Development of a highly effective combination monoclonal antibody therapy against Herpes simplex virus.

BACKGROUND: Infections with Herpes simplex virus (HSV)-1 or -2 usually present as mild chronic recurrent disease, however in rare cases can result in life-threatening conditions with a large spectrum of pathology. Monoclonal antibody therapy has great potential especially to treat infections with virus resistant to standard therapies. HDIT101, a humanized IgG targeting HSV-1/2 gB was previously investigated in phase 2 clinical trials. The aim of this study was to develop a next-generation therapy by combining different antiviral monoclonal antibodies. METHODS: A lymph-node derived phage display library (LYNDAL) was screened against recombinant gB from Herpes simplex virus (HSV) -1 and HDIT102 scFv was selected for its binding characteristics using bio-layer interferometry. HDIT102 was further developed as fully human IgG and tested alone or in combination with HDIT101, a clinically tested humanized anti-HSV IgG, in vitro and in vivo. T-cell stimulating activities by antigen-presenting cells treated with IgG-HSV immune complexes were analyzed using primary human cells. To determine the epitopes, the cryo-EM structures of HDIT101 or HDIT102 Fab bound to HSV-1F as well as HSV-2G gB protein were solved at resolutions < 3.5 Å. RESULTS: HDIT102 Fab showed strong binding to HSV-1F gB with Kd of 8.95 × 10-11 M and to HSV-2G gB with Kd of 3.29 × 10-11 M. Neutralization of cell-free virus and inhibition of cell-to-cell spread were comparable between HDIT101 and HDIT102. Both antibodies induced internalization of gB from the cell surface into acidic endosomes by binding distinct epitopes in domain I of gB and compete for binding. CryoEM analyses revealed the ability to form heterogenic immune complexes consisting of two HDIT102 and one HDIT101 Fab bound to one gB trimeric molecule. Both antibodies mediated antibody-dependent phagocytosis by antigen presenting cells which stimulated autologous T-cell activation. In vivo, the combination of HDIT101 and HDIT102 demonstrated synergistic effects on survival and clinical outcome in immunocompetent BALB/cOlaHsd mice. CONCLUSION: This biochemical and immunological study showcases the potential of an effective combination therapy with two monoclonal anti-gB IgGs for the treatment of HSV-1/2 induced disease conditions.

The roles of ERAP1 and ERAP2 in autoimmunity and cancer immunity: New insights and perspective.

Autoimmunity and cancer affect millions worldwide and both, in principal, result from dysregulated immune responses. There are many well-known molecules involved in immunological process playing as a double-edged sword, by which associating autoimmune diseases and cancer. In this regard, Endoplasmic reticulum aminopeptidases (ERAP) 1, which belongs to the M1 family of aminopeptidases, plays a central role as a "molecular ruler", proteolyzing of N-terminal of the antigenic peptides before their loading onto HLA-I molecules for antigen presentation in the Endoplasmic Reticulum (ER). Several genome-wide association studies (GWAS) highlighted the significance of ERAP1 and ERAP2 in autoimmune diseases, including Ankylosing spondylitis, Psoriasis, Bechet's disease, and Birdshot chorioretinopathy, as well as in cancers. The expression of ERAP1/2 is mostly altered in different cancers compared to normal cells, but how this affects anti-cancer immune responses and cancer growth has been little explored. Recent studies on the immunological outcomes and the catalytic functions of ERAP1 and ERAP2 have provided a better understanding of their potential pathogenetic role in autoimmunity and cancer. In this review, we summarize the role of ERAP1 and ERAP2 in the autoimmune diseases and cancer immunity based on the recent advances in GWAS studies.

Promoter region single nucleotide polymorphism of siglec-8 gene associates with susceptibility to allergic asthma.

Aim: Siglec-8 is exclusively expressed on mast cells, eosinophils and basophils. Possible association of six siglec-8 single nucleotide polymorphisms (SNPs) with susceptibility to allergic asthma in the Azeri population of Iran was investigated in this study. Materials & methods: A total of 194 patients and 190 normal subjects were enrolled. PCR single strand conformation polymorphism (PCR-SSCP) was used to determine the genotypes of the studied SNPs. Results: The rs36498 showed significant association with allergic asthma (odds ratio [OR]: 0.65; p = 0.022) and the T allele was found as a protective allele (OR: 0.61; p = 0.008). Also, eosinophil count in the CC genotype was significantly higher than that in the other genotypes (p = 0.026). Conclusion: The rs36498 is thought to influence the expression level of siglec-8. Siglec-8 could be a potential therapeutic target for allergic asthma.

Progression or suppression: Two sides of the innate lymphoid cells in cancer.

Innate lymphoid cells (ILCs) as key players in innate immunity have been shown to be significantly associated with inflammation, lymphoid neogenesis, tissue remodeling, mucosal immunity and lately have been considered a remarkable nominee for either tumor-promoting or tumor-inhibiting functions. This dual role of ILCs, which is driven by intrinsic and extrinsic factors like plasticity of ILCs and the tumor microenvironment, respectively, has aroused interest in ILCs subsets in past decade. So far, numerous studies in the cancer field have revealed ILCs to be key players in the initiation, progression and inhibition of tumors, therefore providing valuable insights into therapeutic approaches to utilize the immune system against cancer. Herein, the most recent achievements regarding ILCs subsets including new classifications, their transcription factors, markers, cytokine release and mechanisms that led to either progression or inhibition of many tumors have been evaluated. Additionally, the available data regarding ILCs in most prevalent cancers and new therapeutic approaches are summarized.

Isolation and characterization of human amniotic fluid and SH-SY5Y/ BE(2)-M17 cell derived exosomes.

The application of stem cells as a therapy for degenerative disease holds great promise. Substantial evidence suggests that stem cell derived exosomes are a novel cell-free therapy for the corresponding cells. Exosomes are less complex as compared to their parental cells, due to the fewer number of membrane proteins. In addition, the smaller size and lower risk of immunogenicity makes exosomes potentially safe therapeutic nano-carriers. A large number of ongoing research studies are focused on characterizing exosomes that were derived from different sources, for their potential use in various therapeutic applications. In the present study, we focused on characterizing human amniotic fluid stem cell derived exosomes for future therapeutic applications, such as paracrine therapy/nano carrier. In addition, we characterized exosomes derived from SH-SY5Y and BE(2)-M17 cells, which are a known neuronal model, for further characteristic analyses of neuronal differentiation and neurobiology. Finally, we compared various exosome isolation techniques and procedures and evaluated exosome yield.

The role of immune regulatory molecules in multiple sclerosis.

Multiple sclerosis (MS) is the most common demyelinating disease which mainly impacts the integrity of central nervous system (CNS). MS etiology is not clearly known but genetic, environmental factors and immune system are the most frequently explored risk factors. Adaptive immune responses have a critical role in MS pathogenesis in which auto-reactive T-cells and autoantibodies are main orchestrators. Immune responses are modulated by inhibitory molecules which regulates adaptive system activation and hemostasis interface. These molecules suppress immune responses through inhibition of cytokine secretion and T cell proliferation and subsequently reducing the inflammation and respective damage. Therefore the critical role of inhibitory molecules in regulating the healthy and safe immune responses make them very attractive target for immunotherapy. In this review paper, the role of inhibitory molecules expressed on the various immune cell types in MS pathogenesis and experimental autoimmune encephalomyelitis (EAE) animal model will be summarized.

The role of microRNAs in prostate cancer migration, invasion, and metastasis.

Prostate cancer (PCa) is considered the most prevalent malignancy and the second major cause of cancer-related death in males from Western countries. PCa exhibits variable clinical pictures, ranging from dormant to highly metastatic cancer. PCa suffers from poor prognosis and diagnosis markers, and novel biomarkers are required to define disease stages and to design appropriate therapeutic approach by considering the possible genomic and epigenomic differences. MicroRNAs (miRNAs) comprise a class of small noncoding RNAs, which have remarkable functions in cell formation, differentiation, and cancer development and contribute in these processes through controlling the expressions of protein-coding genes by repressing translation or breaking down the messenger RNA in a sequence-specific method. miRNAs in cancer are able to reflect informative data about the current status of disease and this might benefit PCa prognosis and diagnosis since that is concerned to PCa patients and we intend to highlight it in this paper.

ABO Blood Group and Prevalence of Osteoporosis and Osteopenia in the Elderly Population: An Amirkola Health and Ageing Project (AHAP)-Based Study.

Osteoporosis is known as a degenerative disease of the skeletal system and its main complication is fracture, which influences quality of life in the elderly. There are 4 major blood groups in humans based on the presence of A and B antigens. According to the investigations, there are reported relations between blood types and some diseases. In this study, the association between the ABO blood group and the prevalence of osteoporosis and osteopenia in an elderly population was investigated. Medical records of 990 elderly people were investigated in a cross-sectional study and the association between their blood group and the incidence of osteoporosis and osteopenia was analyzed using SPSS version 17.0 (SPSS Inc., Chicago, IL, USA). The results showed that ABO blood groups had no association with the prevalence of osteoporosis in both elderly men and women. The association between age and osteoporosis was significant and the association between this disorder and gender was significant too. The results also indicate that there is no association between RH+ and RH- blood types and osteoporosis and osteopenia in both men and women. Based on this finding, it would be reasonable to conduct extensive studies.

Migration of dendritic cells to the lymph nodes and its enhancement to drive anti-tumor responses.

Better prognoses associated with increased T cell infiltration of tumors, as seen with chimeric antigen receptor (CAR) T cell therapies and immune checkpoint inhibitors, portray the importance and potential of the immune system in controlling tumors. This has rejuvenated the field of cancer immunotherapy leading to an increasing number of immunotherapies developed for cancer patients. Dendritic Cells (DCs) vaccines represent an appealing option for cancer immunotherapy since DCs have the ability to circumvent tolerance to tumors by its adjuvant properties and to induce memory T cells that can become persistent after initial tumor clearance to engage potential metastatic tumors. In the past, DC-based cancer vaccines have elicited only poor clinical response in cancer patients, which can be attributed to complex and a multitude of issues associated with generation, implementing, delivery of DC vaccine and their potential interaction with effector cells. The current review mainly focuses on migration/trafficking of DCs, as one of the key issues that affect the success of DC-based cancer vaccines, and discusses strategies to enhance it for cancer immunotherapy. Additionally, impact of maturation, route of DC delivery and negative effects of tumor microenvironment (TME) on DC homing to LN are reviewed. Moreover, strategies to increase the expression of genes involved in Lymph node homing, preconditioning of the vaccination site, enhancing lymph node ability to attract and receive DCs, while limiting negative impact of TME on DC migration are discussed.

A molecular perspective on rituximab: A monoclonal antibody for B cell non Hodgkin lymphoma and other affections.

Rituximab (a chimeric anti-CD20 monoclonal antibody) is the first Food and Drug Administration approved anti-tumor antibody. Immunotherapy by rituximab, especially in combination-therapy, is a mainstay for a vast variety of B-cell malignancies therapy. Its therapeutic value is unquestionable, yet the mechanisms of action responsible for anti-tumor activity of rituximab and rituximab resistance mechanisms are not completely understood. Investigation of the mechanisms of action that contribute to the rituximab activity have eventually directed to a suite of novel combinations and novel treatment schedules, and also have resulted new generations of antibodies with more desired effects. Although, further investigations are needed to define the mechanisms of rituximab resistance and prominent effector activity of the altered next generation anti-CD20 to improve their efficacies and develop new anti-CD20 monoclonal antibodies in NHL treatment. This article focuses on the properties of CD20 which led scientists to select it as an effective therapeutic target and the molecular details of mechanisms of rituximab action and resistance. We also discuss about the impact of rituximab in monotherapy and in combination with chemotherapy regimens. Finally, we comparatively summarize the next generations of anti CD20 monoclonal antibodies to highlight their advantages relative to their ancestor: Rituximab.

Interleukin-13 as an important cytokine: A review on its roles in some human diseases.

Interleukin-13 (IL-13) as a pleiotropic cytokine acts through the IL-13Ra1/IL-4Ra complex to induce activation responses which contribute to the inflammatory diseases. Genetic polymorphisms in IL-13 and its receptor components have been proved to be associated with higher disease prevalence rates. Animal models such as in IL-13 deficient mice and transgenic animals also have been confirmed the critical role of this cytokine in the immune responses, mostly by IL-13 neutralization and IL-13/IL-4 dual neutralization strategies. This review highlights IL-13 structure as well as its pivotal roles in the normal physiologic and pathologic states. It is followed by a section on the recent findings on IL-13 receptors and signalling mechanisms to briefly summarize its functions in the immune systems. IL-13 roles in the human diseases such as asthma, systematic sclerosis, and some inflammatory diseases are described concisely. Finally some of the ongoing therapeutic applications are presented to comprehensively review IL-13 mediator roles.

Investigation of IL-21 gene polymorphisms (rs2221903, rs2055979) in cases with multiple sclerosis of Azerbaijan, Northwest Iran.

BACKGROUND: Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the Central Nervous System that is immunologically mediated in genetically susceptible individuals. IL-21, a cytokine produced by TCD4(+) cells, particularly by Th-17 cells, is believed to play an important role in the MS pathogenesis. OBJECTIVE: This study was performed to investigate the impact of genetic polymorphisms in IL-21 gene on MS susceptibility and clinical profiles. METHODS: Seventy Iranian patients with clinically definite relapsing-remitting MS and 110 age, sex and ethic matched controls were genotyped for IL-21 gene polymorphisms using PCR-RFLP method. RESULTS: Our results showed that the IL-21 rs2221903 SNP is not polymorphic in our population. Also, the allelic and genotypic frequencies of the IL-21 rs2055979 did not differ significantly between the MS patients and controls (P = 0.413 and P = 0.565 respectively, and OR = 1.122, 95% CI = 0.79-1.87 for T allele). However, our results showed that IL-21 rs2055979 (G/T) T allele positive (TT+GT) MS patients had lower (PI ≤ 1.5) disease progression compared to rs2055979 T allele negative (GG) patients (P = 0.009). CONCLUSION: Our results showed that no outstanding association exists between IL-21 alleles and susceptibility to MS. However, our clinical analysis showed significant association of IL-21 gene polymorphism with the progression of multiple sclerosis disease. Our results indicate that the G allele promotes, or the T allele protects against disease progression. To clarify the role of IL-21 rs2055979 in MS pathogenesis, further comprehensive studies with larger sample sizes among different ethnicity populations are recommended.

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)-ß, 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.

Is there association between ABO blood group and the risk factors of unfavorable outcomes of pregnancy?

There are four major blood groups in human based on the presence of A and B antigens. ABO gene encodes A and B antigens on the surface of red blood cells and there are reported relations between this blood phenotype and pregnancy outcomes in the women. In this study, medical records of 792 healthy pregnant women were investigated and their age and blood test results including blood group with fasting blood sugar, hemoglobin, hematocrit, urea, creatinine and red blood cell counts were analyzed in statistical package for the social sciences. The RBC count in AB blood type was significantly higher than A and O blood group, also FBS level in the people with AB blood group was meaningfully higher than A group. But the mean of HGB and HCT were not significantly different between groups. The serum urea in the AB group was higher than the three other groups and also it was significantly higher in B compared to O and A blood groups. The serum creatinine in the AB group was higher than the three other groups too. Also it was significantly higher in the B group compared to A blood groups. These results indicate that the ABO blood group may have association with some of the risk factors of the unfavorable outcomes of pregnancy and it may be one of the prognostic tools, also it addresses more extensive studies.

Molecular analysis of interleukin-25 exons 1 and 2 and its serum levels in Iranian patients with multiple sclerosis.

Overexpression of Interleukin-17 (IL-17) family has been shown in a variety of autoimmune diseases. IL-25 (IL-17E), as a member of this family of cytokines, induces the overexpression of IL-13 and impedes Th17/IL-17 responses. In the present study potential single nucleotide polymorphisms (SNP) of IL-25, its serum level in Multiple Sclerosis (MS) patients have been surveyed. Blood samples were obtained from 100 Relapsing-Remitting MS cases, and 100 healthy controls. Serum levels of IL-25 were measured by ELISA. IL-25 exons 1 and 2 were sequenced. IL-25 serum levels investigation showed significant association in cases compared to controls. Molecular analysis of IL-25exons 1 and 2 depicted significant differences in polymorphisms of exon 2 between two groups of study. However, no significant differences were found in polymorphisms for IL-25 exon. These results demonstrate that serum levels of IL-25 are reduced in MS patients compared to controls. This is the first study in Iran that shows polymorphisms in IL-25 among MS patients. Considering the role of IL-25 in suppression of the effects of IL-17A and active phase of Experimental Autoimmune Encephalomyelitis (EAE) in vivo, this cytokine seems to have therapeutic potentials for autoimmune diseases like MS.

Association of IL-13 single nucleotide polymorphisms in Iranian patients to multiple sclerosis.

MS is an autoimmune disease and interleukin 13 (IL-13) has been proposed to be an important neuroprotective mediator in MS. Because of plausible effect of single nucleotide polymorphisms (SNPs) in expression level or biological activity of any cytokine, we sought to investigate association of IL-13 SNPs, C-1112T, A-1512C and G+2044A, with risk to MS. Sixty-eight RRMS patients and 110 healthy controls were involved in this study. After extraction of genomic DNA, frequency of genotypes and alleles were determined by PCR-RFLP and data were analyzed statistically. Results showed significant higher frequency of CC, CC, and AA genotypes and C, C, and A alleles of -1112CT, -1512AC and +2044GA SNPs respectively, in patients group. There was significant association between -1112C allele with onset age of MS. No significant association was seen between any of genotypes or alleles with expanded disability status scale (EDSS) of patients. Our findings showed significant association between three studied SNPs of IL-13 with susceptibility to MS in Iranian patients. More studies should be done on other IL-13 SNPs, and also polymorphisms of IL-13 receptor and other cytokines to determine the exact role of SNPs in protecting or predisposing of individuals for MS.