancy influences Th17/Treg ratio in peripheral blood and enhances Treg and decreases Th17 responses.

Antiproliferative and apoptotic effects of a specific anti-insulin-like growth factor I receptor single chain antibody on breast cancer cells

Insulin-like growth factor I receptor (IGF-IR) is expressed on breast cancer cells and involves in metastasis, survival, and proliferation. Currently, application of IGF-IR-targeting monoclonal antibodies (mAbs), alone or in combination with other drugs, is a promising strategy for breast cancer therapy. Single-chain fragment variable (scFv) antibodies have been introduced as appropriate tools for tumor-targeting purposes because of their advantages over whole antibodies. In the present study, we employed a naïve phage library and isolated scFvs against a specific epitope from extracellular domain of IGF-IR by panning process. The selected scFvs were further characterized using polyclonal and monoclonal phage ELISA, soluble monoclonal ELISA, and colony PCR and sequencing. Antiproliferative and apoptotic effects of selected scFv antibodies on breast cancer cell lines were also evaluated by MTT and Annexin V/PI assays. The results of ELISA indicated specific reactions of the isolated scFvs against the IGF-IR peptide, and analyses of PCR product and sequencing confirmed the presence of full length VH and Vκ inserts. Treatment of MCF7 and SKBR3 cells with anti-IGF-IR scFv led to a significant growth inhibition. The results also showed that scFv treatment significantly augmented trastuzumab growth inhibitory effects on SKBR3 cells. The percentage of the apoptotic MCF7 and SKBR3 cells after 24-h treatment with scFv was 39 and 30.70 %, respectively. Twenty-four-hour treatment with scFv in combination with trastuzumab resulted in 44.75 % apoptosis of SKBR3 cells. Taken together, our results demonstrate that the targeting of IGF-IR by scFv can be an effective strategy in the treatment of breast cancer and provide further evidence for effectiveness of dual targeting of HER2 and IGF-IR in breast cancer therapy.