Functional Characteristics and Application of Mesenchymal Stem Cells in Systemic Lupus Erythematosus
Wen‑Yan Tang · Jia‑Hua Liu · Chun‑Jin Peng · Yao Liao · Jie‑Si Luo · Xi Sun · Yan‑Lai Tang · Xue‑Qun Luo
Abstract
Systemic lupus erythematosus (SLE) is a rare, heterogeneous autoimmune and autoinflammatory disease that affects both exes and all races, although this disease exhibits its highest incidence/prevalence among the black population and shows a predilection for women of reproductive age. Although SLE has no cure, treatment can help decrease its signs and symptoms. Thus, we should focus primarily on personalized treatment. Mesenchymal stem/stromal cells (MSCs), which are multipo-tent cells capable of differentiating into osteoblasts, chondrocytes, adipocytes, and myoblasts, among other cell types, are potential candidates for use in a promising strategy to treat severe and refractory SLE. MSCs have an immunomodulatory function that can suppress the proliferation and activities of many immune cells, such as T lymphocytes, B lymphocytes, natural killer cells, macrophages and dendritic cells. Substantial progress has recently been made in MSC therapy, and experimental and clinical data suggest that such a therapy is a promising strategy for the treatment of severe and refractory SLE. In this review, we highlight the effects of MSCs on different immune cell types, describe the mechanisms underlying MSC-mediated immunoregulation, and discuss the treatment of SLE with MSCs from different sources in various animal models and clinical applications.
Keywords Mesenchymal stem cells · Systemic lupus erythematosus · Transplantation · Application
Cancer Immunoprevention: Current Status and Future Directions
Mahsa Keshavarz‑Fathi · Nima Rezaei
Abstract
Cancer is one of the most serious diseases affecting health and the second leading cause of death worldwide. Despite the development of various therapeutic modalities to deal with cancer, limited improvement in overall survival of patients has been yielded. Since there is no certain cure for cancer, detection of premalignant lesions, and prevention of their progression are vital to the decline of high morbidity and mortality of cancer. Among approaches to cancer prevention, immunopreven- tion has gained further attention in recent years. Deep understanding of the tumor/immune system interplay and successful prevention of virally-induced malignancies by vaccines have paved the way toward broadening cancer immunoprevention application. The identification of tumor antigens in premalignant lesions was the turning point in cancer immunopreven-tion that led to designing preventive vaccines for various malignancies including multiple myeloma, colorectal, and breast cancer. In addition to vaccines, immune checkpoint inhibitors are also being tested for the prevention of oral squamous cell carcinoma (SCC), and imiquimod which is an established drug for the prevention of skin SCC, is a non-specific immu- nomodulator. Herein, to provide a bench-to-bedside understanding of cancer immunoprevention, we will review the role of the immune system in suppression and promotion of tumors, immunoprevention of virally-induced cancers, identification of tumor antigens in premalignant lesions, and clinical advances of cancer immunoprevention.
Keywords Precancerous lesion · Precursor · Prevention · Tumor antigen · Immunosurveillance · Preventive vaccine · Prophylactic vaccine · Immune checkpoint blockade · Biomarker · Oral proliferative verrucous leukoplakia · Actinic keratosis · Colon polyp · Smoldering myeloma · Ductal carcinoma in situ of the breast
Leukemia Inhibitory Factor: A Potential Biomarker and Therapeutic Target in Pancreatic Cancer
Ewa Wrona · Piotr Potemski · Francesco Sclafani · Maciej Borowiec
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive, treatment-resistant cancer. Five-year survival rate is about 9%, one of the lowest among all solid tumors. Such a poor outcome is partly due to the limited knowledge of tumor biology, and the resulting lack of effective treatment options and robust predictive biomarkers. The leukemia inhibitory factor (LIF) has recently emerged as a potential biomarker and therapeutic target for PDAC. Accumulating evidence has suggested that LIF plays a role in supporting cancer evolution as a regulator of cell differentiation, renewal and survival. Interestingly, it can be detected in the serum of PDAC patients at higher concentrations than healthy individuals, this supporting its potential value as diagnostic biomarker. Furthermore, preliminary data indicate that testing for LIF serum concentration or tissue expression may help with treatment response monitoring and prognostication. Finally, studies in PDAC mouse models have also shown that LIF may be a valuable therapeutic target, and first-in-human clinical trial is currently ongoing. This article aims to review the available data on the role of LIF in PDAC promotion, and to discuss the evidence supporting its potential role as a biomarker and target of effective anti-cancer therapy in this setting.
Keywords Pancreatic ductal adenocarcinoma · Leukemia inhibitory factor · Biomarker · Therapeutic target
The Potential of Developing Pan‑Coronaviral Antibodies to Spike Peptides in Convalescent COVID‑19 Patients
Andrii Rabets · Galyna Bila · Roman Grytsko · Markian Samborskyy · Yuriy Rebets · Sandor G. Vari · Quentin Pagneux · Alexandre Barras · Rabah Boukherroub · Sabine Szunerits · Rostyslav Bilyy
Abstract
Coronaviruses share conservative spike protein (S) on their enveloped membrane surface, where S1 subunit recognizes and binds the cellular receptor, and the S2 subunit mediates membrane fusion. This similarity raises the question: does coronaviral infection by one create protection to others? Convalescent SARS-CoV-2 (COVID-19) sera were tested for cross reactivity with peptides from Middle East respiratory syndrome coronavirus (MERS-CoV) which shares 74% homology. Our results showed significant cross-reactivity with a peptide of the heptad repeat 2 (HR2) domain of the MERS-CoV spike protein. Sera samples of 47 validated seropositive convalescent COVID-19 patients and 40 sera samples of control patients, collected in pre-COVID time were used to establish cross-bind reactivity with the MERS-CoV peptide. Significantly stronger binding (p < 0.0001) was observed for IgG antibodies in convalescent COVID-19 patients compared to the control group. In ELISA, MERS-CoV peptide helps to discriminate post-COVID-19 populations and non-infected ones by the presence of antibodies in blood samples. This suggests that polyclonal antibodies established during SARS-CoV-2 infection can recognize and probably decrease severity of MERS-CoV and other coronaviral infections. The high homology of the spike protein domain also suggests that the opposite effect can be true: coronaviral infections produce cross-reactive antibodies effective against SARS-CoV-2. The collected data prove that despite the core HR2 region is hidden in the native viral conformation, its expo-sure during cell entry makes it highly immunogenic. Since inhibitory peptides to this region were previously described, this opens new possibilities in fighting coronaviral infections and developing vaccines effective even after possible viral mutations.
Keywords SARS-CoV-2 · COVID-9 · Coronavirus · Antibodies · Immunoglobulins
γδ T Lymphocytes in Asthma: a Complicated Picture
Michał K. Zarobkiewicz · Ewelina Wawryk‑Gawda · Wioleta Kowalska · Mariola Janiszewska · Agnieszka Bojarska‑Junak
Abstract
A minor subset (approximately 5%) of peripheral T cells has their TCR build up from γ and δ chains instead of α and β—those are the γδ T lymphocytes. They can be functionally divided into subsets, e.g., Th1-, Th2-, Th9-, Th17-, Tfh-, and Treg-like γδ T cells. They share some specifics of both innate and adaptive immunity, and are capable of rapid response to a range of stimuli, including some viral and bacterial infections. Atopic diseases, including asthma, are one of major health-related problems of modern western societies. Asthma is one of the most common airway diseases, affecting people of all ages and having potential life-threatening consequences. In this paper, we review the current knowledge about the involvement of γδ T cells in the pathogenesis of asthma and its exacerbations. We summarize both the studies performed on human subjects as well as on the murine model of asthma. γδ T cells seem to be involved in the pathogenesis of asthma, different subsets prob- ably perform opposite functions, e.g., symptom-exacerbating Vγ1 and symptom-suppressing Vγ4 in mice model of asthma.
Keywords γδ T lymphocytes · Asthma · γδ T subsets
Recent Advances in the Use of Lipid‑Based Nanoparticles Against Glioblastoma Multiforme
Benita Ortega‑Berlanga · Carmen Gonzalez · Gabriela Navarro‑Tovar
Abstract
Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults. Although the overall incidence is less than 10 per 100,000 individuals, its poor prognosis and low survival rate make GBM a crucial public health issue. The main challenges for GBM treatment are related to tumor location and its complex and heterogeneous biology. In this sense, a broad range of nanoparticles with different sizes, architectures, and surface properties, have been engineered as brain drug delivery systems. Among them, lipid-based nanoparticles, such as liposomes, have been pointed out as promising materials to deliver antitumoral drugs to the central nervous system and thus, to improve brain drug targeting and therapeutic efficiency. Here, we describe the synthesis and general characteristics of lipid-based nanoparticles, as well as evidence in the past 5 years regarding their potential use to treat GBM.
Keywords Glioblastoma · Liposomes · Lipid-based nanoparticles · Solid lipid nanoparticles · Blood–brain barrier
Selected Clinical Features Fail to Predict Inflammatory Gene Expressions for TNF‑α, TNFR1, NSMAF, Casp3 and IL‑8 in Tendons of Patients with Rotator Cuff Tendinopathy
Slawomir Struzik · Bozena Czarkowska‑Paczek · Aleksandra Wyczalkowska‑Tomasik · Paweł Maldyk · Leszek Paczek
Abstract
The pathophysiology of rotator cuff tendinopathy is not fully understood, particularly in terms of the local inflammatory process. This study aimed to investigate the expression of selected molecules in the tumour necrosis factor (TNF)-α transduction pathway, including TNF-α, TNF receptor 1 (TNFR1), neutral sphingomyelinase activation associated factor (NSMAF), caspase 3 (Casp3), and interleukin (IL)-8, in patients with rotator cuff tendinopathy that had undergone surgical treatment. We included 44 participants that underwent arthroscopy, due to rotator cuff tendinopathy. Samples from the injured tendon were collected during arthroscopy, and RT-PCR was performed to determine gene expression. Pearson correlation analyses or U-Mann–Whitney test were performed to identify associations with the following parameters: sex, age at admission, body mass index, the presence of night pain, previous treatment (nonsteroidal anti-inflammatory drugs and/or steroids), medical history of the shoulder injury, upper subluxation of the humeral head, and the number of tendons injured. RT-PCR showed that the selected pro-inflammatory factors involved in the TNF-α signalling pathway expression levels were expressed in the tendon tissues. However, the levels of expression varied from patient to patient. Variations were over 250-fold for TNF- α, about 130-fold for TNFR1, NSMAF, and Casp3, and 1000-fold for IL-8. We could not confirm that any of the clinical parameters investigated were associated with the level of gene expression in the TNF-α pathway and IL-8.
Keywords Rotator cuff tendinopathy · Cytokines · TNF pathway · Interleukin 8 · Caspase-3
Visfatin Regulates Inflammatory Mediators in Mouse Intestinal Mucosa Through Toll‑Like Receptors Signaling Under Lipopolysaccharide Stress
Xin Xin Pang · Abdur Rahman Ansari · Wen Jie Yang · Xiao Yu Niu · Ling Dong · Hui Zhen Li · Fen Liang Xu · Zhe Wei Zhang · Ke Xiao · Song Hui
Abstract
Visfatin is a multifunctional protein involved in inflammatory immune stress. The aim of current study was to explore the role of visfatin in lipopolysaccharide (LPS)-induced intestinal mucosal inflammation and to confirm its cellular effect in inflammatory immune response through silencing of Toll-like receptors (TLRs). We divided Kunming mice into three groups: Saline group, LPS group, and LPS + visfatin group and performed hematoxylin and eosin staining, immunohistochemistry, quantitative polymerase chain reaction, Western blot, enzyme linked immunosorbent assay and RNA-seq analysis. Pretreat- ment of visfatin improves LPS-stimulated reduction of tight junction protein 1 (ZO-1) and secretory immunoglobulin A, inhibits overexpression of Claudin-1 and vascular endothelial growth factor, and reduces intestinal mucosal damage and inflammation. RNA-seq analysis of cellular transcriptomes indicated that visfatin is involved in down-regulation of mRNA level of TLR4 as well as attenuation of protein levels of TLR8 and nucleotide-binding oligomerization domain-containing protein 2, revealing that visfatin could reduce intestinal mucosal inflammation through TLR signaling pathway in mice ileum. In RAW264.7 cells, the genes silencing of Toll/IL-1R family, such as TLR4, TLR2, and IL-1R1, was accompanied by decreased expressions of inflammatory factors (TNF-α, IL-1β, IL-6 and MCP-1) along with lower cellular visfatin levels. Hence, visfatin maintains the intestinal mucosal barrier structure and attenuates the intestinal mucosal inflammation through the TLR signaling pathway. Likewise, the Toll/IL-1R family regulates the release of visfatin, which can participate in the inflammatory reaction through the regulation of inflammatory factors.
Keywords Visfatin · Intestinal mucosa · Lipopolysaccharide · TLR · RAW264.7 cells
5_2021_Article_611
5_2021_611_MOESM1_ESM
5_2021_611_MOESM2_ESM
Placebo Controls: Now???
Arnold I. Caplan
New Approaches to the Prevention and Treatment of Viral Diseases
Alexander V. Pronin · Alexander N. Narovlyansky · Alexander V. Sanin
Abstract
The review discusses a new approach to the prevention and treatment of viral infections based on the use of pine needles polyprenyl phosphate (PPP) and associated with the infringement of prenylation process—the attachment of farnesol or geranyl geraniol to the viral protein. Currently, prenylation has been detected in type 1 adenovirus, hepatitis C virus, several herpes viruses, influenza virus, HIV. However, this list is far from complete, given that prenylated proteins play an extremely important role in the activity of the virus. We assume that the interferon produced in response to PPP may suppress expression of the SREBP2 transcription factor. As a result, the mevalonic acid pathway is violated and, as a result, the formation of early polyprenols precursors (geraniol, geranyl geraniol, farnesol), which are necessary for the prenylation of viral proteins, is blocked and the formation of mature, virulent virus particles is broken. As a consequence, the maturation of viral particles is inhibited, and defective particles are formed. Polyprenol was extracted from greenery (pine, fir and spruce needles, mulberry leaves, etc.), purified by chromatography, phosphorylated and identified by HPLC and NMR. Obtained PPP was used as antiviral in some experimental models in vitro and in vivo. During numerous studies, it was found that PPP manifested versatile antiviral effects, both in vitro and in vivo. The maximum effect was observed with viruses in which the presence of prenylated proteins was established, namely influenza A virus, HIV-1, tick-borne encephalitis virus, hepatitis A and C viruses, herpes simplex viruses type 1 and 2, some coronavirus. The available data obtained both in the experimental conditions and during clinical trials allow us to regard PPPs as safe and effective medicine for prevention and treatment of viral diseases.
Keywords Plant polyprenols · Prenylation · Viral infection · Interferons · SREBP2 · Coronavirus
Donor Recipient Chimeric Cells Induce Chimerism and Extend Survival of Vascularized Composite Allografts
Joanna Cwykiel · Arkadiusz Jundzill · Aleksandra Klimczak · Maria Madajka‑Niemeyer · Maria Siemionow
Abstract
This study evaluated the efficacy of donor recipient chimeric cell (DRCC) therapy created by fusion of donor and recipient derived bone marrow cells (BMC) in chimerism and tolerance induction in a rat vascularized composite allograft (VCA) model. Twenty-four VCA (groin flaps) from MHC-mismatched ACI (RT1a) donors were transplanted to Lewis (RT1l) recipi- ents. Rats were randomly divided into (n = 6/group): Group 1—untreated controls, Groups 2—7-day immunosuppression controls, Group 3—DRCC, and Group 4—DRCC with 7-day anti-αβTCR monoclonal antibody and cyclosporine A protocol. DRCC created by polyethylene glycol-mediated fusion of ACI and Lewis BMC were cultured and transplanted (2–4 × 106) to VCA recipients via intraosseous delivery route. Flow cytometry assessed peripheral blood chimerism while fluorescent microscopy and PCR tested the presence of DRCC in the recipient’s blood, bone marrow (BM), and lymphoid organs at the study endpoint (VCA rejection). No complications were observed after DRCC intraosseous delivery. Group 4 presented the longest average VCA survival (79.3 ± 30.9 days) followed by Group 2 (53.3 ± 13.6 days), Group 3 (18 ± 7.5 days), and Group 1 (8.5 ± 1 days). The highest chimerism level was detected in Group 4 (57.9 ± 6.2%) at day 7 post-transplant. The chimerism declined at day 21 post-transplant and remained at 10% level during the entire follow-up period. Single dose of DRCC therapy induced long-term multilineage chimerism and extended VCA survival. DRCC introduces a novel concept of customized donor-recipient cell-based therapy supporting solid organ and VCA transplants.
Keywords Donor recipient chimeric cells · Vascularized composite allotransplantation · Cell fusion · Groin flap
Neoantigen Cancer Vaccines: Real Opportunity or Another Illusion?
Karen Manoutcharian1 · Jesus Guzman Valle1 · Goar Gevorkian1
Abstract
In this communication, we will analyze some important factors and immunological phenomena related to neoantigen cancer vaccines, with particular emphasis on recently published Phase I clinical trials. Several obstacles and issues are addressed that challenge the current paradigm and inquire if neoantigens, which are essentially single-use vaccine candidates, are legitimate targets to induce protective immune responses with regard to the evolving mutational landscape. We also share insights into the striking similarities between cancer and antigenically variable pathogens and suggest that any successful vaccine against either should demonstrate a similar property: efficient induction of a diverse pool of immune cells equipped to prevent immune escape. Hence, to confront antigenic variability directly, we have employed our innovative vaccine concept, Variable Epitope Libraries, composed of large combinatorial libraries of heavily mutated epitopes, as a “universal” vaccine platform. Collectively, we offer critical analyses on key issues, which ultimately reflect on the prospective clinical relevance of personalized neoantigen vaccines which is still undefined.
Keywords Neoantigen cancer vaccine · Variable epitope library · Immune escape
Gut Microbiota Diversity in HIV‑Infected Patients on Successful Antiretroviral Treatment is Linked to Sexual Preferences but not CD4 Nadir
Elżbieta Jabłonowska · Joanna Strzelczyk · Anna Piekarska · Kamila Wójcik‑Cichy
Abstract
The effects of HIV infection and antiretroviral therapy (ART) on the gut microbiome are poorly understood and the literature data are inconsistent. The aim of this study was to assess the alpha and beta diversity of the fecal microbiota in HIV-infected patients on successful antiretroviral therapy with regard to sexual preferences and CD4 nadir. Thirty-six HIV-infected ART- treated patients with HIV viremia below 20 copies/ml and CD4 > 500 cells/μl were divided into two subgroups based on CD4 nadir. The composition of the intestinal microbiota was assessed by 16SrRNA sequencing (MiSeq Illumina). The alpha and beta diversity were analyzed according to CD4 nadir count and sexual preference. Several alpha diversity indexes were significantly higher in the MSM group than in heterosexual patients. The alpha diversity did not differ significantly between patients with CD4 nadir > 500 cells/μl and CD4 nadir < 200 cells/μl. Beta diversity was also associated with sexual prefer- ence. A significant difference in Weighted Unifrac was observed between all MSM and all non-MSM participants (p = 0.001). The MSM group was more diverse and demonstrated greater distances in Weighted Unifrac than the non-MSM group. The relative abundance of the Prevotella enterotype was higher in the MSM than the non-MSM group. Sexual preferences demonstrated a stronger influence on alpha and beta diversity in HIV-infected patients following successful antiretroviral treatment than HIV infection itself. The observed lack of association between CD4 nadir and alpha and beta diversity may be caused by the restoration of the faecal microbiota following antiretroviral treatment.
Keywords Gut microbiota · HIV · CD4 nadir · MSM
Osteopontin and Transplantation: Where Are We Now?
Beata Kaleta
Abstract
Organ transplantation represents the optimal therapeutic tool for patients with end-stage organ failure. Hematopoietic stem cell transplantation (HSCT) is likewise an effective therapy for a wide range of malignant and non-malignant diseases. Better understanding of transplantation immunology and the use of multi-modal immunosuppression protocols, can decrease the risk of graft failure and graft-versus-host disease (GVHD) after HSCT. Nevertheless, a major challenge of modern trans-plantology still seems to be finding non-invasive biomarkers for recipients selection, monitoring of allograft function, and
diagnosis of rejection. Since proinflammatory cytokine osteopontin (OPN) is closely involved in regulating both adaptive and innate immune responses, as well as the pathogenesis of inflammatory and autoimmune diseases, it is likely to play an important role in organ and HSC transplantation. This review is to summarize recent advances in our knowledge about
OPN function in the kidney, heart, liver, lung, and HSC transplantation. Most studies found that elevated OPN is associated with poorer graft function in kidney, heart, liver and lung recipients. Moreover, some reports suggested that this protein can play role in GVHD pathogenesis. However, due to relatively small number of similar studies, as well as some inconclusive results, future investigation in this field is needed to verify if OPN can serve as a biomarker of organ and HSC transplanta- tion. The knowledge about such markers will promote our understanding of the mechanisms underlying graft dysfunction and posttransplant mortality. In addition, such knowledge may be helpful in the development of new treatment strategies and identification of recipients with increased risk of allograft failure.
Keywords Immunomodulation · Osteopontin · Rejection · Transplantation
CTLA‑4 Expression and Its Clinical Significance in Breast Cancer
Rodrigo Kern · Carolina Panis
Abstract
Breast cancer is the leading cause of women’s death among all cancers. The main reason associated with this is the development of metastasis and therapy-resistant breast carcinoma (BC), which pose the main challenge of oncology nowadays. Evidence suggest that these tumors seem to have inhibitory mechanisms that may favor their progression and surveillance. Cancer cells can evade antitumor T cell responses by expressing some immune inhibitory molecules such as the cytotoxic T-lymphocyte antigen-4 (CTLA-4), whose clinical meaning has emerged in the last few years and is poorly understood in the BC context. This systematic literature review aims at identifying studies on CTLA-4 expression in BC, and address what is known about its clinical meaning. A literature search was performed in PubMed and LILACS databases, using the MESH terms “breast cancer”; “CTLA-4 Antigen/antagonists and inhibitors”; and “Lymphocytes, Tumor-Infiltrating/immunology”, published in the last 10 years. In total, 12 studies were included in this review. Systematic review used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Despite the small number of eligible studies, the literature reports some associations between CTLA-4 expression in the tumor microenvironment and worse BC outcomes, regardless of its molecular subtype. CTLA-4 expression in BC is a putative marker of clinical significance and a rationale therapeutic target in the emerging field of immunotherapy.
Keywords Breast neoplasms · CTLA-4 antigen/antagonists and inhibitors · Lymphocytes · Tumor-infiltrating/immunology · Ipilimumab · Immunohistochemistry · Flow cytometry
Post Transplantation Cyclophosphamide Improves Outcome of Autologous Hematopoietic Stem Cell Transplantation in Animal Model of Multiple Sclerosis
Kaja Kasarełło · Emilian Snarski · Dorota Sulejczak · Tomasz Ciesielski · Agnieszka Wiśniewska · Robert Wrzesień · Agnieszka Cudnoch‑Jędrzejewska
Abstract
Experimental allergic encephalomyelitis (EAE) is the animal model of multiple sclerosis (MS). Autologous hematopoietic stem cell transplantation (AHSCT) has recently been recognized as the standard treatment for MS. The aim of our experiment was to investigate the effect of AHSCT with the addition of low-dose post-transplantation cyclophosphamide (Cy) on EAE in rats. Low dose post-transplantation Cy is used in haploidentical HSCT to reduce the risk of graft versus host disease. We hypothesized that it could bring additional benefit in autologous HSCT in autoimmune diseases. Rats with evoked EAE were treated with high dose (125 mg/kg) Cy, followed by AHSCT or high dose (125 mg/kg) Cy followed by AHSCT followed by low dose (20 mg/kg) Cy in two-time schedules—with the therapy applied during the pre-symptomatic or symptomatic phase of the disease. Both AHSCT and AHSCT with post-transplantation Cy in accordance with both time schedules reduce the intensity of the inflammatory response in the CNS, in comparison with non-treated EAE rats. The reduction of clinical symptoms was present in all AHSCT treatment protocols, however, it was significantly stronger when post-transplantation Cy was given during the symptomatic phase of the disease. AHSCT with the addition of post HSCT low dose Cy improved the results of AHSCT by not only reducing the intensity of inflammation in the CNS but also by significantly reducing the clinical symptoms in treated animals when compared to AHSCT alone. We provide an experimental rationale that the addition of post-transplantation Cy may improve the outcome of HSCT in MS.
Keywords Experimental allergic encephalomyelitis · Multiple sclerosis · Hematopoietic stem cell transplantation · Post-transplantation cyclophosphamide
Changes in γδT Cells in Peripheral Blood of Patients with Ulcerative Colitis Exacerbations
Andrzej Gryglewski · Piotr Richter · Marian Szczepanik
Abstract
The role of γδT cells in ulcerative colitis (UC) is well confirmed in experimental animals and demonstrated in many clinical observations. Recent investigations have indicated that UC is associated with several forms of immune imbalance, such as an imbalance between effector T cells and regulatory T cells. However, little is known about the cellular aspect of clinical colitis exacerbations. We observed 140 patients with histologically confirmed UC over the course of 8 years. We investigated the percentage of γδT and αβT cells in peripheral blood of patients and also the expression of various surface markers (CD25, CD54, CD62L). Patients were assembled into stable colitis and exacerbated colitis groups. The percentage of γδT and αβT cells was evaluated by Ortho Cytorone Absolute flow cytometer. In patients with exacerbated colitis we observed a decrease of γδT cells in peripheral blood and an increased ratio of αβT/γδT. Additionally, we found that exacerbation results in a significant increase of percentage of γδTCD25, γδTCD54 and γδTCD62L lymphocytes in peripheral blood when compared to patients with stable colitis. Exacerbation of ulcerative colitis results in a decreased percentage of γδT cells in peripheral blood with increase of CD25, CD54 and CD62L expressing γδT cells. This may represent the effect of cell activation and migration, similar to that observed after the surgical trauma. We hope that this observation may help to predict exacerbations in colitis patients.
Keywords Immunosuppression · Ulcerative colitis · Colitis exacerbations · γδT lymphocytes · αβT lymphocytes
Journal Impact Factor and Self‑Citations
Andrzej Górski · Michał Zimecki · Hubert Krotkiewski
Should Nano‑Particles be Weighed or Counted? Technical Considerations to In Vitro Testing Originated from Corpuscular Nature of Nano‑Particles
Wojciech Kałas
Abstract
The abundance of nanoparticles introduced to household products created the great expectations towards the application of nanotechnology in biology and medicine. That calls for cost-effective preliminary assessment of its cytotoxicity and biological activity. There are many attempts for creating proper guidance and standards for performing studies regarding nanoparticles. But still some important aspects crucial for in vitro testing of nanomaterials need more attention. Particulate nature is an obvious and widely unappreciated property of nanoparticles. In the context of in vitro studies, this property is critical, and it should be, but rarely is, considered when designing, performing, describing or interpreting the experiments involving the solid nanoparticles. First, we should be aware of relatively small and limited number of nanoparticles in the experimental setup. Even crude estimation of its number will be useful for proper interpretation of results. Second, we should not presume even distribution of particles in the solution, moreover we should expect that sedimentation and aggregation play an important role in interactions of nanoparticles with cells. In that case, expressing the dose in mass/volume units may lead as astray. Finally, the relation of size, weight, and number of nanoparticles makes comparisons of activity of nanoparticles of different sizes very complex. Estimations of number of nanoparticles in the dose should be an integral part of experiment design, its validation and interpretation.
Keywords Nanoparticles · Dosing · Nano-compounds · In vitro · Cytotoxicity · Particulate matter · Inorganic nanoparticles
Anti‑ANX A1 Antibody Therapy in MRL/lpr Murine Model of Systemic Lupus Erythematosus
Silvya Bradyanova1 · Nikolina Mihaylova1 · Petroslav Chipinski1 · Yordan Manassiev2 · Melinda Herbáth3 · Dobroslav Kyurkchiev4 · József Prechl3,6 · Andrey I. Tchorbanov1,5
Abstract
Systemic lupus erythematosus (SLE) is a severe autoimmune disease characterized by dysfunction of immune regulation, overproduction of inflammatory cytokines and attack on normal tissues by self-reactive cells and antibodies. The main role in the pathogenesis plays the autoreactive tandem of B-T cells, responsible for lupus progression and acceleration. Both activated B and T cells express a phospholipid binding protein Annexin A1 and abnormal levels of the protein were found in murine and human autoimmune syndromes, potentiating its role as a therapeutic target. Here, using anti-annexin A1 antibody we explore its property to modulate the autoimmune response in MRL/lpr mouse model of lupus. Anti-ANX A1 antibody was tested in vitro using spleen cells from MRL/lpr mice to determine the effect on lymphocyte activation, plasma cells differentiation, apoptosis and proliferation by flow cytometry and ELISpot assays. Subsequently, several groups of young (disease-free) and old (sick) MRL/lpr mice were treated with the antibody to determine the levels of panel auto-antibodies and cytokines, T cell arrest and migration. Treatment of splenocytes with anti-ANX A1 antibody inhibited T-cell activation and proliferation, suppressed anti-dsDNA antibody-producing plasma cells and affected B cell apoptosis. Administration of the antibody to MRL/lpr mice resulted to decreased autoantibody levels to various lupus antigens, suppressed T cell migration from lymph nodes and increased the levels of IL4 mRNA compared to the control group. Anti-ANX A1 antibody therapy suppresses B and T cell over-activation and down- modulates disease activity.
Keywords Systemic lupus · Anti-annexin A1 antibody · MRL/Lpr mice · Antibody therapy
Stimulation of Innate and Adaptive Immune Cells with Graphene Oxide and Reduced Graphene Oxide Affect Cancer Progression
Muhammad Amir Yunus · Muhammad Mahyiddin Ramli · Nurul Huda Osman · Rafeezul Mohamed
Abstract
Sole nanomaterials or nanomaterials bound to specific biomolecules have been proposed to regulate the immune system. These materials have now emerged as new tools for eliciting immune-based therapies to treat various cancers. Graphene, graphene oxide (GO) and reduced GO (rGO) are the latest nanomaterials among other carbon nanotubes that have attracted wide interest among medical industry players due to their extraordinary properties, inert-state, non-toxic and stable dispersion in a various solvent. Currently, GO and rGO are utilized in various biomedical application including cancer immunotherapy. This review will highlight studies that have been carried out in elucidating the stimulation of GO and rGO on selected innate and adaptive immune cells and their effect on cancer progression to shed some insights for researchers in the development of various GO- and rGO-based immune therapies against various cancers.
Keywords Graphene oxide · Reduced graphene oxide · Innate immune cells · Adaptive immune cells · Cancers
Lower BAFF Levels in Myasthenic Patients Treated with Glucocorticoids
Ewa Sobieszczuk · Piotr Szczudlik · Justyna Kubiszewska · Beata Szyluk · Marta Lipowska · Małgorzata Dutkiewicz · Anna Kostera‑Pruszczyk
Abstract
B-cell activating factor (BAFF), a member of tumor necrosis factor family, activates B cells, promotes their survival and proliferation. BAFF is considered to have an influence on development of autoimmune diseases including myasthenia gravis (MG). We aimed to evaluate BAFF serum levels in MG patients, their potential connection with therapy and course of MG. Cross-sectional study. Two hundred eighteen adult patients with MG (67% women, age: 18–89 years, 82.6% AChR antibody seropositive (AChRAb(+)). Serum BAFF levels, their relationship with severity of clinical symptoms, therapy conducted, clinical and demographic features and other factors were analyzed. Patients with AChRAb(+) MG demonstrated significantly higher BAFF levels than MuSK-MG patients (831.2 ± 285.4 pg/ml vs. 745.6 ± 633.4 pg/ml, respectively; p = 0.030). Serum BAFF levels in women were significantly higher than in men (855.9 ± 302.5 vs. 756.6 ± 289.4, respectively; p = 0.017). Mean serum BAFF level was significantly decreased in patients who were ever treated with corticosteroids (CS) (770.4 ± 327.8 pg/ ml vs. 891.3 ± 246.1 pg/ml, respectively; p = 0.001). Thymoma-MG patients demonstrated significantly lower BAFF levels (671.2 ± 244.9 vs. 833.5 ± 302.4, respectively; p = 0.044). Thymectomized patients did not differ in BAFF levels from the MG patients who had not undergone thymectomy. In multiple linear regression model, recent CS therapy and male sex were found to be independent predictors of lower BAFF levels. Serum BAFF level is decreased in patients treated with CS, which may suggest inhibiting influence of CS on BAFF—a potential mechanism contributing to the effectiveness of such therapy.
Keywords Myasthenia gravis · BAFF · B-cell activating factor · Glucocorticoids · MG · Cytokine
Chronic Prostatitis and Pelvic Pain Syndrome: Another Autoimmune Disease?
Lei Chen · Meng Zhang · Chaozhao Liang
Abstract
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), characterized by chronic pain in the perineum or lower abdomen regions, is a frequent disorder in men. Previous studies demonstrated that the immune mediators, including interleukin (IL)-1β, IL-6, interferon-γ, tumor necrosis factor-α, and immunoglobulins, are elevated in the expressed prostate secretions and seminal fluid of CP/CPPS men. The memory T, T helper 1 (Th1), Th17, and Th22 cells increase in the peripheral blood of CP/CPPS men. Additionally, prostate antigens specific-autoreactive T cells are identified in CP/CPPS patients. After generally reviewing and comparing the inflammatory responses in autoimmune diseases and CP/CPPS, we presumed that CP/CPPS is more likely to be defined as an autoimmune disease. Thus, a better understanding of autoimmune diseases would contribute to a deeper understanding of the CP/CPPS and provide new inspirations for the treatment of this disease.
Keywords Chronic prostatitis/chronic pelvic pain syndrome · Pathogenesis · Autoimmunity · Autoimmune diseases
Casein Kinase‑1‑Alpha Inhibitor (D4476) Sensitizes Microsatellite Instable Colorectal Cancer Cells to 5‑Fluorouracil via Authophagy Flux Inhibition
Morvarid Siri · Hamid Behrouj · Sanaz Dastghaib · Mozhdeh Zamani · Wirginia Likus · Sedigheh Rezaie · Jacek Hudecki · Saeed Khazayel · Marek J. Łos · Pooneh Mokarram · Saeid Ghavami
Abstract
Adjuvant chemotherapy with 5-fluorouracil (5-FU) does not improve survival of patients suffering from a form of colorectal cancer (CRC) characterized by high level of microsatellite instability (MSI-H). Given the importance of autophagy and multi-drug-resistant (MDR) proteins in chemotherapy resistance, as well as the role of casein kinase 1-alpha (CK1α) in the regulation of autophagy, we tested the combined effect of 5-FU and CK1α inhibitor (D4476) on HCT116 cells as a model of MSI-H colorectal cancer. To achieve this goal, the gene expression of Beclin1 and MDR genes, ABCG2 and ABCC3 were analyzed using quantitative real-time polymerase chain reaction. We used immunoblotting to measure autophagy flux (LC3, p62) and flow cytometry to detect apoptosis. Our findings showed that combination treatment with 5-FU and D4476 inhibited autophagy flux. Moreover, 5-FU and D4476 combination therapy induced G2, S and G1 phase arrests and it depleted mRNA of both cell proliferation-related genes and MDR-related genes (ABCG2, cyclin D1 and c-myc). Hence, our data indicates that targeting of CK1α may increase the sensitivity of HCT116 cells to 5-FU. To our knowledge, this is the first description of sensitization of CRC cells to 5-FU chemotherapy by CK1α inhibitor.
Keywords 5-Fluorouracil · Casein kinase 1 alpha inhibitor · Colorectal cancer · Combination treatment · Autophagy · Chemoresistance
Are Host Defense Peptides and Their Derivatives Ready to be Part of the Treatment of the Next Coronavirus Pandemic?
Bruno Rivas‑Santiago · Yolanda Jacobo‑Delgado · Adrian Rodriguez‑Carlos
Abstract
The term host defense peptides arose at the beginning to refer to those peptides that are part of the host’s immunity. Because of their broad antimicrobial capacity and immunomodulatory activity, nowadays, they emerge as a hope to combat resistant multi-drug microorganisms and emerging viruses, such as the case of coronaviruses. Since the beginning of this century, coronaviruses have been part of different outbreaks and a pandemic, and they will be surely part of the next pandemics, this review analyses whether these peptides and their derivatives are ready to be part of the treatment of the next coronavirus pandemic.
Keywords Coronavirus · Host defense peptides · Antimicrobial peptides · Cathelicidin · Defensin · Treatment
The Positive Impact of Donor Bone Marrow Cells Transplantation into Immunoprivileged Compartments on the Survival of Vascularized Skin Allografts
Arkadiusz Jundziłł · Aleksandra Klimczak · Erhan Sonmez · Grzegorz Brzezicki · Maria Siemionow
Abstract
Using the vascularized skin allograft (VSA) model, we compared the tolerogenic effects of different allogeneic bone marrow transplantation (BMT) delivery routes into immunoprivileged compartments under a 7-day protocol immunosuppressive therapy. Twenty-eight fully MHC mismatched VSA transplants were performed between ACI (RT1a) donors and Lewis (RT11) recipients in four groups of seven animals each, under a 7-day protocol of alfa/beta TCRmAb/CsA (alpha/beta-TCR monoclonal antibodies/Cyclosporine A therapy). Donor bone marrow cells (BMC) (100 × 106 cells) were injected into three different immunoprivileged compartments: Group 1: Control, without cellular supportive therapy, Group 2: Intracapsular BMT, Group 3: Intragonadal BMT, Group 4: Intrathecal BMT. In Group 2, BMC were transplanted under the kidney capsule. In Group 3, BMC were transplanted into the right testis between tunica albuginea and seminiferous tubules, and in Group 4, cells were injected intrathecally. The assessment included: skin evaluation for signs and grade of rejection and immunohistochemistry for donor cells engraftment into host lymphoid compartments. Donor-specific chimerism for MHC class I (RT1a) antigens and the presence of CD4+/CD25+ T cells were assessed in the peripheral blood of recipients. The most extended allograft survival, 50–78 days, was observed in Group 4 after intrathecal BMT. The T cells CD4+/CD25+ in the peripheral blood were higher after intrathecal BMC injection than other experimental groups at each post-transplant time point. Transplantation of BMC into immunoprivileged compartments delayed rejection of fully mismatched VSA and induction of robust, donor-specific chimerism.
Keywords Bone marrow cells transplantation · Cells supportive therapy · Immunoprivileged compartments · Vascularized composite allotransplantation · Groin flap
Cyclosporine A, in Contrast to Rapamycin, Affects the Ability of Dendritic Cells to Induce Immune Tolerance Mechanisms
Maja Machcińska· Monika Kotur · Aleksandra Jankowska · Marta Maruszewska‑Cheruiyot · Artur Łaski · Zuzanna Kotkowska · Katarzyna Bocian · Grażyna Korczak‑Kowalska
Abstract
Following organ transplantation, it is essential that immune tolerance is induced in the graft recipient to reduce the risk of rejection and avoid complications associated with the long-term use of immunosuppressive drugs. Immature dendritic cells (DCs) are considered to promote transplant tolerance and may minimize the risk of graft rejection. The aim of the study was to evaluate the effects of immunosuppressive agents: rapamycin (Rapa) and cyclosporine A (CsA) on generation of human tolerogenic DCs (tolDCs) and also to evaluate the ability of these cells to induce mechanisms of immune tolerance. tolDCs were generated in the environment of Rapa or CsA. Next, we evaluated the effects of these agents on surface phenotypes (CD11c, MHC II, CD40, CD80, CD83, CD86, CCR7, TLR2, TLR4), cytokine production (IL-4, IL-6, IL-10, IL-12p70, TGF-β), phagocytic capacity and resistant to lipopolysaccharide activation of these DCs. Moreover, we assessed ability of such tolDCs to induce T cell activation and apoptosis, Treg differentiation and production of Th1- and Th2-characteristic cytokine profile. Data obtained in this study demonstrate that rapamycin is effective at generating maturation-resistant tolDCs, however, does not change the ability of these cells to induce mechanisms of immune tolerance. In contrast, CsA affects the ability of these cells to induce mechanisms of immune tolerance, but is not efficient at generating maturation-resistant tolDCs.
Keywords Dendritic cells · Immune tolerance · T cells · Immunosuppressive agents · Rapamycin · Cyclosporine A
The Role of Non‑essential Amino Acids in T Cell Function and Anti‑tumour Immunity
Helen Carrasco Hope · Robert J. Salmond
Abstract
T cell activation, differentiation and proliferation is dependent upon and intrinsically linked to a capacity to modulate and adapt cellular metabolism. Antigen-induced activation stimulates a transcriptional programme that results in metabolic reprogramming, enabling T cells to fuel anabolic metabolic pathways and provide the nutrients to sustain proliferation and effector responses. Amino acids are key nutrients for T cells and have essential roles as building blocks for protein synthesis as well as in numerous metabolic pathways. In this review, we discuss the roles for uptake and biosynthesis of non-essential amino acids in T cell metabolism, activation and effector function. Furthermore, we highlight the effects of amino acid metabolism and depletion by cancer cells on T cell anti-tumour function and discuss approaches to modulate and improve T cell metabolism for improved anti-tumour function in these nutrient-depleted microenvironments.
Keywords Non-essential amino acid · Metabolism · T cell · Immunotherapy · Tumour microenvironment
Differential Leukocyte MicroRNA Responses Following Pan T Cell, Allorecognition and Allosecretome‑Based Therapeutic Activation
Xining Yang1 · Wendy M. Toyofuku3,4 · Mark D. Scott2,3,4
Abstract
Effective immunomodulation of T-cell responses is critical in treating both autoimmune diseases and cancer. Our previous studies have demonstrated that secretomes derived from control or methoxypolyethylene glycol mixed lymphocyte alloactivation assays exerted potent immunomodulatory activity that was mediated by microRNAs (miRNA). The immunomodulatory effects of biomanufactured miRNA-based allo-secretome therapeutics (SYN, TA1, IA1 and IA2) were compared to Pan T-cell activators (PHA and anti-CD3/CD28) and lymphocyte alloactivation. The differential effects of these activation strategies on resting peripheral blood mononuclear cells (PBMC) were assessed via T-cell proliferation, subset analysis and miRNA expression profiles. Mitogen-induced PBMC proliferation (> 85%) significantly exceeded that arising from either allostimulation (~ 30%) or the pro-inflammatory IA1 secretome product (~ 12%). Consequent to stimulation, the ratio of CD4 to CD8 cells of the resting PBMC (CD4:CD8; 1.7 ± 0.1) decreased in the Pan T cell, allrecognition and IA1 activated cells (averages of 1.1 ± 0.2; 1.2 ± 0.1 and 1.0 ± 0.1). These changes arose consequent to the expansion of both CD4+CD8+ and CD4–CD8– populations as well as the shrinkage of the CD4 subset and the expansion of the CD8 T cells. Importantly, these activation strategies induced vastly different miRNA expression profiles which were associated with significant differences in cellular differentiation and biological function. These findings support the concept that the “differential patterns of miRNA expression” regulate the biologic immune response in a “lock and key” manner. The biomanufacturing of miRNA-enriched secretome biotherapeutics may be a successful therapeutic approach for the systemic treatment of autoimmune diseases (TA1) and cancer (IA1).
Keywords T lymphocyte · Immunomodulation · miRNA · Alloactivation · Secretome · Therapeutics
Molecular Genetics Diversity of Primary Hemophagocytic Lymphohistiocytosis among Polish Pediatric Patients
Katarzyna Bąbol‑Pokora · Magdalena Wołowiec · Katarzyna Popko · Aleksandra Jaworowska · Yenan T. Bryceson · Bianca Tesi · Jan‑Inge Henter · Wojciech Młynarski · Wanda Badowska · Walentyna Balwierz · Katarzyna Drabko · Krzysztof Kałwak · Lucyna Maciejka‑Kembłowska · Anna Pieczonka · Grażyna Sobol‑Milejska · Sylwia Kołtan · Iwona Malinowska
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a clinical syndrome of life-threatening inflammation caused by an excessive, prolonged and ineffective immune response. An increasing number of HLH cases is recognized in Poland, but the genetic causes of familial HLH (FHL) have not been reported. We investigated the molecular genetics and associated outcomes of pediatric patients who met HLH criteria. We studied 54 patients with HLH, 36 of whom received genetic studies. Twenty- five patients were subjected to direct sequencing of the PRF1, UNC13D, STX11, XIAP and SH2D1A genes. Additionally, 11 patients were subjected to targeted next-generation sequencing. In our study group, 17 patients (31%) were diagnosed with primary HLH, with bi-allelic FHL variants identified in 13 (36%) patients whereas hemizygous changes were identified in 4 patients with X-linked lymphoproliferative diseases. In addition, one patient was diagnosed with X-linked immunodefi-ciency with magnesium defect, Epstein–Barr virus infection and neoplasia due to a hemizygous MAGT1 variant; another newborn was diagnosed with auto-inflammatory syndrome caused by MVK variants. The majority (65%) of FHL patients carried UNC13D pathogenic variants, whereas PRF1 variants occurred in two patients. Novel variants in UNC13D, PRF1 and XIAP were detected. Epstein–Barr virus was the most common trigger noted in 23 (65%) of the patients with second- ary HLH. In three patients with secondary HLH, heterozygous variants of FHL genes were found. Overall survival for the entire study group was 74% with a median of 3.6 years of follow-up. Our results highlight the diversity of molecular causesof primary HLH in Poland.
Keywords Hemophagocytic lymphohistiocytosis · Genetics · Novel variants · Clinical course
Immunology and Donor‑Specific Antibodies in Corneal Transplantation
Joanna Major · Bartosz Foroncewicz · Jacek Paweł Szaflik · Krzysztof Mucha
Abstract
The first human corneal transplantation was performed in 1905 by Eduard Zirm in the Olomouc Eye Clinic, now Czech Republic. However, despite great advancements in microsurgical eye procedures, penetrating keratoplasty in high-risk patients (e.g., vascularized or inflamed corneal tissue, consecutive transplants) remains a challenge. The difficulty is mainly due to the risk of irreversible allograft rejection, as an ocular immune privilege in these patients is abolished and graft rejection is the main cause of corneal graft failure. Therefore, tailored immunosuppressive treatment based on immunological monitoring [e.g., donor-specific antibodies (DSA)] is considered one of the best strategies to prevent rejection in transplant recipients. Although there is indirect evidence on the mechanisms underlying antibody-mediated rejection, the impact of DSA on cornea transplantation remains unknown. Determining the role of pre-existing and/or de novo DSA could advance our understanding of corneal graft rejection mechanisms. This may help stratify the immunological risk of rejection, ultimately leading to personalized treatment for this group of transplant recipients.
Keywords Corneal transplantation · DSA · HLA · Keratoplasty · Rejection
A Novel Human Recombinant Lactoferrin Inhibits Lung Adenocarcinoma Cell Growth and Migration with No Cytotoxic Effect on Normal Human Epithelial Cells
Paulina Olszewska · Barbara Pazdrak · Marian L. Kruzel
Abstract
Lung cancer remains the leading cause of cancer death worldwide. Despite the recent advances in cancer treatment, only a subset of patients responds to targeted and immune therapies, and many patients developing resistance after an initial response. Lactoferrin (Lf) is a natural glycoprotein with immunomodulatory and anticancer activities. We produced a novel recombinant human Lf (rhLf) that exhibits glycosylation profile compatible with the natural hLf for potential parenteral therapeutic applications. The aim of this study was to evaluate the anticancer effects of this novel rhLf in human lung adenocarcinoma cells and its mechanisms of action. The results showed a concentration-dependent inhibition of A549 cancer cell growth in response to rhLf. Treatment with 1 mg/ml of rhLf for 24 h and 72 h resulted in a significant inhibition of cancer cell growth by 32% and 25%, respectively. Moreover, rhLf increased fourfold the percentage of early and late apoptotic cells compared to the control. This effect was accompanied by increased levels of caspase-3 activity and cell cycle arrest at the S phase in rhLf-treated cancer cells. Furthermore, rhLf significantly attenuated A549 cell migration. Importantly, treatment of normal human bronchial epithelial (NHBE) cells with rhLf showed the cell viability and morphology comparable to the control. In contrast, chemotherapeutic etoposide induced cytotoxicity in NHBE cells and reduced the cell viability by 40%. These results demonstrate the selective anticancer effects of rhLf against lung adenocarcinoma cells without cytotoxicity on normal human cells. This study highlights a potential for clinical utility of this novel rhLf in patients with lung cancer.
Keywords Recombinant human lactoferrin · Lung cancer · Glycosylation · Apoptosis
Peroxiredoxins as Markers of Oxidative Stress in IgA Nephropathy, Membranous Nephropathy and Lupus Nephritis
Natalia Krata · Bartosz Foroncewicz · Radosław Zagożdżon · Barbara Moszczuk · Magdalena Zielenkiewicz · Leszek Pączek · Krzysztof Mucha
Abstract
IgA nephropathy (IgAN), membranous nephropathy (MN), and lupus nephritis (LN) represent important causes of chronic kidney disease. They belong to the immune-mediated glomerulonephritis (GNs), and have distinct pathogenesis, distinct clinical courses, and variable responses to treatment. Therefore, specific diagnostic procedures are necessary for more effec tive patient management. Recently, a role for oxidative stress has been proposed in various renal disorders. Thus, molecules related to oxidative stress, such as 2-Cys-peroxiredoxins (PRDXs), may represent plausible candidates for biomarkers in renal pathologies. The aim of this study was to assess whether there are differences between individual GNs and healthy controls in the context of PRDXs serum concentration. We enrolled 108 patients with biopsy-proven IgAN (47), MN (26), LN (35) and 30 healthy age- and sex-matched controls. The serum concentrations of PRDX 1–5 were measured with ELISA assays and correlated with demographic and clinical data. The PRDXs’ concentration varied depending on the GN type. We also observed an association of PRDXs with lower estimated glomerular filtration rates, complement, hemoglobin, and body mass index. Our study indicates that individual PRDX can play roles in pathophysiology of selected GNs and that their serum concentrations may become useful as a new supplementary diagnostic markers in IgAN, MN as well as LN. The results of this study open a new avenue for prospective research on PRDXs in renal diseases.
Keywords Chronic kidney disease · IgA nephropathy · Lupus nephritis · Membranous nephropathy · Oxidative stress · Peroxiredoxins
5_2021_Article_638
5_2021_638_MOESM1_ESM
AITE Celebrates Its 70th Year of Publication (1953–2022)
Hubert Krotkiewski · Michał Zimecki · Andrzej Górski
Prospects for Development of Induced Pluripotent Stem Cell‑Derived CAR‑Targeted Immunotherapies
Roberta Mazza · John Maher
Abstract
Technologies required to generate induced pluripotent stem cells (iPSC) were first described 15 years ago, providing a strong impetus to the field of regenerative medicine. In parallel, immunotherapy has finally emerged as a clinically meaningful modality of cancer therapy. In particular, impressive efficacy has been achieved in patients with selected haematological malignancies using ex vivo expanded autologous T cells engineered to express chimeric antigen receptors (CARs). While solid tumours account for over 90% of human cancer, they currently are largely refractory to this therapeutic approach. Nonetheless, given the considerable innovation taking place worldwide in the CAR field, it is likely that effective solutions for common solid tumours will emerge in the near future. Such a development will create significant new challenges in the scalable delivery of these complex, costly and individualised therapies. CAR-engineered immune cell products that originate from iPSCs offer the potential to generate unlimited numbers of homogeneous, standardised cell products in which multiple defined gene modification events have been introduced to ensure safety, potency and reproducibility. Here, we review some of the emerging strategies in use to engineer CAR-expressing iPSC-derived drug products.
Keywords Chimeric antigen receptor (CAR) · Induced pluripotent stem (iPS) cell · T-cell · NK cell · Macrophage
The Role of Gut Microbiota in Gastrointestinal Tract Cancers
Marta Grochowska · Karol Perlejewski · Tomasz Laskus · Marek Radkowski
Abstract
Disturbances in gastrointestinal (GI) microbiota could play a significant role in the development of GI cancers, but the underlying mechanisms remain largely unclear. While some bacteria seem to facilitate carcinogenesis, others appear to be protective. So far only one bacterium (Helicobacter pylori) has been classified by the International Agency for Cancer Research as carcinogenic in humans but many other are the subject of intense research. Most studies on the role of microbiota in GI tract oncogenesis focus on pancreatic and colorectal cancers with the following three species: Helicobacter pylori, Escherichia coli, and Porphyromonas gingivalis as likely causative factors. This review summarizes the role of bacteria in GI tract oncogenesis.
Keywords Microbiota · Gastrointestinal tract · Cancer · Oral · Esophageal · Gastric · Pancreatic · Hepatocellular · Colorectal