Treatment with Lycopodium clavatum 200dH Intensifies Kidney and Liver Injury in Mice Infected with Toxoplasma gondii
Andréia Vieira Pereira · Marcelo Biondaro Gois · Katiucha Rebeca Jennifer Lopes Lera · Milena Menegazzo Miranda‑Sapla · Gislane Janaina Falkowski‑Temporini · Juliana Evangelista Bezerril · Gerson Zanusso‑Junior · Fabiana Nabarro Ferraz · Suelen Santos da Silva · Denise Lessa Aleixo · Ivete Conchon‑Costa · Debora de Mello Gonçales Sant’Ana · Idessania Nazareth da Costa · Silvana Marques de Araújo · Wander Rogério Pavanelli
Abstract
The effects of infection with Toxoplasma gondii vary from asymptomatic to the development of alterations in various organs (including the liver and kidneys) which may be irreversible, and lead to the death of the host. Whereas homeopathy is an alternative and effective method for treating various diseases, including those caused by protozoa, we questioned the effect of using Lycopodium clavatum in mice infected with T. gondii. One hundred male Swiss mice, 60 days old, were divided into four groups (n = 25/group): NIC (uninfected and untreated control), IC (infected and treated with un-dynamized 7% alcohol solution [vehicle]), G48 (infected and treated 48 h before infection and treated three more times; at 2, 4, and 6 days postinfection (dpi) with L. clavatum 200dH), and G72 (infected and treated for 3 consecutive days before infection with L. clavatum 200dH). In this study, physiological, histopathological, and immunological parameters were evaluated. The L. clavatum 200dH intensified renal damage in mice infected with T. gondii from 7 dpi, causing severe and progressive alterations during this period, such as various degrees of inflammation, edema, atrophy, and tubular cystic dilation, degenerated tubules with intra-cytoplasmic vacuoles and coalescing spots, severe vascular lesions, glomerulonephritis, and peri-glomerular congestion. In the G72 animals, which received L. clavatum 200dH, more severe cortex damage was observed (91.66–96.66%) as compared to the IC group (55–80%) and more renal corpuscle, and renal tubule injury was observed (80 ± 5 to 96.7% ± 2.89 of the total area) during all periods, as compared to the IC group (p < 0.05). Both groups presented high liver enzyme levels, and the highest values for AST were observable at 60 dpi. We observed significant increases of type I and III collagen, as well as high levels of TGF-β1 in both organs of the treated animals, the main factor involved in fibrosis in areas damaged by the process. L. clavatum 200dH intensifies kidney and liver alterations in mice infected with T. gondii. Our results reinforce caution when indicating administration schemes and dosages for ultra-diluted drugs.
Keywords Toxoplasmosis · Histopathological · Phytotherapy · Homeopathy · Glomerulonephritis · Hepatitis
Can Interferon‑γ Release Assays Be Useful for Monitoring the Response to Anti‑tuberculosis Treatment?: A Systematic Review and Meta‑analysis
Babak Pourakbari1 · Setareh Mamishi1,2 · Sepideh Benvari3 · Ilaria Sauzullo4 · Andrea Bedini5 · Piero Valentini6 · Naoto Keicho7 · Shima Mahmoudi1
Abstract
The number of studies which evaluated interferon-gamma release assays (IGRAs) results after anti-tuberculosis (TB) treatment has been rapidly increasing. The aim of this study was to investigate the potential use of IGRAs (QFT-GIT, T-SPOT. TB, QFT-Plus) in assessing the response to anti-TB treatment. We searched all studies in English language published from 1 October 2011 to 18 November 2018 in PubMed, Web of Science, and Scopus. Our search included the term “tuberculosis treatment AND interferon-γ release assay”. We included studies evaluating the performance of commercial IGRAs (including QFT-GIT, T-SPOT.TB and QFT-Plus) before and after the anti-TB treatment. We performed subgroup analysis based on the age (children, adults), type of TB (active, latent, active and latent, and contacts exposed to MDR defined as MDR LTBI), type of IGRAs (QFT-GIT and T-SPOT.TB), and follow-up interval (2, 3, 4, 6, 9 months). Of the 18 included studies, 12 used QFT-GIT for assessment of IGRA performance after therapy, 1 used T-SPOT.TB, and 3 used both QFT-GIT and T-SPOT.TB. Since then, only two studies have assessed the QFT-Plus performance during therapy. According to the results of the meta-analysis, the pooled rate of positive IGRAs (QFT-GIT and T-SPOT.TB) following anti-TB therapy was estimated at 76% [95% CI 70–81%] and no difference was found compared to the pooled positive rate of IGRAs before initiation of therapy which was 76% [95% CI 60–89%]. The subgroup analysis showed that the pooled rate of positive IGRAs (QFT-GIT and T-SPOT.TB) after anti-TB therapy was significantly higher in monitoring active TB subjects [80% (95% CI 74–88%)] than LTBI [71% (95% CI 70–81%)]. Available data are now sufficient to suggest that monitoring changes in the IGRAs (QFT-GIT and T-SPOT.TB) response during anti-TB treatment may have limited use in evaluating the effectiveness of treatment, while the monitoring changes in QFT-Plus during anti-tubercular treatment are recommended to determine treatment efficacy or for treatment monitoring. Further research is needed to establish the efficacy of this new assay as marker
on a larger scale for treatment monitoring.
Keywords Igras · Tuberculosis · Treatment
Desloratadine Ameliorates Olfactory Disorder and Suppresses AMPA Receptor GluA1 Expression in Allergic Rhinitis Rat
Shenling Li · Xiaotian Zhang · Zhiyuan Li · Xiaodan Jiang · Niankai Zhang · Jisheng Zhang · Yichuan Huang · Han Zhao · Yan Jiang · Na Li
Abstract
Allergic rhinitis (AR) is an IgE-mediated inflammation which causes olfactory dysfunction. Antihistamines have been widely used to treat AR while few studies have investigated the effect of antihistamines on improving the sense of smell. In addition, the underlying mechanisms are not well elucidated. We established the ovalbumin (OVA)-induced allergic rhinitis rat model and administrated desloratadine to AR rats. The AR symptoms, serum level of OVA-specific IgE and IL-17, and expression of IL-4, IL-5 and IL-13 in nasal mucosa were measured. The olfactory dysfunction was monitored by buried food test and the expression of GluR1 was measured. Desloratadine treatment alleviated AR symptoms, decreased serum level of OVA-specific IgE and IL-17 in AR rats. Desloratadine decreased IL-4, IL-5, and IL-13 expression in nasal mucosa of AR rats. Desloratadine ameliorated olfactory dysfunction in AR rats and decreased GluR1 expression in AR rats. Desloratadine treatment alleviated AR symptoms and ameliorated olfactory dysfunction in AR rats. The expression of AMPA receptor subunit GluR1 in olfactory bulb was associated with olfactory disorder.
Keywords Allergic rhinitis · Desloratadine · Olfactory dysfunction · AMPA receptor
Correction to: Human Gyrovirus‑Apoptin Interferes with the Cell Cycle and Induces G2/M Arrest Prior to Apoptosis
Wiem Chaabane · Saeid Ghavami · Andrzej Małecki · Marek J. Łos
Correction to: Arch Immunol Ther Exp (2017) 65:545–552
https ://doi.org/10.1007/s0000 5-017-0464-8
The authors would like to correct the following error:
In page 551 in Acknowledgemets is: “SG acknowledges Manitoba Medical Service Founda- tion, and University of Manitoba Research Grant Program. MJŁ kindly acknowledges the support from NCN Grant #: 2016/21/B/NZ1/0281.”
Should be: “SG acknowledges Manitoba Medical Service Foundation, and University of Manitoba Research Grant Program.”
Autotransplantation of the Adipose Tissue‑Derived Mesenchymal Stromal Cells in Therapy of Venous Stasis Ulcers
Leszek Masłowski1 · Maria Paprocka2 · Agnieszka Czyżewska‑Buczyńska1 · Aleksandra Bielawska‑Pohl2 · Danuta Duś2 · Ryszard Grendziak1 · Wojciech Witkiewicz1 · Anna Czarnecka1,3
Abstract
Adipose tissue is a reliable source of mesenchymal stromal cells (MSC) for use in regenerative medicine. The aim of this pilot study was to describe the method, and assess the safety and the potential efficacy of transplantation of autologous adipose tissue-derived MSC for the treatment of chronic venous stasis ulcers. Study group consisted of 11 patients (mean age: 66.6 ± 9.5 years) with chronic venous stasis ulcers. Adipose tissue was harvested by tumescent-aspiration method. Stromal cells were separated using a dedicated closed system in a real-time bedside manner. The phenotype of cells was determined immediately after separation. Cell concentrate was implanted subcutaneously around the wound and the wound bed. All ulcers were assessed planimetrically before autotransplantation and every two weeks during the six-month follow-up. During the study all patients received standard local and general treatment. The preparation contained an average of 5.6 × 106 ± 4 × 106 cells per milliliter. The phenotype of 65–82% of transplanted cells expressed MSC markers: CD73+ CD90+ and CD34+. An improvement was observed in 75% of ulcers. The data showed highly significant negative correlation (p < 0.0001) between wound size and wound closure degree. There was no correlation of ulcer healing with other parameters evaluated, including age of the patients. No serious side effects were observed. Autotransplantation of adipose tissue stromal cells may be a safe and promising treatment method for chronic venous ulcers.
Keywords Adipose tissue-derived mesenchymal stromal cells · CELLUTION 800 · Regenerative medicine · Wound healing · Venous stasis ulcers
HLA‑A and ‑B Type and Haplotype Frequencies in IgG Subclass Deficiency Subgroups
James C. Barton · Jackson C. Barton · Luigi F. Bertoli · Ronald T. Acton
Abstract
We sought to determine whether HLA-A and -B type and haplotype frequencies differ between subgroups of adults with IgG subclass deficiency (IgGSD). We retrospectively compared type and haplotype frequencies of three subgroups of 269 unrelated adult IgGSD patients (70 subnormal IgG1; 121 subnormal IgG3; 78 subnormal IgG1/IgG3) and controls (1,321 for types; 751 for haplotypes). We selected types and haplotypes because their uncorrected frequencies differed significantly from controls in a previous adult IgGSD/common variable immunodeficiency cohort: A*24; B*14; B*35; B*40; B*49; B*50; B*58; B*62; A*01,B*08; A*02,B*44; A*02,B*60; A*03,B*07; A*03,B*14; A*03,B*44; A*31,B*40; and A*32,B*14. We used χ2 analysis (2 × 4 tables) to identify frequency differences across three subgroups and controls. If the null hypothesis was rejected (p < 0.05), we computed 2 × 2 χ2 tables to compare six combinations of subgroup and control frequencies [Bonferroni p < 0.0083 (< 0.05/6)]. Mean age was 48 ± 13 years; 82.2% were women. B*35 and B*40 frequencies were higher in subnormal IgG1 than subnormal IgG3 patients (0.1000 vs. 0.0248 and 0.0571 vs. 0.0083, respectively; p ≤ 0.0061). B*62 frequencies were lower in three IgGSD subgroups than controls (p < 0.0001, respectively). A*02, B*44 frequency was higher in subnormal IgG1/IgG3 patients than controls (0.1282 vs. 0.0632, respectively; p = 0.0024). A*02, B*60 frequency was lower in subnormal IgG3 patients than controls (0.0 vs. 0.0233, respectively; p = 0.0051). HLA-B*35 and -B*40 frequencies differ significantly between some IgGSD subgroups. B*62, A*02, B*44, and A*02, B*60 frequencies differ significantly between some IgGSD subgroups and controls.
Keywords Common variable immunodeficiency · HLA-A*02, B*44 · HLA-B*35 · HLA-B*40 · HLA-B*62 · Major histocompatibility complex
Antibodies to Heat Shock Proteins 90α and 90β in Psoriasis
Aleksandra Damasiewicz‑Bodzek · Magdalena Szumska · Krystyna Tyrpień‑Golder
Abstract
One of many hypotheses of psoriasis pathogenesis supposes an overexpression of heat shock proteins (Hsps) in different skin layers and systemic immunologic response to them. Hsp90 is one of the most abundant chaperone in eukaryotic cells. The number of studies concerning the role of Hsp90 and anti-Hsp90 antibodies in etiopathogenesis of various diseases is also constantly expanding. Still, there are not many reports concerning potential involvement of this Hsp family or anti-Hsp90 immunization in pathomechanism of psoriasis. The aim of the study was the estimation of anti-Hsp90α and anti-Hsp90β IgG antibodies in the sera of the psoriatic patients at different phases of disease activity in comparison to the sera of healthy individuals. The study material consisted of sera from psoriasis patients (n = 80) in active phase and in the remission phase and healthy individuals (n = 80). Concentrations of anti-Hsp90α and anti-Hsp90β IgG antibodies were determined using ELISA technique. In the patients with psoriasis (both in the active phase of the disease and in the remission phase) concentrations of anti-Hsp90α antibodies were significantly higher than in healthy individuals and they correlated positively with psoriasis area severity index values. The mean concentrations of anti-Hsp90β antibodies in the psoriatic patients and healthy controls were comparable. The obtained results indicate an existence of increased immunological response to Hsp90α in psoriasis. It may suggest the role of the extracellular form of this chaperone and/or anti-Hsp90α antibodies in etiopathogenesis of this dermatosis. The inhibition of Hsp90α may represent a novel therapeutic approach to treat psoriasis.
Keywords Psoriasis · Hsp90α · Hsp90β · Anti-Hsp90α antibodies · Anti-Hsp90β antibodies
Antibodies to Heat Shock Proteins 90α and 90β in Psoriasis
Aleksandra Damasiewicz‑Bodzek · Magdalena Szumska · Krystyna Tyrpień‑Golder
Abstract
One of many hypotheses of psoriasis pathogenesis supposes an overexpression of heat shock proteins (Hsps) in different skin layers and systemic immunologic response to them. Hsp90 is one of the most abundant chaperone in eukaryotic cells. The number of studies concerning the role of Hsp90 and anti-Hsp90 antibodies in etiopathogenesis of various diseases is also constantly expanding. Still, there are not many reports concerning potential involvement of this Hsp family or anti-Hsp90 immunization in pathomechanism of psoriasis. The aim of the study was the estimation of anti-Hsp90α and anti-Hsp90β IgG antibodies in the sera of the psoriatic patients at different phases of disease activity in comparison to the sera of healthy indi- viduals. The study material consisted of sera from psoriasis patients (n = 80) in active phase and in the remission phase and healthy individuals (n = 80). Concentrations of anti-Hsp90α and anti-Hsp90β IgG antibodies were determined using ELISA technique. In the patients with psoriasis (both in the active phase of the disease and in the remission phase) concentrations of anti-Hsp90α antibodies were significantly higher than in healthy individuals and they correlated positively with psoriasis area severity index values. The mean concentrations of anti-Hsp90β antibodies in the psoriatic patients and healthy controls were comparable. The obtained results indicate an existence of increased immunological response to Hsp90α in psoriasis. It may suggest the role of the extracellular form of this chaperone and/or anti-Hsp90α antibodies in etiopathogenesis of this dermatosis. The inhibition of Hsp90α may represent a novel therapeutic approach to treat psoriasis.
Keywords Psoriasis · Hsp90α · Hsp90β · Anti-Hsp90α antibodies · Anti-Hsp90β antibodies
Specific T‑Cell Subsets Can Predict the Efficacy of Anti‑TNF Treatment in Inflammatory Bowel Diseases
Sonja Dulic1 · Gergely Toldi2 · Florentina Sava2 · László Kovács1 · Tamás Molnár3 · Ágnes Milassin3 · Klaudia Farkas3 · Mariann Rutka3 · Attila Balog1
Abstract
The effect of TNF-blockers on T-lymphocyte subsets is largely unknown in inflammatory bowel diseases (IBDs). The aim of the present study was to analyze the prevalence of T-cell subtypes and their correlation to therapeutic response. Sixtyeight patients with Crohn’s disease (CD), 46 with ulcerative colitis (UC) were enrolled. (1) The clinical course was followed after the initiation of TNF-blockers (prospective study). (2) The immunophenotype was also compared between long-term anti-TNF treated-responders and non-responders (cross-sectional study). The results were compared with those of therapynaïve patients with active disease and those in remission with non-biological immunosuppressive therapy, and with healthy controls. Fourteen subtypes of peripheral blood T cells were measured with flow cytometry. The prevalence of Th2 and Th17 cells, of HLA-DR- and CD69-positive CD4 and CD8 cells, was higher, whereas the percentage of CD45RA-positive CD4 and CD8 cells was lower in both IBDs than in controls. CD8CD69 cell frequency was lower in remission, and decreased during anti-TNF therapy in CD responders. CD8CD45RO memory cells had higher prevalence in UC non-responders than in those starting anti-TNF. CD4CD45RO percentage < 49.05 at the initiation of TNF-blockers was predictive of a subsequent therapeutic response in CD, and Th2 and Th17 prevalence correlated with the duration of remission on TNF-blockers in UC. This study provided a detailed description of the T-cell composition in IBDs. CD8CD69 prevalence may be an activity marker in CD, and CD4CD45RO, Th2 and Th17 levels could be predictive for a therapeutic response to anti-TNF.
Keywords Th17 · Memory T cell · Therapeutic response
Current Status of M1 and M2 Macrophages Pathway as Drug Targets for Inflammatory Bowel Disease
Seyede Sara Seyedizade · Khashayar Afshari · Saba Bayat · Fatemeh Rahmani · Saeideh Momtaz · Nima Rezaei · Amir Hossein Abdolghaffari
Abstract
Chronic inflammation of the gastrointestinal system is mediated by both the immune system activity and homeostasis, mainly through releasing of various cytokines and chemokines, as well as the transmigration of the inflammatory cells to the affected site. In between, macrophages are key mediators of the immune system, nearly located all over the gastrointestinal tract. Macrophages have vital influence on the inflammatory condition with both pro-inflammatory and anti-inflammatory functions. Their polarization status has been linked to numerous metabolic disorders such as inflammatory bowel disease (IBD). The equilibrium between the phenotypes and functions of inflammatory M1 and anti-inflammatory M2 cells is regulated by both extracellular and intracellular stimuli, determining how the disease progresses. Thereby, factors that interchange such balance in the direction of increasing M2 macrophages offer unique approaches for future management of IBD. This study reflects the novel IBD treatment targets via the immune system’s pathway, reporting the latest treatments that regulate the M1/M2 macrophages distribution in a way to favor IBD.
Keywords Inflammatory bowel disease · M1 and M2 macrophages · Immune system · Inflammation · Gastrointestinal system
In Vitro Immunological Effects of CXCR3 Inhibitor AMG487 on Dendritic Cells
Chenchen Qin · Huihui Liu · Bo Tang · Min Cao · Zhengyu Yu · Beichen Liu · Wei Liu · Yujun Dong · Hanyun Ren
Abstract
AMG 487 is the targeted blocker of chemokine receptor CXCR3 and improves inflammatory symptoms by blocking the inflammatory cycle. Here we investigated whether AMG 487 affects dendritic cell (DC) biology and function. The expression of co-stimulatory markers on DCs was reduced, indicating the semi-mature state of DC when AMG 487 was added throughout the in vitro differentiation period. Additionally, when added solely during the final lipopolysaccharide-induced activation step, AMG 487 inhibited DC activation, as demonstrated by a decreased expression of activation markers. AMG487 also promoted the expression of PD-L2 and impaired the ability to induce antigen-specific T cell responses. Our results demonstrated that AMG 487 significantly affects DC maturity in vitro and function leading to impaired T cell activation, inducing DCs to have characteristics similar to tolerogenic DCs. AMG 487 may directly play an immunomodulatory role during DC development and functional shaping.
Keywords AMG 487 · Dendritic cells · Development inhibition · Dysfunction
Crosstalk Between Immunity System Cells and Pancreas. Transformation of Stem Cells Used in the 3D Bioprinting Process as a Personalized Treatment Method for Type 1 Diabetes
Paulina Niedźwiedzka‑Rystwej · Mikołaj Wołącewicz · Piotr Cywoniuk · Marta Klak · Michał Wszoła
Abstract
Interactions between the immune system and the pancreas are pivotal in understanding how and why β cells’ damage causes problems with pancreas functioning. Pancreatic islets are crucial in maintaining glucose homeostasis in organs, tissue and cells. Autoimmune aggression towards pancreatic islets, mainly β cells, leads to type 1 diabetes—one of the most prevalent autoimmune disease in the world, being a worldwide risk to health of many people. In this review, we highlight the role of immune cells and its influence in the development of autoimmunity in Langerhans islets. Moreover, we discuss the impact of the immunological factors on future understanding possible recurrence of autoimmunity on 3D-bioprinted bionic pancreas.
Keywords Type 1 diabetes · Immune cells · Pancreas · Bioprintig · CRISP/CAS9
BW5147 and Derivatives for the Study of T Cells and their Antigen Receptors
Janice White1 · Rebecca L. O’Brien1,2 · Willi K. Born1,2
Abstract
Like B cells, T cells can be immortalized through hybridization with lymphoma cells, a technique that has been particularly useful in the study of the T cell receptors (TCR) for antigen. In T cell hybridizations, the AKR mouse strain-derived thymus lymphoma BW5147 is by far the most popular fusion line. However, the full potential of this technology had to await inactivation of the productively rearranged TCR-α and -β genes in the lymphoma. BWα-β-, the TCR-gene deficient variant of the original lymphoma, which has become the fusion line of choice for αβ T cells, is now available with numerous modifications, enabling the investigation of many aspects of TCR-mediated responses and TCR-structure. Unexpectedly, inactivating BW’s functional TCR-α gene also rendered the lymphoma more permissive for the expression of TCR-γδ, facilitating the study of γδ T cells, their TCRs, and their TCR-mediated reactivity.
Keywords BW5147 · BWα-β- · Thymus lymphoma · T cell hybridoma · T cell receptor
Decreased Serum Adiponectin Reflects Low Vitamin D, High Interleukin 6, and Poor Physical Performance in Knee Osteoarthritis
Wanvisa Udomsinprasert · Pacharee Manoy · Pongsak Yuktanandana · Aree Tanavalee · Wilai Anomasiri · Sittisak Honsawek
Abstract
Obesity is a major contributor to deterioration of physical function toward sarcopenia in knee osteoarthritis (OA) due to its effect mediated through adipokines-derived molecules that have pro-/anti-inflammatory properties. This study aimed to inves- tigate relationships of serum adiponectin, 25-hydroxyvitamin D (25(OH)D), interleukin (IL)-6, and physical performance in knee OA patients. A total of 175 knee OA patients and 52 healthy controls were recruited. Serum adiponectin, 25(OH)D, IL-6, biochemical markers, knee pain and functional scores, muscle strength, physical performance, metabolic parameters, and body composition were evaluated. Serum adiponectin levels were significantly higher in knee OA patients than that in controls, while its serum levels were significantly decreased in obese patients, especially those with sarcopenia. Furthermore, there were independent relationships of serum adiponectin with body composition parameters, knee pain scores, physical function tests, and metabolic parameters in knee OA patients. Besides, serum adiponectin levels were positively associated with 25(OH)D levels, and negatively correlated with C-reactive protein and IL-6 levels in knee OA. Additionally, low serum adiponectin could be used to distinguish knee OA patients with sarcopenic obesity from those without sarcopenic obesity. Circulating adiponectin levels may serve as a possible surrogate biomarker for exacerbated physical function in knee OA patients—particularly sarcopenic obesity.
Keywords Adiponectin · Vitamin D · IL-6 · Knee osteoarthritis · Sarcopenic obesity · Poor physical performance
Exopolysaccharide from Lactobacillus rhamnosus KL37 Inhibits T Cell‑dependent Immune Response in Mice
Bernadeta Nowak · Małgorzata Śróttek · Marta Ciszek‑Lenda · Anna Skałkowska · Andrzej Gamian · Sabina Górska · Janusz Marcinkiewicz
Abstract
Exopolysaccharides (EPSs), major components of the bacterial biofilm, display strong strain-specific immunomodulatory properties. Previously, we have shown that crude EPS derived from Lactobacillus rhamnosus KL37 depresses the production of arthritogenic anti-collagen IgG and ameliorates collagen-induced arthritis (CIA) in DBA/1 mice, when lipopolysaccha- ride (LPS) was used as adjuvant. In this study, we used highly purified EPS from L. rhamnosus KL37 (EPS-37) to verify its anti-inflammatory properties and the ability to suppress T cell-dependent humoral response. We have employed the model of active CIA, in which mice immunized with type II collagen (CII) along with LPS were treated with pure EPS-37. Intrave- nous administration of purified EPS-37 markedly ameliorated arthritis and reduced CII-specific antibody production. EPS- 37 injected subcutaneously reduced the clinical symptoms of CIA but without the reduction of arthritogenic antibodies. In addition, the effect of EPS-37 on T-cell functions was tested ex vivo and in vitro. EPS-37 inhibited the in vitro proliferation of T cells activated both in vivo (CII immunization) and in vitro (antigen/mitogen), and markedly reduced the production of interferon (IFN)-γ. These results together with other reports suggest that anti-inflammatory potential of EPS-37 depends on its ability to inhibit either one or the other or both possible inflammatory signaling pathways. Namely, Th1 → IFN-γ → M1 inflammatory macrophages → arthritis and/or Th1 → IFN-γ → B cells → arthritogenic antibodies → arthritis. We suggest that L. rhamnosus KL37 EPS might be utilized to control T cell-dependent immune responses in various inflammatory diseases. However, the most effective route of EPS-37 administration needs to be tailored for a given disorder.
Keywords Exopolysaccharide · Lactobacillus rhamnosus · Immunomodulation · Collagen-induced arthritis · Inflammation · T cells
Comparative Study of Immunomodulatory Agents to Induce Human T Regulatory (Treg) Cells: Preferential Treg‑Stimulatory Effect of Prednisolone and Rapamycin
Michał Janyst · Beata Kaleta · Karolina Janyst · Radosław Zagożdżon · Ewa Kozlowska · Witold Lasek
Abstract
T regulatory (Treg) cells play a critical role in the maintenance of self-tolerance, as well as in inhibition of inflammation and exaggerated immune response against exogenous antigens. They develop in the thymus (tTreg cells) but also may be generated at the peripheral tissues, including tumor microenvironment (pTreg cells), or induced in vitro in the presence of transforming growth factor (TGF)-β (iTreg cells). Since tTreg cells constitute a minor fraction of peripheral blood lympho- cytes in physiological conditions, an alternative way to obtain high number of functional Treg cells for therapeutic purposes is their generation in vitro from conventional T cells. In our studies, we compared effectiveness of several pharmacologi- cal agents with suggested immunomodulatory effects on Treg development (rapamycin, prednisolone, inosine pranobex, glatiramer acetate, sodium butyrate, and atorvastatin) to optimize Treg-inducing protocols. All but one (atorvastatin) immu- nomodulators augmented induction of polyclonal Treg cells in cultures. They were effective both in increasing the number of CD4+CD25highFoxp3high cells and Foxp3 expression. Rapamycin and prednisolone were found the most effective. Both drugs prolonged also phenotypic stability of Treg cells and induced fully active Treg cells in a functional assay. In the assay, prednisolone appeared superior versus rapamycin. The results, on the one hand, may be helpful in planning optimal protocols for generation of Treg cells for clinical application and, on the other hand, shed some light on mechanisms of the immunomodulatory activity of some tested agents observed in vivo.
Keywords Treg cells · Prednisolone · Rapamycin · Glatiramer acetate · Inosine pranobex · Atorvastatin
WNT7A Expression is Downregulated in T Lymphocytes after T‑Cell Receptor Activation Due to Histone Modifications and in T‑ALL by DNA Methylation
Christian Barreto‑Vargas · Monserrat Alvarez‑Zavala · Mariel Garcia‑Chagollan · Georgina Hernandez‑Flores · Adriana Aguilar‑Lemarroy · Luis F. Jave‑Suarez
Abstract
WNT signaling pathway regulates several processes involved in the homeostasis of normal cells. Its dysregulation is associ- ated with pathological outcomes like cancer. We previously demonstrated that downregulation of WNT7A correlates with higher proliferation rates in acute lymphoblastic leukemia. However, the regulation of this gene in pathological and normal conditions remains unexplored. In this work, we aimed to analyze the transcriptional regulation of WNT7A in leukemic cells and in normal T lymphocytes after a proliferative stimulus. WNT7A expression was measured in blood cells and in T lymphocytes after phytohemagglutinin-L (PHA-L) treatment or T-cell receptor (TCR) activation by qPCR and Western blot. Promoter methylation was assessed using methylation-sensitive restriction enzymes, and histone modifications were determined by chromatin immunoprecipitation and qPCR. In T-cell acute lymphoblastic leukemia (T-ALL), WNT7A expres- sion is silenced through DNA methylation of CpG island in the promoter region. In normal peripheral blood cells, WNT7A is mainly expressed by monocytes and T lymphocytes. TCR activation induces the downregulation of WNT7A in normal T lymphocytes by changes in histone methylation marks (H3K4me2/3) and histone deacetylases. A proliferative stimulus mediated by IL-2 keeps WNT7A expression at low levels but in the absence of IL-2, the expression of this gene tends to be restored. Furthermore, after TCR activation and WNT7A downregulation, target genes associated with the WNT canoni- cal pathway were upregulated indicating an independent activity of WNT7A from the WNT canonical pathway. WNT7A expression is silenced by long-term DNA methylation in T-ALL-derived cells and downregulated by histone modifications after TCR activation in normal T lymphocytes.
Keywords WNT signaling · Epigenetics · Transcription regulation · T lymphocytes · Leukemia · DNA methylation · Histone modification
Siponimod (Mayzent) Downregulates RhoA and Cell Surface Expression of the S1P1 and CX3CR1 Receptors in Mouse RAW 264.7 Macrophages
Ahmed Uosef · Nicole Vaughn · Xiufeng Chu · Mahmoud Elshawwaf · Ahmed Adel Abbas Abdelshafy · Kamal Mamdoh Kamal Elsaid · Rafik Mark Ghobrial · Malgorzata Kloc
Abstract
The Siponimod (Mayzent) is a newly developed drug, similar to Fingolimod (FTY720) but with fewer side effects, approved by the Food and Drug Administration for the treatment of multiple sclerosis (MS). The therapeutic effect of siponimod and FTY720 in MS relies on their inhibitory effect on the sphingosine 1-phosphate (S1P) signaling. These drugs bind to the S1P receptors and block the CCL2 chemokine pathway that is responsible for the exit of the immune cells from the lymphoid organs, and circulation, thus preventing immune cell-dependent injury to the nervous system. We recently found that FTY720 beside its effect on the S1P pathway also blocks the RhoA pathway, which is involved in the actin cytoskeleton-related func- tion of macrophages, such as expression/recycling of fractalkine (CX3CL1) receptors (CX3CR1), which direct macrophages to the transplanted organs during the development of the long-term (chronic) rejection. Here we tested the effects of siponi- mod on the RhoA pathway and the expression of the S1P1 and CX3CR1 receptors in mouse RAW 264.7 macrophages. We found that siponimod downregulates the expression of RhoA protein and decreases the cell surface expression of S1P1 and CX3CR1 receptors. This newly discovered crosstalk between S1P and RhoA/CX3CR1 pathways may help in the develop- ment of novel anti-chronic rejection therapies in clinical transplantation.
Keywords Siponimod · FTY720 · S1P1 · CX3CR1 · RhoA · Macrophage · Actin
Cathepsin G and its Dichotomous Role in Modulating Levels of MHC Class I Molecules
Timo Burster · Uwe Knippschild · Ferdinand Molnár · Anuar Zhanapiya
Abstract
Cathepsin G (CatG) is involved in controlling numerous processes of the innate and adaptive immune system. These features include the proteolytic activity of CatG and play a pivotal role in alteration of chemokines as well as cytokines, clearance of exogenous and internalized pathogens, platelet activation, apoptosis, and antigen processing. This is in contrast to the capability of CatG acting in a proteolytic-independent manner due to the net charge of arginine residues in the CatG sequence which interferes with bacteria. CatG is a double-edged sword; CatG is also responsible in pathophysiological conditions, such as autoimmunity, chronic pulmonary diseases, HIV infection, tumor progression and metastasis, photo-aged human skin, Papillon–Lefèvre syndrome, and chronic inflammatory pain. Here, we summarize the latest findings for functional responsibiliies of CatG in immunity, including bivalent regulation of major histocompatibility complex class I molecules, which underscore an additional novel role of CatG within the immune system.
Keywords Cathepsin G · Proteases · T regulatory cells · NK cells · MHC · Lactoferrin · Protease-activated receptor
Activity‑Based Protein Profiling of Serine Proteases in Immune Cells
Jan Pascal Kahler · Roeland Vanhoutte · Steven H. L. Verhelst
Abstract
Multiple types of immune cells utilize serine proteases in their mechanisms of defense against pathogens or altered host cells. Dysregulation of the serine protease activity from these cells underlies different diseases. In the past, the technique of activity-based protein profiling proved to be especially useful for the study of proteases, and various studies have used smallmolecule activity-based probes to covalently label and detect serine proteases from immune cells. In this review, we give an overview of the different activity-based probes that have been designed for serine proteases and how their selectivity can be steered. We also discuss how these have been utilized in the detection of various serine proteases from immune cells by different analysis methods (gel electrophoresis, microscopy and flow cytometry) and what biological insights these studies have produced. Overall, activity-based protein profiling has the potential to address functional aspects of serine proteases in the immune system and future efforts may bring translation into clinical application.
Keywords Activity-based probes · Cathepsin G · Covalent protease inhibitors · Neutrophil elastase
A Tolerogenic Role of Cathepsin G in a Primate Model of Multiple Sclerosis: Abrogation by Epstein–Barr Virus Infection
Bert A. ‘t Hart
Abstract
Using a non-human primate model of the autoimmune neuroinflammatory disease multiple sclerosis (MS), we have unraveled the role of B cells in the making and breaking of immune tolerance against central nervous system myelin. It is discussed here that B cells prevent the activation of strongly pathogenic T cells present in the naïve repertoire, which are directed against the immunodominant myelin antigen MOG (myelin oligodendrocyte glycoprotein). Prevention occurs via destructive processing of a critical epitope (MOG34-56) through the lysosomal serine protease cathepsin G. This effective tolerance mechanism is abrogated when the B cells are infected with Epstein–Barr virus, a ubiquitous γ1-herpesvirus that entails the strongest non-genetic risk factor for MS.
Keywords EAE · Autoimmune · Tolerance · B cells · Antigen presentation
Professor Elwira Lisowska Celebrates Her 90th Birthday AITE Editor (1975–1980), Member of AITE Advisory Board (1980–2016)
Hubert Krotkiewski · Marcin Czerwinski · Ewa Jaskiewicz · Kazimiera Wasniowska · Radoslaw Kaczmarek
Polymorphisms within the RANK and RANKL Encoding Genes in Patients with Rheumatoid Arthritis: Association with Disease Progression and Effectiveness of the Biological Treatment
Joanna Wielińska · Katarzyna Kolossa · Jerzy Świerkot · Marta Dratwa · Milena Iwaszko · Bartosz Bugaj · Barbara Wysoczańska · Monika Chaszczewska‑Markowska · Sławomir Jeka · Katarzyna Bogunia‑Kubik
Abstract
Inconsistency of the results regarding the genetic variability within genes coding for receptor activator of nuclear factor κB (RANK) and its ligand (RANKL) in rheumatoid arthritis (RA) prompted us to study the RANK and RANKL polymorphisms as potential biomarkers associated with disease predisposition and response to anti-TNF treatment in a group of Polish patients with RA. This study enrolled 318 RA patients and 163 controls. RANK (rs8086340, C > G; rs1805034, C > T) and RANKL (rs7325635, G > A; rs7988338 G > A) alleles were determined by real-time PCR with melting curve analysis and related with clinical parameters. In addition, RANKL serum levels were measured by ELISA. The RANK rs8086340-G allele was overrepresented among patients as compared to controls (OD = 1.777, p = 0.038). C-reactive protein (CRP) levels were significantly (p < 0.05) associated with RANK rs8086340 polymorphism and were higher in the CC-homozygotes at the baseline while lower in the GG-carriers at the 12th week of the treatment. At the latter time point RANKL rs7325635-GG- positive patients also showed significantly lower CRP concentrations. Higher alkaline phosphatase levels before induction of anti-TNF therapy were observed in RANK rs8086340 and RANK rs1805034 CC homozygotes (p = 0.057 and p = 0.035, respectively). The GG homozygosity of both RANKL single nucleotide polymorphisms was significantly associated with the number of swollen joints (rs7988338 and rs7325635, before and at the 12th week of therapy, respectively, p < 0.05 in both cases). These results imply that polymorphisms within the RANK and RANKL genes affect RA susceptibility and anti-TNF treatment outcome.
Keywords RANK · RANKL · Polymorphism · Anti-TNF therapy · Rheumatoid arthritis
IL‑6 Contributes to the TGF‑β1‑Mediated Epithelial to Mesenchymal Transition in Human Salivary Gland Epithelial Cells
Margherita Sisto · Roberto Tamma · Domenico Ribatti · Sabrina Lisi
Abstract
To determine the role of IL-6 in bringing about the EMT, in SGEC obtained from healthy subjects. Human salivary gland (SGs) epithelial cells (SGEC) from primary Sjögren’s syndrome (pSS) are able to synthesize interleukin (IL)-6, which is a critical mediator of the SGs modifications in response to chronic inflammation. Recently, a hypothetical link between epithelial-mesenchymal transition (EMT)-dependent salivary gland fibrosis and chronic inflammatory conditions has been suggested for pSS; the present study was conducted to evaluate this link. Primary cultures of human SGEC from salivary mucoceles were stimulated with increasing concentrations of IL-6 for 24–72 h. Microscopy, RT-PCR, Real-time PCR, immunoblotting and flow cytometry were used to detect morphological changes, mRNA and protein expression of the EMT markers E-Cadherin, Vimentin and Collagen type I following IL-6 stimulation. The data collected demonstrate that IL-6 can induce SGEC to undergo a morphological and phenotypical transition to a mesenchymal phenotype, in a dose-dependent manner. Decreased mRNA levels of E-Cadherin accompanied by higher mRNA levels of Vimentin and Collagen type I were observed in the IL-6-treated cells compared to control cells (all p < 0.05). This was confirmed at the protein level, demonstrating the decreased E-Cadherin expression, while Vimentin and Collagen type I expression was increased in IL-6-treated SGEC compared to controls (all p < 0.05). The results obtained corroborate the hypothesis that dysregulated cytokines IL-6 may contribute to the EMT-dependent fibrosis, offering a more complete understanding of the role of the EMT during SGs fibrosis in pSS.
Keywords Salivary gland · Sjögren’s syndrome · IL-6 · EMT · TGF-β1
Gene Expression Profiling Studies Using Microarray in Osteoarthritis: Genes in Common and Different Conditions
Weidong Liu · Yan Jiao · Cheng Tian · Karen Hasty · Lijie Song · Derek M. Kelly · Jianwei Li · Hong Chen · Weikuan Gu · Songjiang Liu
Abstract
Osteoarthritis (OA), which is characterized mainly by cartilage degradation, is the most prevalent joint disorder worldwide. Although OA is identified as a major cause of joint pain, disability, and socioeconomic burden, the etiology of OA is still not clearly known. Recently, gene microarray analysis has become an efficient method for the research of complex diseases and has been employed to determine what genes and pathways are involved in the pathological process of OA. In this review, OA study results over the last decade are summarized for gene expression profiling of various tissues, such as cartilage, subchondral bone, and synovium in human OA and mouse OA models. Many differentially expressed genes, which mainly involve matrix metabolism, bone turnover, and inflammation pathways, were identified in diseased compared with “normal” tissues Nevertheless, rare common genes were reported from studies using different tissue sources, microarray chips, and research designs. Thus, future novel and carefully designed microarray studies are required to elucidate underlying genetic mechanisms in the pathogenesis of OA as well as new directions for potential OA-targeted pharmaceutical therapies.
Keywords Osteoarthritis · Gene expression profiles · Articular cartilage · Subchondral bone · Synovium
The expression of bitter taste receptor TAS2R38 in patients with chronic rhinosinusitis
Karolina Zborowska‑Piskadło · Małgorzata Stachowiak · Natalia Rusetska · Elżbieta Sarnowska · Janusz Siedlecki · Karolina Dżaman
Abstract
Chronic rhinosinusitis (CRS) is a frequent disease with high social impact and multifactorial pathogenesis. Recently, the bitter taste receptor TAS2R38 has been described to play a role in upper airway innate mucosal defense. The aim was to determine the localization and expression of the TAS2R38 in the selected cell lines and tissue collected from patient suffered from CRS as well as to correlate the results with clinical data. Moreover, the purpose was the estimation of the TAS2R38 distribution changes during acute and CRS. Forty-two patients undergoing nasal surgery were enrolled in the study. The TAS2R38 expression was assessed in the collected tissues using immunohistochemistry and immunocytochemistry methods. The western blot analysis was performed on human cell lines HeLa, MCF7, MDA-MB-231 to assess the location of the TAS2R38 protein. Moreover, the HeLa cell line was used as a model of acute inflammation induces by lipopolysaccharide. Immunohistochemistry analysis displayed a statistically significant difference of TAS2R38 level in the patients with CRS compared to healthy control and was different in CRS with and without nasal polyps. The results showed the abundance of TAS2R38 receptor in the cell nucleus in patients with CRS and cell lines. The variance in TAS2R38 receptor expression in two CRS types suggests their different pathogenesis. The first time in literature, we confirmed the presence of plasma membrane TAS2R38 receptor in the cell nuclei in CRS as well as in cell lines, what strongly suggests the different than membrane TAS2R38 function.
Keywords TAS2R38 · Chronic rhinosinusitis · Bitter taste receptor
Intestinal Nematode Infection Affects Metastasis of EL4 Lymphoma Cells
Katarzyna Donskow‑Łysoniewska · Katarzyna Krawczak · Maja Machcińska · Klaudia Brodaczewska
Abstract
An effective host immune system prevents the growth of most cancer cells. However, as intestinal nematodes are able to induce both immunotolerance and immunosuppression in the host, it is possible that their presence could allow co-occurring cancer cells to proliferate and metastasize. Our findings indicate that previous, subsequent or concurrent intestinal nematode infection affects the formation of lung metastatic nodules in mice experimentally infected with Heligmosomoides polygyrus. In addition, pre-infection with nematodes renders mice resistant to metastasis development in lungs, with the inoculated EL4 cancer cells being located mainly in mesenteric lymph nodes. The present paper discusses the nematode-induced mechanisms which may influence the metastatic process.
Keywords Immunomodulation · Intestinal nematodes · Tumour · Metastasis
Pattern Recognition Receptors: Significance of Expression in the Liver
Jan Żeromski · Agata Kierepa · Bartosz Brzezicha · Arleta Kowala‑Piaskowska · Iwona Mozer‑Lisewska
Abstract
Pattern recognition receptors (PRRs) are a pivotal part of the immune system. They are distributed in almost every site of higher organisms, able to recognize foreign pathogens or unwanted remnants of metabolism and mount innate immune response. Moreover, PRRs create bridging signaling to initiate adaptive immunity. The liver being the largest organ of the body, exposed to myriads of foreign substances often being immunogenic, is well equipped with PRRs. They act as sentinels of the organ, both in health and disease. In viral hepatitis C at least two of them, RIG-1 and TLR3 sense HCV, induce protective interferon production and create proinflammatory status. The hepatitis B virus is apparently invisible to PRRs, which has recently been denied. Besides, they are active in the course of infection. In liver injury and hepatic fibrogenesis Toll-like receptors (TLRs), predominantly TLR4, TLR3 and TLR9 are associated with gut microflora-related products and DNA from dying hepatocytes, lead to the activation of hepatic stellate cells. The latter initiate production of fibrillar collagens, the main agents forming hepatic fibrosis. Tumor cells of primary liver cancer also express PRRs, mainly TLRs. In concert with non-resolving liver inflammation, they are considered pivotal factors leading to carcinogenesis.
Keywords PRRs · TLRs · Liver · Hepatitis · Hepatic fibrosis · Hepatocarcinogenesis
In Mixed Lymphocyte Reaction, the Hypoxia‑Inducible Factor Prolyl‑Hydroxylase Inhibitor Roxadustat Suppresses Cellular and Humoral Alloimmunity
Theodoros Eleftheriadis · Georgios Pissas · Athanasios Mavropoulos · Evdokia Nikolaou · Georgios Filippidis · Vassilios Liakopoulos · Ioannis Stefanidis
Abstract
Hypoxia-inducible factor (HIF) prolyl-hydroxylase inhibitors are currently used for the treatment of renal anemia. Since HIF affects immune cells, we evaluated the effect of such a drug, the roxadustat, on adaptive immunity. Cell proliferation was assessed in a two-way mixed lymphocyte reaction (MLR) with BrdU assay. In CD4+ T cells isolated from the two-way MLRs, western blotting was performed to detect the impact of roxadustat on HIF-1α and HIF-2α, the apoptotic marker cleaved caspase-3, and the master transcription factors of CD4+ T cells differentiation towards Th1, Th2, Th17, Treg and Tfh subsets. The signature cytokines of the above CD4+ T-cell subsets IFN-γ, IL-4, IL-17, IL-10, and IL-21 were measured in the supernatants. For assessing humoral immunity, we developed a suitable antibody-mediated complement-dependent cytotoxicity assay. Roxadustat stabilized HIF-1α and HIF-2α, suppressed cell proliferation, inhibited CD4+ T-cell differentiation into Th1 and Th17 subsets, while it favored differentiation towards Th2, Treg and Tfh. Roxadustat suppressed humoral immunity too. These immunosuppressive properties of roxadustat indicate that the recently introduced HIF prolylhydroxylase inhibitors in medical therapeutics may render the patients vulnerable to infections. This possibility should be further evaluated in clinical trials.
Keywords Roxadustat · Hypoxia-inducible factor · Cellular immunity · Humoral immunity · T-cell differentiation
A Proliferation‑Inducing Ligand Regulation in Polymorphonuclear Neutrophils by Panax ginseng
Wioletta Ratajczak‑Wrona1 · Natalia Wawrusiewicz‑Kurylonek2 · Marzena Garley1 · Adam Jacek Kretowski2,3 · Ewa Jablonska1
Abstract
A proliferation-inducing ligand (APRIL) is a member of the tumor necrosis factor superfamily that was first identified as a factor favoring tumorigenesis. APRIL is important fitness and survival factors for B cells and plasma cells in the periphery. Considering this, as well as the quantitative predominance of neutrophils among the peripheral blood leukocytes, we carried out the first study assessing the influence of the transforming growth factor (TGF)-β signaling pathway on APRIL expression in these cells. Furthermore, as the Rb1 ginsenoside is known to exhibit multiple pharmacological activities, we verified if the saponin is capable of modulating the process. The present study shows that TGF-β increased the expression of APRIL and the level of phospho-p38, phospho-Akt(T308), and phospho-Akt(S473) in the cytoplasmic fraction, as well as the expression of Fra1, c-Fos, and c-Jun in the nuclear fraction, of neutrophils. However, exposure of these cells to Rb1 reduced the expression and level of the investigated proteins. No changes were found in the expression of APRIL and the level of p-p38 in the cytoplasmic fraction of neutrophils following the application of Rb1 alone, as well as in the neutrophils incubated first with Rb1 and then with TGF-β, whereas a higher level of phosphorylation was observed for Akt and PI3 kinases in the cells. Moreover, a higher expression of all the studied transcription factors was observed in the nuclear fraction of neutrophils. Based on the observed changes, it may be assumed that the expression of APRIL molecule in TGF-β-induced neutrophils and its regulation by Rb1 are associated with PI3K/AKT signaling pathways and transcription factors Fra-1, Fra-2, c-Jun, and c-Fos. Rb1 appears to be a favorable factor that may be potentially used in the modulation of tumor-promoting APRIL expression.
Keywords APRIL · TGF-β · Ginsenoside Rb1 · Neutrophils · PI3K/Akt · p38
Astragaloside IV Exerts Anti‑tumor Effect on Murine Colorectal Cancer by Re‑educating Tumor‑Associated Macrophage
Feng Liu1 · Fang Ran2 · Hongqin He1 · Linyun Chen2
Abstract
Astragaloside IV (AS-IV) has shown anti-tumorigenic properties in certain cancers for its effect of boosting the body’s immune system, but its role in colorectal cancer (CRC) remains unclear. In this study, we investigated the therapeutic effect of AS-IV in CRC and explored its underlying mechanism. CT26 colon cancer cells and mouse model by injection of CT26 cells subcutaneously were used as in vitro and in vivo model. M1 and M2 macrophage-associated markers, mRNA and protein expression levels were analyzed after AS-IV treatment. Inflammatory factors and cytokines in the tumors from mouse model were detected. Repolarization effect of AS-IV in vitro on bone-marrow-derived macrophages was also detected. In vitro, AS-IV inhibited the proliferation of CT26 cells and induced cell apoptosis dose-dependently, and significantly reduced M2 macrophages and increased M1 macrophages. In mouse model, it suppressed tumor growth and decreased the production of anti-inflammatory factors such as TGF-β, IL-10 and VEGF-A, while increased the production of pro-inflammatory factors like IFN-γ, IL-12 and TNF-α in tumor. Combination of AS-IV and checkpoint inhibitor aPD-1 exhibited synergistic antitumor effect by inhibiting tumor growth and increasing T cell infiltration. AS-IV could induce M2 macrophages polarization to the M1 phenotype. Its combination with immune checkpoint inhibitors could be expected to become a potential new strategy for the treatment of CRC.
Keywords Colon cancer · Tumor-associated macrophages · Macrophage polarization · Astragaloside IV · Tumor microenvironmen
The Application of CAR‑T Cells in Haematological Malignancies
Katarzyna Skorka · Katarzyna Ostapinska · Aneta Malesa · Krzysztof Giannopoulos
Abstract
Chimeric antigen receptor (CAR)-T cells (CART) remain one of the most advanced and promising forms of adoptive T-cell immunotherapy. CART represent autologous, genetically engineered T lymphocytes expressing CAR, i.e. fusion proteins that combine components and features of T cells as well as antibodies providing their more effective and direct anti-tumour effect. The technology of CART construction is highly advanced in vitro and every element of their structure influence their mechanism of action in vivo. Patients with haematological malignancies are faced with the possibility of disease relapse after the implementation of conventional chemo-immunotherapy. Since the most preferable result of therapy is a partial or complete remission, cancer treatment regimens are constantly being improved and customized to individual patients. This individualization could be ensured by CART therapy. This paper characterized CART strategy in details in terms of their structure, generations, mechanism of action and published the results of clinical trials in haematological malignancies including acute lymphoblastic leukaemia, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia and multiple myeloma.
Keywords Chimeric antigen receptor · Chimeric antigen receptor T-cell · Lymphoblastic leukaemia · Diffuse large B-cell lymphoma · Chronic lymphocytic leukaemia · Multiple myeloma
SARS‑CoV‑2: Remarks on the COVID‑19 Pandemic
Egbert Piasecki
Abstract
The COVID-19 pandemic developing rapidly in 2020 is triggered by the emergence of a new human virus—SARS-CoV-2. The emergence of a new virus is not an unexpected phenomenon and has been predicted for many years. Since the virus has spread all over the world, it will be very difficult or even impossible to eradicate it. A necessary condition for complete or partial elimination of the virus is to have an effective vaccine. It is possible that SARS-CoV-2 will become milder in the next few years and COVID-19 will then only threaten individuals from risk groups.
Keywords COVID-19 · SARS-CoV-2 · Virus · Pandemic
Immune Checkpoint Blockade in Cancer Immunotherapy: Mechanisms, Clinical Outcomes, and Safety Profiles of PD‑1/PD‑L1 Inhibitors
Yan Yan · Li Zhang · Yun Zuo · Heya Qian · Chang Liu
Abstract
Programmed cell death protein 1 (PD-1) and its ligand PD-L1 are critical for the regulation of T cell exhaustion and activity suppression. Tumor cells expressing immune checkpoints including PD-L1 escape monitoring of T cells from the host immune system. Checkpoint inhibitors are highly promising therapies that function as tumor-suppressing factors via modulation of tumor cell–immune cell interactions as well as boosting T cell-mediated anti-tumor immunity. Notably, PD-1 or PD-L1 monoclonal antibody (mAb) has demonstrated promising therapeutic effects in clinical studies of many types of cancer. These mAbs have caused significant tumor regression with impressive anti-tumor response rates as well as a favorable safety profile in cancer patients. Furthermore, the combination of PD-1/PD-L1 mAbs with other types of anti-tumor agents has also developed to boost the anti-tumor responses and enhance therapeutic effects in cancer patients. This review clarifies the mechanisms of PD-1/PD-L1-mediated anti-cancer immune responses and some clinical studies of mAbs targeting PD-1/PD-L1. The challenges and future of PD-1/PD-L1 blockade therapy are also discussed.
Keywords Immune checkpoints · PD-1 · PD-L1 · Monoclonal antibody · Immunotherapy
DPP4 Inhibitors and COVID‑19–Holy Grail or Another Dead End?
Alicja Krejner‑Bienias · Katarzyna Grzela · Tomasz Grzela
Abstract
A novel coronavirus disease, COVID-19, has emerged as a global public health issue. Clinical course of disease significantly correlates with the occurrence of some comorbidities, among them type 2 diabetes. According to recent structural studies the dipeptidyl peptidase 4, a key molecule in the pathophysiology of diabetes, may influence the course of COVID-19. Since DPP4 inhibitors, gliptins, are widely used in diabetes patients, the exact role of DPP4 modulation in SARS-CoV-2 infection, at least in that group, urgently needs to be clarified. In this short review, we discuss this issue with more detail.
Keywords SARS-CoV-2 · COVID-19 · DPP4 · Gliptins · Diabetes