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Atlantic salmon (Salmo salar) were experimentally infected with Lepeophtheirus salmonis copepodids and aspects of the host’s immune response investigated. Copepodid secretory/excretory product (SEP) produced during early settlement was analysed using fast-protein liquid chromatography (FPLC), sodium dodecyl sulphate (SDS)-electrophoresis and zymography. Following establishment and the appearance of the chalimus stages, the expression of the chemokine interleukin-8 (IL-8) in the heart, spleen, head kidney, fins, liver and pyloric cæca was investigated using real-time (quantitative) PCR (qPCR). Furthermore, the secretions of L. salmonis chalimus were analysed for the presence of the prostanoid PGE2 using commercially available enzyme-linked immunoassay (EIA) kits. Analysis of copepodid secretory/excretory product suggested that any immunosuppressive component is not proteinaceous in nature. Whilst there was a definite increase in protein concentration of SEP relative to control SEP, further analysis using subtractive chromatographic analysis did not reveal any unique fraction present in either SEP or CSEP that was absent in the other. Interleukin-8 expression levels in tissues changed following L. salmonis infection, with heart and spleen showing significant increases in IL-8 gene expression, whilst the head kidney, fins, liver and pyloric cæca showed no significant increase. The increase in splenic IL-8 expression may be linked to its role as one of the major secondary lymphoid organs. However, this is the first record of increase in IL-8 expression in cardiac tissue. The secretions of L. salmonis chalimus were found to contain quantifiable levels of PGE2, albeit in highly variable quantities. This concurs with already published findings for adult L. salmonis (see Fast, et al. 2004). It is proposed that the chalimus states us the PGE2 to modulate the hosts’ immune response at the site of attachment and feeding.

The present chemical investigation on the organic extract of the soft coral Sarcophyton cinereum has contributed to the isolation of four new cembranoids: 16β- and 16α-hydroperoxyisosarcophytoxides (1 and 2), 16β- and 16α-methoxyisosarcophytoxides (3 and 4), and a known cembranoid, lobocrasol (5). The structures of all isolates were elucidated by detailed spectroscopic analysis. Their structures were characterized by a 2,5-dihydrofuran moiety, of which the relative configuration was determined by DU8-based calculation for long-range coupling constants (4JH,H). The cytotoxicity and immunosuppressive activities of all isolates were evaluated in this study.

Voltage-gated potassium channel KV1.3 inhibitors have been shown to be effective in preventing T-cell proliferation and activation by affecting intracellular Ca2+ homeostasis. Here, we present the structure-activity relationship, KV1.3 inhibition, and immunosuppressive effects of new thiophene-based KV1.3 inhibitors with nanomolar potency on K+ current in T-lymphocytes and KV1.3 inhibition on Ltk− cells. The new KV1.3 inhibitor trans-18 inhibited KV1.3 -mediated current in phytohemagglutinin (PHA)-activated T-lymphocytes with an IC50 value of 26.1 nM and in mammalian Ltk− cells with an IC50 value of 230 nM. The KV1.3 inhibitor trans-18 also had nanomolar potency against KV1.3 in Xenopus laevis oocytes (IC50 = 136 nM). The novel thiophene-based KV1.3 inhibitors impaired intracellular Ca2+ signaling as well as T-cell activation, proliferation, and colony formation.

Tumor cells have evolved to express immunosuppressive molecules allowing their evasion from the host’s immune system. These molecules include programmed death ligands 1 and 2 (PD-L1 and PD-L2). Cancer cells can also produce acetylcholine (ACh), which plays a role in tumor development. Moreover, tumor innervation can stimulate vascularization leading to tumor growth and metastasis. The effects of atropine and muscarinic receptor 3 (M3R) blocker, 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP), on cancer growth and spread were evaluated in vitro using murine colon cancer cell line, CT-26, and in vivo in an orthotopic mouse model of colorectal cancer. In the in vitro model, atropine and 4-DAMP significantly inhibited CT-26 cell proliferation in a dose dependent manner and induced apoptosis. Atropine attenuated immunosuppressive markers and M3R via inhibition of EGFR/AKT/ERK signaling pathways. However, 4-DAMP showed no effect on the expression of PD-L1, PD-L2, and choline acetyltransferase (ChAT) on CT-26 cells but attenuated M3R by suppressing the phosphorylation of AKT and ERK. Blocking of M3R in vivo decreased tumor growth and expression of immunosuppressive, cholinergic, and angiogenic markers through inhibition of AKT and ERK, leading to an improved immune response against cancer. The expression of immunosuppressive and cholinergic markers may hold potential in determining prognosis and treatment regimens for colorectal cancer patients. This study’s results demonstrate that blocking M3R has pronounced antitumor effects via several mechanisms, including inhibition of immunosuppressive molecules, enhancement of antitumor immune response, and suppression of tumor angiogenesis via suppression of the AKT/ERK signaling pathway. These findings suggest a crosstalk between the cholinergic and immune systems during cancer development. In addition, the cholinergic system influences cancer evasion from the host’s immunity.

Yasmeen Ezzeldeen,1 Shady Swidan,1,2 Aliaa ElMeshad,3,4 Aya Sebak5 1Department of Pharmaceutics, Faculty of Pharmacy, The British University in Egypt (BUE), El-Sherouk City, Cairo, 11837, Egypt; 2The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo, 11837, Egypt; 3Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt; 4Department of Bio Nano, Faculty of Nanotechnology for Postgraduate Studies, Cairo University, El-Sheikh Zayed, Giza, 12588, Egypt; 5Department of Pharmaceutical Technology, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), Cairo, EgyptCorrespondence: Shady Swidan Tel +20 10-0221-1048Email shady.swidan@bue.edu.egAliaa ElMeshad Tel +20 10-0010-1551Email aliaa.elmeshad@pharma.cu.edu.egBackground: Honokiol (HK) is a natural bioactive compound with proven antineoplastic properties against melanoma. However, it shows very low bioavailability when administered orally. Alternatively, topical administration may offer a promising route. The objective of the current study was to fabricate HK transfersomes (HKTs) for topical treatment of melanoma. As an ultradeformable carrier system, transfersomes can overcome the physiological barriers to topical treatment of melanoma: the stratum corneum and the anomalous tumor microenvironment. Moreover, the immunomodulatory and stemness-regulation roles of HKTs were the main interest of this study.Methods: TFs were prepared using the modified scalable heating method. A three-factor, three-level Box–Behnken design was utilized for the optimization of the process and formulation variables. Intracellular uptake and cytotoxicity of HKTs were evaluated in nonactivated and stromal cell–activated B16F10 melanoma cells to investigate the influence of the complex tumor microenvironment on the efficacy of HK. Finally, ELISA and Western blot were performed to evaluate the expression levels of TGF-β and clusters of differentiation (CD47 and CD133, respectively).Results: The optimized formula exhibited a mean size of 190 nm, highly negative surface charge, high entrapment efficiency, and sustained release profile. HKTs showed potential to alleviate the immunosuppressive characteristics of B16F10 melanoma in vitro via downregulation of TGF-β signaling. In addition, HKTs reduced expression of the “do not eat me” signal — CD47. Moreover, HKTs possessed additional interesting potential to reduce the expression of the stem-like cell marker CD133. These outcomes were boosted upon combination with metformin, an antihyperglycemic drug recently reported to possess different functions in cancer, while combination with collagenase, an extracellular matrix–depleting enzyme, produced detrimental effects.Conclusion: HKTs represent a promising scalable formulation for treatment of the aggressive B16F10 melanoma, which is jam-packed with immunosuppressive and stem-like cell markers.Keywords: honokiol, melanoma, transfersomes, heating method, tumor microenvironment, immunosuppressive, stem-like cell

Immunomodulatory agents are often used in the systemic treatment of non-infectious uveitis. These drugs consist of corticosteroids, conventional immunosuppressives, and biological agents. As it is known that they suppress the immune system, the most important concern associated with immunomodulatory therapy (IMT) is the increased risk of infection. The World Health Organization declared COVID-19 a pandemic on 11 March 2020. Although severe acute respiratory distress syndrome secondary to SARS-CoV-2 infection may develop in all people, patients who receive IMT may be at higher risk in terms of both the transmission of the infection and more severe disease course. Therefore, guidelines on the management of patients receiving IMT due to uveitis during the pandemic are needed. In this review, we examined the immunomodulatory drugs used in the treatment of uveitis in terms of infectious complications and the data of patients who received IMT during the COVID-19 pandemic and discussed recommendations for the use of these drugs. According to the latest information, patients who receive IMT may continue their treatment as long as there are no disruptions in regular complete blood count (especially white blood cell count >4,000/μL) and liver and kidney function tests. Patients diagnosed with COVID-19 should be managed with a multidisciplinary approach.

Background General role of cancer-associated fibroblast (CAF) and its infiltration characteristics in gastric cancer remains to be unknown. Methods We estimate CAF infiltration in bulk tumor tissue with RNA-seq data and analyzed its relationship with gastric cancer subtype, survival and immune microenvironment. Results We revealed CAF intend to have higher infiltration in diffuse, genomically stable, and advanced gastric cancer. CAF is associated with immunosuppressive microenvironment. Wide transcriptomics alterations occur in high CAF infiltrated gastric cancer, PI3K/AKT, TGFB and Hedgehog pathway are remarkable in this procedure. We utilized receptor tyrosine kinases and TGFB pathway ligands to construct risk score system that can predict survival. Conclusion Thus, CAF is associated with aggressive phenotype of gastric cancer and risk score based on RTK and TGFB pathway ligands expression is a promising tool for assessment of gastric cancer survival.

Background Psoriasis is a chronic skin disease that needs continuous medical care. During COVID-19, delivering medical service was negatively affected. Aims To describe the impact of COVID-19 on psoriasis healthcare delivery, management, and practice. Methods This observational cross-sectional study was conducted on 197 dermatologists using a validated online questionnaire. The survey evaluated the effect of COVID-19 on the decisions, prescription patterns, appointments rescheduling, and healthcare delivery for psoriasis patients by dermatologists. The questionnaire was developed and validated with a reliability score >0.7. Results During the pandemic, most dermatologists delayed initiating biological/immunosuppressive therapy for psoriasis unless urgently needed by the patient. For patients already receiving biologics or immunosuppressive treatment, most dermatologists favored continuation of therapy. Almost half (44.2%) of participants do not perform SARS-CoV-2 PCR screening before initiating biologics/immunosuppressive therapy. Dermatologists also reported an increased prescription of topical medications (79.2%), natural sunlight (28.4%), acitretin (26.9%), and home UVB (21.3%). Opinions regarding the use of hydroxychloroquine for COVID-19 treatment/prophylaxis for psoriasis patients were controversial. Intervals between face-to-face follow-up visits were prolonged by 71.6% of dermatologists. More than half of participants reported that their patients discontinued treatment without medical consultation. More than three fourth of responders either agreed or strongly agreed that COVID-19 negatively affected psoriasis patients. Conclusions The COVID-19 pandemic has a negative impact on psoriasis management and healthcare delivery. Dermatologists are cautious about using biologics and immunosuppressive drugs during the pandemic, making case-by-case decisions. Psoriasis patients need compliance monitoring, and psychological support during the pandemic, which can be facilitated by teledermatology.

Highlights Mechanisms underlying immunosuppressive tumor immune microenvironment (TIME) in ‘cold’ tumor are summarized.Recent nanotechnology-based strategies for ‘cold’ TIME firing up are emphasized.Challenges and perspectives of nanomedicines for ‘cold’ tumor treatment are proposed., Although current anticancer immunotherapies using immune checkpoint inhibitors (ICIs) have been reported with a high clinical success rate, numerous patients still bear ‘cold’ tumors with insufficient T cell infiltration and low immunogenicity, responding poorly to ICI therapy. Considering the advancements in precision medicine, in-depth mechanism studies on the tumor immune microenvironment (TIME) among cold tumors are required to improve the treatment for these patients. Nanomedicine has emerged as a promising drug delivery system in anticancer immunotherapy, activates immune function, modulates the TIME, and has been applied in combination with other anticancer therapeutic strategies. This review initially summarizes the mechanisms underlying immunosuppressive TIME in cold tumors and addresses the recent advancements in nanotechnology for cold TIME reversal-based therapies, as well as a brief talk about the feasibility of clinical translation.

Paris criteria remain practical for retaining the diagnosis of overlap syndrome. While liver histology is mandatory, its absence should not be an obstacle to the diagnosis and delay the initiation of treatment in countries where biopsy not available.

Breast cancer is the leading cause of cancer-related death among women despite the significant improvement in diagnosis and treatment. Tumor-associated neutrophils have been shown to suppress antitumor functions of the host. However, how breast cancer tumor microenvironment influences the phenotype and functions of neutrophils to potentiate T cell immunosuppression is unknown. Herein, neutrophils isolated from peripheral blood of healthy donors were treated with supernatants from breast cancer cell lines or recombinant human CCL20. PD-L1 expression on neutrophils was then evaluated by immunofluorescence and flow cytometry. Neutrophils and Jurkat T cells were cocultured to evaluate the effect of tumor-associated neutrophils on T cell functions. Finally, immunohistochemical staining was performed to evaluate the clinical relevance of neutrophils infiltrating breast tumor tissues. Tumor-derived CCL20 activated and upregulated PD-L1 expression on neutrophils. A significant positive correlation was found between CCL20 and CD66b+ neutrophils in tumor tissues. Through in vitro experiment, tumor-associated neutrophils (TANs) effectively suppressed T cell immunity which was reversed upon PD-L1 blockade. Moreover, a high density of TANs was associated with short disease free survival in breast cancer patients. Furthermore, receiver operating curve showed that the density of TANs could accurately predict disease-free survival in breast cancer patients. Our findings suggest that targeting TANs via CCL20 immunosuppressive pathway may be a novel therapeutic strategy for breast cancer treatment.

Background It is debated whether patients with IgAN with heavy proteinuria and decreased eGFR benefit from aggressive treatment consisting of corticosteroids alone or combined with immunosuppressive agents. Methods A retrospective study was performed between January 2008 and December 2016 on patients with IgAN who had urinary protein excretion > 1.0 g/d and an eGFR between 15 and 59 mL/min/1.73 m2. These patients were assigned to receive supportive care alone or supportive care plus immunosuppressive therapy. The primary outcome was defined as the first occurrence of a 50% decrease in eGFR or the development of ESKD. Results All 208 included patients were followed for a median of 43 months, and 92 (44%) patients experienced the primary outcome. Cumulative kidney survival was better in the immunosuppression group than in the supportive care group (p

Rheumatology practice, during Coronavirus Disease 2019 (COVID-19) pandemic, has faced multifaceted challenges. Rheumatologists routinely prescribe immunosuppressant medications to their patients with multisystem autoimmune rheumatic diseases who are concerned about the increased risk of acquiring COVID-19 infection and are anxious to know if they should continue or hold these medications. Rheumatologists are often inundated by calls from their patients and physician colleagues caring for COVID-19 patients in hospitals, about how to manage the immunosuppression. Physicians face the challenging task of keeping up with the most up-to-date information on COVID-19. There are uncertainties about the mode of spread, clinical features, management options as well as long-term complications of COVID-19. Data are rapidly evolving and different studies on treatment options are showing contradictory results. It is known that viral illnesses can trigger a flare-up of underlying rheumatic disease that was previously in remission. To further complicate the scenario, some of the immunosuppressants have shown to have antiviral properties. This has created dilemma in the light of current COVID-19 crisis, as whether to continue or stop the immunosuppressive agents which could be essential to prevent complications of the rheumatic diseases including organ failure but also there is concern about acquiring COVID-19 or developing serious infection. Until we get an effective vaccine, immunosuppressant management for rheumatic diseases as well as other autoimmune diseases and transplants will pose difficult questions. This article is an attempt to review and understand COVID-19 and its impact on the immune system with special emphasis on managing medications used for autoimmune rheumatic diseases. We have provided general guidance about decision making, in regards to the immunosuppressive agents used in rheumatology practice with an understanding that this may change in near future.

Background Over the month of April, Spain has become the European country with more confirmed cases of COVID-19 infection, after surpassing Italy on April 2nd. The community of Castile and León in Spain is one of the most affected by COVID-19 infection and the province of León has a total of 3711 cases and 425 deaths so far. Rheumatic patients should be given special attention regarding COVID-19 infection due to their immunocompromised state resulting from their underlying immune conditions and use of targeted immune-modulating therapies. Studying epidemiological and clinical characteristics of patients with rheumatic diseases infected with SARS-CoV2 is pivotal to clarify determinants of COVID-19 disease severity in patients with underlying rheumatic disease. Objectives To describe epidemiological characteristics of patients with rheumatic diseases hospitalized with COVID-19 and determine risk factors associated with mortality in a third level Hospital setting in León, Spain. Methods We performed a prospective observational study, from 1st March 2020 until the 1st of June including adults with rheumatic diseases hospitalized with COVID-19 and performed a univariate and multivariate logistic regression model to estimate ORs and 95% CIs of mortality. Age, sex, comorbidities, rheumatic disease diagnosis and treatment, disease activity prior to infection, radiographic and laboratorial results at arrival were analysed. Results During the study period, 3711 patients with COVID-19 were admitted to our hospital, of whom 38 (10%) had a rheumatic or musculoskeletal disease. Fifty-three percent were women, with a mean age at hospital admission of 75.3 (IQR 68–83) years. The median length of stay was 11 days. A total of 10 patients died (26%) during their hospital admission. Patients who died from COVID-19 were older (median age 78.4 IQR 74.5–83.5) than those who survived COVID-19 (median age 75.1 IQR 69.3–75.8) and more likely to have arterial hypertension (9 [90%] vs 14 [50%] patients; OR 9 (95% CI 1.0–80.8), p 0.049), dyslipidaemia (9 (90%) vs 12 (43%); OR 12 (95% CI 1.33–108), p 0.03), diabetes ((9 (90%) vs 6 (28%) patients; OR 33, p 0.002), interstitial lung disease (6 (60%) vs 6 (21%); OR 5.5 (95% CI 1.16–26), p 0.03), cardiovascular disease (8 (80%) vs 11 (39%); OR 6.18 (95% IC 1.10–34.7, p 0.04) and a moderate/high index of rheumatic disease activity (7 (25%) vs 6(60%); OR 41.4 (4.23–405.23), p 0.04). In univariate analyses, we also found that patients who died from COVID-19 had higher hyperinflammation markers than patients who survived: C-reactive protein (181 (IQR 120–220) vs 107.4 (IQR 30–150; p 0.05); lactate dehydrogenase (641.8 (IQR 465.75–853.5) vs 361 (IQR 250–450), p 0.03); serum ferritin (1026 (IQR 228.3–1536.3) vs 861.3 (IQR 389–1490.5), p 0.04); D-dimer (12,019.8 (IQR 843.5–25,790.5) vs 1544.3 (IQR 619–1622), p 0.04). No differences in sex, radiological abnormalities, rheumatological disease, background therapy or symptoms before admission between deceased patients and survivors were found. In the multivariate analysis, the following risk factors were associated with mortality: rheumatic disease activity (p = 0.003), dyslipidaemia (p = 0.01), cardiovascular disease (p = 0.02) and interstitial lung disease (p = 0.02). Age, hypertension and diabetes were significant predictors in univariate but not in multivariate analysis. Rheumatic disease activity was significantly associated with fever (p = 0.05), interstitial lung disease (p = 0.03), cardiovascular disease (p = 0.03) and dyslipidaemia (p = 0.01). Conclusions Our results suggest that comorbidities, rheumatic disease activity and laboratorial abnormalities such as C-reactive protein (CRP), D-Dimer, lactate dehydrogenase (LDH), serum ferritin elevation significantly associated with mortality whereas previous use of rheumatic medication did not. Inflammation is closely related to severity of COVID-19.Key Points• Most patients recover from COVID-19.• The use of DMARDs, corticosteroids and biologic agents did not increase the odds of mortality in our study.• Rheumatic disease activity might be associated with mortality.

Mahtabalsadat Mirjalili,1 Mojtaba Shafiekhani,1,2 Afsaneh Vazin1 1Department of Clinical Pharmacy, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; 2Shiraz Organ Transplant Center, Abu-Ali Sina Hospital, Shiraz University of Medical Sciences, Shiraz, IranCorrespondence: Mojtaba ShafiekhaniShiraz Organ Transplant Center, Abu-Ali Sina Hospital, Shiraz University of Medical Sciences, Shiraz, IranTel +9871133441551Fax +987136430038Email mojtabashafiekhani@gmail.comAfsaneh VazinDepartment of Clinical Pharmacy, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, IranTel| Fax +987132424255Email vazeena@sums.ac.irAbstract: The 2019 novel coronavirus disease (COVID-19) was first detected in Wuhan, Hubei Province, China, in late 2019. Since then, COVID-19 has spread to more than 200 countries in the world, and a global pandemic has been declared by the World Health Organization (WHO). At present, no vaccines or therapeutic regimens with proven efficacy are available for the management of COVID-19. Hydroxychloroquine/chloroquine, lopinavir/ritonavir, ribavirin, interferons, umifenovir, remdesivir, and interleukin antagonists, such as tocilizumab, have been recommended as potential treatment options in COVID-19. Transplant patients receiving immunosuppressant medications are at the highest risk of severe illness from COVID-19. At the same time, with regard to receiving polypharmacy and immunosuppressants, treatment options should be chosen with more attention in this population. Considering drug–drug interactions and adverse effects of medications used for the treatment of COVID-19, such as QT prolongation, the dose reduction of some immunosuppressants or avoidance is recommended in transplant recipients with COVID-19. Thus, this narrative review describes clinically important considerations about the treatment of COVID-19 and immunosuppressive regimens regarding modifications, side effects, and interactions in adult kidney or liver allograft recipients.Keywords: SARS-CoV-2, COVID-19, liver transplant, kidney transplant, immunosuppressive, transplantation

The 2019 novel coronavirus disease (COVID-19) was first detected in Wuhan, Hubei Province, China, in late 2019. Since then, COVID-19 has spread to more than 200 countries in the world, and a global pandemic has been declared by the World Health Organization (WHO). At present, no vaccines or therapeutic regimens with proven efficacy are available for the management of COVID-19. Hydroxychloroquine/chloroquine, lopinavir/ritonavir, ribavirin, interferons, umifenovir, remdesivir, and interleukin antagonists, such as tocilizumab, have been recommended as potential treatment options in COVID-19. Transplant patients receiving immunosuppressant medications are at the highest risk of severe illness from COVID-19. At the same time, with regard to receiving polypharmacy and immunosuppressants, treatment options should be chosen with more attention in this population. Considering drug–drug interactions and adverse effects of medications used for the treatment of COVID-19, such as QT prolongation, the dose reduction of some immunosuppressants or avoidance is recommended in transplant recipients with COVID-19. Thus, this narrative review describes clinically important considerations about the treatment of COVID-19 and immunosuppressive regimens regarding modifications, side effects, and interactions in adult kidney or liver allograft recipients.

The time and cost of developing new drugs have led many groups to limit their search for therapeutics to compounds that have previously been approved for human use. Many “repurposed” drugs, such as derivatives of thalidomide, antibiotics, and antivirals have had clinical success in treatment areas well beyond their original approved use. These include applications in treating antibiotic‐resistant organisms, viruses, cancers and to prevent burn scarring. The major theoretical justification for reusing approved drugs is that they have known modes of action and controllable side effects. Coadministering antibiotics with inhibitors of bacterial toxins or enzymes that mediate multidrug resistance can greatly enhance their activity. Drugs that control host cell pathways, including inflammation, tumor necrosis factor, interferons, and autophagy, can reduce the “cytokine storm” response to injury, control infection, and aid in cancer therapy. An active compound, even if previously approved for human use, will be a poor clinical candidate if it lacks specificity for the new target, has poor solubility or can cause serious side effects. Synergistic combinations can reduce the dosages of the individual components to lower reactivity. Preclinical analysis should take into account that severely ill patients with comorbidities will be more sensitive to side effects than healthy trial subjects. Once an active, approved drug has been identified, collaboration with medicinal chemists can aid in finding derivatives with better physicochemical properties, specificity, and efficacy, to provide novel therapies for cancers, emerging and rare diseases.

Coronavirus disease 2019 (COVID-19) was reported as a global pandemic in March 2020 after invading many countries and leaving behind tens of thousands of infected patients in a brief time span. Approval of a few vaccines has been obtained and their efficacy of varying degrees established. Still, there is no effective pharmaceutical agent for the treatment of COVID-19 though several drugs are undergoing clinical trials. Recent studies have shown that dexamethasone, a corticosteroid, can reduce the rate of COVID-19-related mortality in the intensive care unit by 35 % for patients who are on mechanical ventilation. Although variable efficacy of other combination therapies has been reported for treating COVID-19 associated with acute respiratory distress syndrome (ARDS), dexamethasone is an extensively used drug in many treatment regimens against COVID-19. The current review aims to explore the role of dexamethasone as an efficient combination treatment for COVID-19.

Endometriosis is an inflammatory disease that presents with ectopic endometriotic lesions. Reduced immunosurveillance of these lesions has been proposed to be playing a role in the pathology of endometriosis. Mesenchymal stromal cells (MSC) are found in ectopic lesions and may decrease immunosurveillance. In the present study, we examined if MSC contribute to reduced immunosurveillance through their immunosuppressive effects on natural killer (NK) cells. Stromal cells from endometriotic ovarian cysts (ESCcyst) and eutopic endometrium (ESCendo) of women with endometriosis and their conditioned medium were used in co-cultures with allogeneic peripheral blood NK cells. Following culture, NK cells were examined phenotypically for their expression of activating, inhibitory, maturation, and adhesion receptors and co-receptors, as well as the degranulation (CD107a) marker and the immunostimulatory (interferon-γ) and immunosuppressive (transforming growth factor beta 1 and interleukin-10) cytokines. Moreover, NK cell cytotoxicity was examined using chromium 51 release killing assays. There were no differences between ESCcyst and ESCendo regarding their effects on NK cell cytotoxicity in both conditioned medium and direct co-culture experiments. Additionally, there were no differences between ESCcyst and ESCendo regarding their impact on NK cells’ phenotype and degranulation in both conditioned medium and direct co-culture experiments. Although there were no differences found for DNAX accessory molecule-1 (DNAM-1) and NKp44, we found that the expression of the NK cell ligand CD155 that binds DNAM-1 and proliferating cell nuclear antigen (PCNA) that binds NKp44 was significantly less on ESCcyst than on ESCendo. These findings were not supported by the results that the expression of the known and unknown ligands on ESCcyst for DNAM-1 and NKp44 using chimeric proteins was not significantly different compared to ESCendo. In conclusion, the results suggest that ectopic MSC may not contribute to reduced immunosurveillance in endometriosis through their inhibitory effects on NK cells. This suggests that NK cell inhibition in the pelvic cavity of women with endometriosis develops due to other factors.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by inflammation and joint destruction. Herein, an inflamed joint‐targeting delivery platform is developed based on platelet‐derived extracellular vesicles (PEVs) that are naturally occurring nanoparticles released by platelets, loaded with berberine (BBR) for suppressing the progress of RA. It is found that PEVs could selectively target the inflamed arthritis site in RA mice. In addition, BBR‐loaded PEVs exert anti‐inflammatory effects by reshaping the inflammatory environment in affected joints. It is shown that intravenous injection of BBR‐loaded PEVs into RA mice can effectively reduce joint swelling and bone erosion and restore mobility compared with free drug therapy. This strategy can effectively enhance the efficacy of RA treatment with limited side effects.

Epstein-Barr virus (EBV) is endemic worldwide and is associated with a number of human tumors. EBV-associated tumors have unique mechanisms of tumorigenesis. EBV encodes multiple oncogenic molecules that can be loaded into exosomes released by EBV+ tumor cells to mediate intercellular communication. Moreover, different EBV+ tumor cells secrete exosomes that act on various target cells with various biological functions. In addition to oncogenicity, EBV+ exosomes have potential immunosuppressive effects. Investigating EBV+ exosomes could identify the role of EBV in tumorigenesis and progression. The present review summarized advances in studies focusing on exosomes and the functions of EBV+ exosomes derived from different EBV-associated tumors. EBV+ exosomes are expected to become a new biomarker for disease diagnosis and prognosis. Therefore, exosome-targeted therapy displays potential.

O transplante renal é tipo mais frequente de transplante de órgãos no Brasil, possui processo complexo, envolvendo aspectos éticos, imunológicos somados a condições específicas do doador e do receptor, e que podem acarretar problemas pós-operatórios, incluindo a hipertensão arterial. A HAS desenvolvida pós-transplante renal se correlaciona com desfechos cardiovasculares e renais negativos, cursando com deficiência de função renal, diminuição da sobrevida do enxerto e maior mortalidade por essas causas. A proposta consiste em uma revisão integrativa de literatura sobre a gênese da hipertensão arterial sistêmica em pacientes após realização de transplante renal, composto por artigos originais, publicados no período de 2012 a 2022, em periódicos revisados por pares, nos idiomas português, inglês e espanhol, e que permitam acesso integral ao conteúdo. Foi visto que a gênese da HAS em pacientes transplantados renais pode ser relacionada a fatores como produção de substâncias vasopressoras mantenedoras do SRAA, uso de imunossupressores como glicocorticoides e INC, além de estenose ou trombose da artéria do enxerto renal, associada ou não a fístula arteriovenosa e presença de proteinúria após o procedimento de transplante, bem como a predisposição genética como fator estimulante, especialmente mutações genéticas do tipo APOL1 e CAV-1, sejam do doador ou do receptor. Concluiu-se que a hipertensão arterial sistêmica em transplantados renais tem gênese multifatorial e pode prejudicar de forma sistemática a função fisiológica normal do órgão, bem como a perda do enxerto e diminuição da expectativa de vida desses pacientes. Kidney transplantation is the most frequent type of organ transplantation in Brazil, has a complex process, involving ethical, immunological aspects added to specific conditions of the donor and the recipient, and that can cause postoperative problems, including hypertension. The SAH developed after renal transplantation correlates with negative cardiovascular and renal outcomes, leading to impaired renal function, decreased graft survival and increased mortality from these causes. The proposal consists of an integrative review of the literature on the genesis of systemic arterial hypertension in patients after renal transplantation, composed of original articles, published from 2012 to 2022, in peer-reviewed journals, languages, and that allow full access to the content. It was seen that the genesis of hypertension in renal transplant patients can be related to factors such as the production of vasopressor substances that support RAAS, use of immunosuppressants such as glucocorticoids and INC, as well as stenosis or thrombosis of the renal graft artery, Arteriovenous fistula and the presence of proteinuria after the transplantation procedure, as well as genetic predisposition as a stimulating factor, especially genetic mutations such as APOL1 and CAV-1, whether from the donor or the recipient. It was concluded that systemic arterial hypertension in renal transplants has multifactorial genesis and can systematically impair the normal physiological function of the organ, as well as the loss of the graft and decreased life expectancy of these patients. El trasplante renal es un tipo más frecuente de trasplante de órganos en Brasil, posee un proceso complejo, involucrando aspectos éticos, inmunológicos sumados a condiciones específicas del donante y del receptor, y que pueden acarrear problemas postoperatorios, incluyendo la hipertensión arterial. La HAS desarrollada post-trasplante renal se correlaciona con resultados cardiovasculares y renales negativos, cursando con deficiencia de función renal, disminución de la supervivencia del injerto y mayor mortalidad por esas causas. La propuesta consiste en una revisión integrativa de literatura sobre la génesis de la hipertensión arterial sistémica en pacientes tras realización de trasplante renal, compuesto por artículos originales, publicados en el período de 2012 a 2022, en revistas revisadas por pares, en los idiomas portugués, inglés y español, y que permitan acceso integral al contenido. Se ha visto que la génesis de la HAS en pacientes trasplantados renales puede estar relacionada a factores como producción de sustancias vasopresoras mantenedoras del SRAA, uso de inmunosupresores como glucocorticoides y INC, además de estenosis o trombosis de la arteria del injerto renal, asociada o no a la fístula arteriovenosa y presencia de proteinuria después del procedimiento de trasplante, así como la predisposición genética como factor estimulante, especialmente mutaciones genéticas del tipo APOL1 y CAV-1, sean del donante o del receptor. Se concluyó que la hipertensión arterial sistémica en trasplantados renales tiene génesis multifactorial y puede perjudicar de forma sistemática la función fisiológica normal del órgano, así como la pérdida del injerto y disminución de la expectativa de vida de esos pacientes.

Simple Summary Hyperglycosylated cancer cells are often decorated with abundant sialic acids, which are recognized by Sialic acid binding immunoglobulin type lectins (Siglecs) expressed on immune cells. As sialic acids are normally expressed on almost all cell types, Siglecs can function as receptors for “self”. Presently, 15 human Siglecs (including non-sialic acid binding Siglec XII) are known, of which most are immunoinhibitory receptors that induce strong inhibitory signaling when Siglecs bind sialic acids. Hence, tumor cells use hyper sialic acid expression in their favor to modify the immune system that can lead to immune suppression. Such engagement along the Siglec-sialic acid axis can dampen major killing modes of effector immune cells and suppress the activation of immune responses, which can lead to immune tolerance and tumor growth. In this review, we emphasized recent studies on all 15 Siglecs found in humans, many of which still remain understudied. In addition, we highlighted different strategies in disrupting the surface Siglec-sialic acid interactions, including antibodies and glycan moieties, which can steer back antitumor immune responses to reduce tumor size and improve overall survival of cancer patients. Abstract Hypersialylation is a common post-translational modification of protein and lipids found on cancer cell surfaces, which participate in cell-cell interactions and in the regulation of immune responses. Sialic acids are a family of nine-carbon α-keto acids found at the outermost ends of glycans attached to cell surfaces. Given their locations on cell surfaces, tumor cells aberrantly overexpress sialic acids, which are recognized by Siglec receptors found on immune cells to mediate broad immunomodulatory signaling. Enhanced sialylation exposed on cancer cell surfaces is exemplified as “self-associated molecular pattern” (SAMP), which tricks Siglec receptors found on leukocytes to greatly down-regulate immune responsiveness, leading to tumor growth. In this review, we focused on all 15 human Siglecs (including Siglec XII), many of which still remain understudied. We also highlighted strategies that disrupt the course of Siglec-sialic acid interactions, such as antibody-based therapies and sialic acid mimetics leading to tumor cell depletion. Herein, we introduced the central roles of Siglecs in mediating pro-tumor immunity and discussed strategies that target these receptors, which could benefit improved cancer immunotherapy.

Tumor protein D52-like 2 (TPD52L2) belongs to the members of the TPD52 family. TPD52L2 was reported to regulate proliferation and apoptosis in cancer cells. However, its role in lung adenocarcinoma (LUAD) was uncertain. We evaluated the expression, methylation, copy number alteration, and prognostic significance of TPD52L2 using RNA-seq data from The Cancer Genome Atlas (TCGA). Enrichment analysis of TPD52L2 was conducted using the R package “clusterProfiler.” We further assessed the association between TPD52L2 and immune cell infiltration level, immunosuppressive genes, and tumor mutational burden (TMB). The difference of gene mutant frequency in high- and low-TPD52L2 groups was also analyzed. The results showed that TPD52L2 was over-expressed and predicted worse survival status in LUAD. We also found that TPD52L2 expression was positively associated with the infiltration levels of immunosuppressive cells, such as regulatory T cells (Tregs) and tumor-associated macrophages (TAMs), and negatively correlated with immune killer cells, such as CD8+ T and NK cells in pan-cancer, including LUAD. In addition, TPD52L2 expression was associated with immunosuppressive genes and TMB. High expression of TPD52L2 was with more mutant frequency of TP53. In summary, our results show that TPD52L2 is an oncogene and a potential prognostic biomarker in LUAD. High TPD52L2 expression is a possible indicator of immune infiltration and associated with tumor immunosuppressive status in LUAD.

Tripterygium wilfordii Hook. f. is a well-known traditional Chinese medicine used to treat autoimmune diseases. Sesquiterpene pyridine alkaloids (SPAs) are a major class of components found in this herb that have piqued the interest of researchers due to their complex and diverse structures as well as significant biological activities. In this study, ten new SPAs, wilfordatine A–J (1–10), were isolated from the roots of T. wilfordii, along with ten known analogues (11–20). Their structures were primarily elucidated by extensive 1D and 2D NMR spectroscopic analysis. To search for more immunosuppressive ingredients related to the clinical efficacy of T. wilfordii, the total alkaloids (TA) and compounds 4, 5, and 9–16 were tested for their inhibitory effects on nuclear factor-kappa B (NF-κB) pathway in Lipopolysaccharide (LPS) induced HEK293/NF-κB-Luc cells. Among them, TA, compounds 5, 11, and 16 showed potent immunosuppressive activity, with IC50 values of 7.25 μg/mL, 8.75 μM, 0.74 μM, and 15.66 μM, respectively, and no influence on the cell viability at a concentration of 100 μg/mL (TA) or 100 μM (5, 11, and 16). Accordingly, TA, 5, 11, and 16, especially 11, were identified as promising candidates for further investigation into their potential use as immunosuppressive agents.

Background: An increasing number of studies have shown that Isthmin 1 (ISM1), a secreted protein, is important in tumorigenesis and invasion, including in colorectal cancer (CRC). However, the mechanisms are still unclear. This study aims to explore the function and prognosis capacity of ISM1 in CRC.Methods: We investigated the expression of ISM1 in 18 CRC tissues vs. adjacent normal tissues from GSE50760, 473 CRC tissues vs. 41 normal tissues from The Cancer Genome Atlas (TCGA), and across gastrointestinal cancer types. Differences were further confirmed in CRC tissues via quantitative real-time polymerase chain reaction (qRT-PCR). Then, we analyzed correlations between clinicopathologic features and ISM1 expression, including prognostic prediction value, using the Kaplan–Meier method and multivariate Cox regression. Gene set enrichment analysis (GSEA) was performed to identify ISM1-related pathways. In vitro experiments were performed to verify the role of ISM1 in epithelial-mesenchymal transition (EMT) and CRC progression.Results: Multiple datasets showed that ISM1 is upregulated in CRC tissues, which was validated. Patients with higher ISM1 expression had shorter overall survival (OS), and ISM1 expression served as an independent prognostic factor. Enrichment analysis showed that ISM1 upregulation was positively correlated with cancer-related pathways, such as EMT, hypoxia, and the Notch and KRAS signaling pathways. We were exclusively interested in the connection between ISM1 and EMT because 71% of genes in this pathway were significantly positively co-expressed with ISM1, which may account for why patients with higher ISM1 expression are prone to regional lymph node involvement and progression to advanced stages. In addition, we found that ISM1 was positively correlated with multiple immunosuppressive pathways such as IL2/STAT5, TNF-α/NF-κB, and TGF-β, and immune checkpoints, including PD-L1, PD-1, CTLA-4, and LAG3, which may account for upregulation of ISM1 in immunotherapy-resistant patients. Notably, through in vitro experiments, we found that ISM1 promoted EMT and colon cancer cell migration and proliferation.Conclusion: ISM1 is critical for CRC development and progression, which enhances our understanding of the low response rate of CRC to immunotherapy via immunosuppressive signaling pathways.

In humans, various sites like cannabinoid receptors (CBR) having a binding affinity with cannabinoids are distributed on the surface of different cell types, where endocannabinoids (ECs) and derivatives of fatty acid can bind. The binding of these substance(s) triggers the activation of specific receptors required for various physiological functions, including pain sensation, memory, and appetite. The ECs and CBR perform multiple functions via the cannabinoid receptor 1 (CB1); cannabinoid receptor 2 (CB2), having a key effect in restraining neurotransmitters and the arrangement of cytokines. The role of cannabinoids in the immune system is illustrated because of their immunosuppressive characteristics. These characteristics include inhibition of leucocyte proliferation, T cells apoptosis, and induction of macrophages along with reduced pro-inflammatory cytokines secretion. The review seeks to discuss the functional relationship between the endocannabinoid system (ECS) and anti-tumor characteristics of cannabinoids in various cancers. The therapeutic potential of cannabinoids for cancer—both in vivo and in vitro clinical trials—has also been highlighted and reported to be effective in mice models in arthritis for the inflammation reduction, neuropathic pain, positive effect in multiple sclerosis and type-1 diabetes mellitus, and found beneficial for treating in various cancers. In human models, such studies are limited; thereby, further research is indispensable in this field to get a conclusive outcome. Therefore, in autoimmune disorders, therapeutic cannabinoids can serve as promising immunosuppressive and anti-fibrotic agents.

It is essential to differentiate intestinal tuberculosis from Crohn's disease because of the therapeutic implications of Crohn's disease, which can exacerbate the symptoms of tuberculosis.

The impact of Covid-19 pneumonia caused by SARS-CoV-2 on transplanted populations under chronic immunosuppression seems to be greater than in normal population. Clinical management of the disease, particularly in those patients worsening after a cytokine storm, with or without allograft impairment and using available therapeutic approaches in the absence of specific drugs to fight against the virus, involves a major challenge for physicians. We herein provide evidence of the usefulness of high-dose intravenous immunoglobulin (IVIG) combined with steroid pulses to successfully treat a case of Covid-19 pneumonia in a single-kidney transplanted patient with mechanical ventilation and hemodialysis requirements in the setting of a cytokine storm. A rapid decrease in the serum level of inflammatory cytokines, particularly IL-6, IL-8, TNF-α, MCP-1 and IL-10, as well as of acute-phase reactants such as ferritin, D-dimer and C-reactive protein was observed after the IVIG infusion and methylprednisolone bolus administration with a parallel clinical improvement and progressive allograft function recovery, allowing the patient’s final discharge 40 days after the treatment onset. The immunomodulatory effect of IVIG together with the anti-inflammatory and immunosuppressive potential of steroids could be an alternative strategy to treat severe cases of Covid-19 pneumonia associated with an uncontrolled inflammatory response in transplanted populations.

Background The etiology of idiopathic chronic hepatitis (ICH) in dogs is poorly understood, but evidence supports an immune‐mediated pathogenesis in some dogs. Objectives To describe a case series of dogs with presumed ICH treated with cyclosporine (CsA) with or without concurrent medications and to document the incidence of biochemical remission and factors associated with failure to attain remission. Animals Forty‐eight client‐owned dogs diagnosed with presumed ICH, treatment of which included CsA. Methods Two‐institution, retrospective case series of dogs between 2010 and 2017. All dogs were treated with CsA with or without concurrent medications for ≥2 weeks. Data were collected from medical records. Results Biochemical remission (

当院における過去3年間の免疫抑制・化学療法によるB型肝炎ウイルス(HBV)再活性化を検討した。2015年1月〜2017年12月に抗癌剤プロトコールに登録された2,105例(固形癌1,848例、血液腫瘍257例)、自己免疫疾患に対して免疫抑制剤を投与された845例、計2,950例中7例(0.24%)でHBV再活性化を認めた。1例はHBs抗原陽性、6例は既往感染例だった。抗癌剤2,105例中HBV再活性化は2例で、いずれも悪性リンパ腫(R-CHOPリツキシマブ、シクロフォスファミド、ドキソルビシン、ビンクリスチン、プレドニゾロン)だった。自己免疫疾患845例中5例でHBV再活性化を認め、関節リウマチ3例(アバタセプト、サラゾスルファピリジン、メトトレキサート)、強皮症1例(シクロフォスファミド)、膿疱性乾癬1例(セクキヌマブ)だった。7例とも核酸アナログ投与により再活性化に伴う肝炎の発生は予防された。(著者抄録)

Inducing antigen-specific tolerance is a promising treatment for preventing or reversing Type 1 diabetes (T1D). In contrast to a vaccine that induces immune responses against pathogens, a tolerogenic vaccine can suppress immunity against antigens causing diseases by administrating a mixture of self-antigens with an adjuvant that decreases the strength of antigen-specific response. Kynurenine (Kyn) is an endogenous substance that can inhibit the natural killer cell and T cell proliferation and promote the differentiation of naïve T cells into regulatory T cells (Tregs). In this study, we evaluated the efficacy of Kyn as a novel suppressive adjuvant. Kyn was co-immunized with GAD65 phage vaccine to induce Tregcells and tolerogenic responses for the prevention of T1D in NOD mouse model. Mice were subcutaneously immunized two times with 1011Pfu (100μL,1012Pfu/ml) GAD65 phage vaccine doses mixed with 200 μg of Kyn. Serum antibodies and cytokines were detected by ELISA and electrochemiluminescence, respectively. Flow cytometry assay was used to analyze DC and Treg. MTS was used for the analysis of spleen lymphocyte proliferation. RNA sequencing was used to investigate mRNA and miRNA expression profiles in spleen lymphocytes. Compared to GAD65 phage vaccine alone, co-immunization of Kyn and GAD65 phage vaccine resulted in the prevention of hyperglycemia in 60% of mice for at least one month. Further, Kyn enhances GAD65-specific Th2-mediated immune responses; regulates the Th1/Th2 imbalance and increases the secretion of Th2 cytokines and the number of CD4+CD25+Foxp3+T cells; suppresses DC maturation and GAD65-specific T lymphocyte proliferation. Moreover, we integrated Kyn related miRNA and mRNA expression profiles obtained from the spleen lymphocyte RNA-sequencing which was stimulated by Kynin vitro. These data provide an important basis for understanding the mechanisms underlying Kyn as an immunosuppressive adjuvant which regulated the immune response. These findings suggest that Kyn can serve as an effective suppressive adjuvant candidate for Type 1 diabetes vaccines.

Triptolide is the main bioactive constituent isolated from the Chinese herb Tripterygium wilfordii Hook F., which possesses a variety of pharmacological properties. MicroRNAs (miRNAs/miRs) are short non-coding RNAs that regulate gene expression post-transcriptionally. miRNAs are implicated in several intracellular processes, whereby their dysregulation contributes to pathogenesis of various diseases. Thus, miRNAs have great potential as biomarkers and therapeutic targets for diseases, and are implicated in drug treatment. Previous studies have reported that specific miRNAs are targeted, and their expression levels can be altered following exposure to triptolide. Thus, miRNAs are emerging as crucial mediators in the pharmacological activities of triptolide. The present review summarizes current literature on miRNAs as target molecules in the pharmacological activities of triptolide, including antitumor, anti-inflammatory, immunosuppressive, renal protective, cardioprotective, antiangiogenesis activities and multiorgan toxicity effects. In addition, the diverse signaling pathways involved are discussed to provide a comprehensive understanding of the underlying molecular mechanisms of triptolide in the regulation of target miRNAs.

The growing insights in the complex interactions between metastatic cancer-cells and platelets have revealed that platelet tumor cell interactions in the blood stream are an important factor supporting tumor metastasis. An increased coagulability of platelets facilitates the vascular evasion and establishment of solid tumor metastasis. Furthermore, platelets can support an immunosuppressive tumor microenvironment or shield tumor cells directly from engagement of cytotoxic lymphocytes as e.g., natural killer (NK) cells. Platelets are both in the tumor microenvironment and systemically the quantitatively most important source of TGF-β, which is a key cytokine for immunosuppression in the tumor microenvironment. If similar platelet-tumor interactions are of physiological relevance in hematological malignancies remains less well-studied. This might be important, as T- and NK cell mediated graft vs. leukemia effects (GvL) are well-documented and malignant hematological cells have a high exposure to platelets compared to solid tumors. As NK cell-based immunotherapies gain increasing attention as a therapeutic option for patients suffering from hematological and other malignancies, we review the known interactions between platelets and NK cells in the solid tumor setting and discuss how these could also apply to hematological cancers. We furthermore explore the possible implications for NK cell therapy in patients with solid tumors and patients who depend on frequent platelet transfusions. As platelets have a protective and supportive effect on cancer cells, the impact of platelet transfusion on immunotherapy and the combination of immunotherapy with platelet inhibitors needs to be evaluated.

In host-parasitoid interactions, antagonistic relationship drives parasitoids to vary in virulence in facing different hosts, which makes these systems excellent models for stress-induced evolutionary studies. Venom compositions varied between two strains of Tetrastichus brontispae, Tb-Bl and Tb-On. Tb-Bl targets Brontispa longissima pupae as hosts, and Tb-On is a sub-population of Tb-Bl, which has been experimentally adapted to a new host, Octodonta nipae. Aiming to examine variation in parasitoid virulence of the two strains toward two hosts, we used reciprocal injection experiments to compare effect of venom/ovarian fluids from the two strains on cytotoxicity, inhibition of immunity and fat body lysis of the two hosts. We found that Tb-Onvenom was more virulent towards plasmatocyte spreading, granulocyte function and phenoloxidase activity than Tb-Blvenom. Tb-Blovary was able to suppress encapsulation and phagocytosis in both hosts, however, Tb-Onovary inhibition targeted only B. longissima. Our data suggest that the venom undergoes rapid evolution when facing different hosts, and that the wasp has good evolutionary plasticity.

Inflammatory bowel disease (IBD) is an immune disorder that develops due to chronic inflammation in several cells. It is known that colorectal and T cells are mainly involved in the pathogenesis of IBD. Chrysophanol is an anthraquinone family member that possesses several bioactivities, including anti-diabetic, anti-tumor, and inhibitory effects on T cell activation. However, it is unknown whether chrysophanol suppresses the activity of colorectal cells. In this study, we found that chrysophanol did not induce cytotoxicity in HT-29 colorectal cells. Pre-treatment with chrysophanol inhibited the mRNA levels of pro-inflammatory cytokines in tumor necrosis factor-α (TNF-α)-stimulated HT-29 cells. Western blot analysis revealed that pre-treatment with chrysophanol mitigates p65 translocation and the mitogen-activated protein kinase (MAPK) pathway in activated HT-29 cells. Results from the in vivo experiment confirmed that oral administration of chrysophanol protects mice from dextran sulfate sodium (DSS)-induced IBD. Chrysophanol administration attenuates the expression of pro-inflammatory cytokines in colon tissues of the DSS-induced IBD model. In addition, we found that oral administration of chrysophanol systemically decreased the expression of effector cytokines from mesenteric lymph nodes. Therefore, these data suggest that chrysophanol has a potent modulatory effect on colorectal cells as well as exhibiting a beneficial potential for curing IBD in vivo.

In host-parasitoid interactions, antagonistic relationship drives parasitoids to vary in virulence in facing different hosts, which makes these systems excellent models for stress-induced evolutionary studies. Venom compositions varied between two strains of Tetrastichus brontispae, Tb-Bl and Tb-On. Tb-Bl targets Brontispa longissima pupae as hosts, and Tb-On is a sub-population of Tb-Bl, which has been experimentally adapted to a new host, Octodonta nipae. Aiming to examine variation in parasitoid virulence of the two strains toward two hosts, we used reciprocal injection experiments to compare effect of venom/ovarian fluids from the two strains on cytotoxicity, inhibition of immunity and fat body lysis of the two hosts. We found that Tb-Onvenom was more virulent towards plasmatocyte spreading, granulocyte function and phenoloxidase activity than Tb-Blvenom. Tb-Blovary was able to suppress encapsulation and phagocytosis in both hosts; however, Tb-Onovary inhibition targeted only B. longissima. Our data suggest that the venom undergoes rapid evolution when facing different hosts, and that the wasp has good evolutionary plasticity.

Background: IgA nephropathy (IgAN) is one of the significant contributing factors of end-stage renal disease (ESRD). It is reported that over half of patients with IgAN accompany multiple high-risk factors, which increase the risk of ESRD progression. Studies have shown that immunosuppressive agents were beneficial in high-risk IgAN, but the efficacy and safety have not been fully demonstrated yet. The present study aims to elucidate the efficacy of commonly used immunosuppressants in high-risk IgAN and their relative safety profiles via a network meta-analysis strategy. Methods: Randomized controlled trials (RCTs) eligible for this network meta-analysis were included to evaluate the efficacy and safety of different immunosuppressants for high-risk IgAN. Main outcomes and measures include incidence of renal composite end point, the rate of total remission, adverse events, and proteinuria. Besides, subgroup analysis and cluster analysis were carried out. Results: This network meta-analysis of 37 RCTs involving 3012 participants found that Mycophenolate mofetil (MMF) combined with corticosteroids (CS) was superior to other interventions in end point events and proteinuria. Cyclosporine A (CsA) plus CS was the best option for clinical remission rate, and supportive care (SC) was the safest treatment. Cluster analysis showed that MMF+CS and Leflunomide (LEF)+CS were best protocols in efficacy and safety. Subgroup analysis indicated the best benefits of MMF were presented among the Asian population, and the benefits increased with the increase of follow-up duration. The effect of Cyclophosphamide (CTX) +CS on crescent IgAN was better than that of other risk factors. Moreover, the increasing follow-up duration was negatively associated with the effect. Conclusions: MMF+CS and LEF+CS appear to serve as the best choice for treating high-risk IgAN than other immunosuppressive therapies.

Fibroblast activation protein-α (FAP) is a type II integral serine protease that is specifically expressed by activated fibroblasts. Cancer-associated fibroblasts (CAFs) in the tumor stroma have an abundant and stable expression of FAP, which plays an important role in promoting tumor growth, invasion, metastasis, and immunosuppression. For example, in females with a high incidence of breast cancer, CAFs account for 50–70% of the cells in the tumor’s microenvironment. CAF overexpression of FAP promotes tumor development and metastasis by influencing extracellular matrix remodeling, intracellular signaling, angiogenesis, epithelial-to-mesenchymal transition, and immunosuppression. This review discusses the basic biological characteristics of FAP and its applications in the diagnosis and treatment of various cancers. We review the emerging basic and clinical research data regarding the use of nanomaterials that target FAP.

Hemolytic anemia is a disease caused by autoantibodies and resulting in various complaints and clinical symptoms. In about half of cases, the cause of autoimmune hemolytic anemia can not be determined. Corticosteroids are the first-line treatment option for warm autoantibody-related hemolytic anemia. In patients who develop steroid side effects or do not respond adequately, other immunosuppressives may be preferred. In case a rapid response is required or fulminant hemolysis occur, human immunoglobulins (IVIGs) may be added to treatment. Finally, plasma exchange (PE) may additionally be utilised. The essence of PE is based on the removal of immune complexes, protein-bound toxins, autoantibodies and high molecular weight solutes and protein-bound solutes. The main clinical aim of the removal of solutes is usually to gain a faster response than immunosuppressive therapy. Studies related to hemolytic anemia and PE are usually based on case reports. Our case report is about a patient with severe IgG subtype hemolytic anemia. The treatment was started with 1 mg/kg methylprednisolone; to which there was no response with weekly rituximab 375 mg/m2 and IVIG administered. Because of unresponsiveness to all of the immunosuppresives, a total of 5 sessions of PE were added to the treatment procedure every other day. After these sessions, the requirement for transfusions has decreased and the patient underwent splenectomy. The patient is currently being followed up only on oral cyclosporine and the last hemoglobin level was 14.7 g /dl. In severe and refractory anemia, especially in the case of cardiovascular imbalance in fulminant hemolysis, PE may be preferred as a third series option after immunosuppressive treatments and play a role as a bridge to splenectomy. WOS:000697004600014 34412947 Q4

Background Recently, mesenchymal stem cells therapy has been performed in dogs, although the outcome is not always favorable. Objectives To investigate the therapeutic efficacy of mesenchymal stem cells (MSCs) using dog leukocyte antigen (DLA) matching between the donor and recipient in vitro. Methods Canine adipose-derived MSCs (cA-MSCs) isolated from the subcutaneous tissue of Dog 1 underwent characterization. For major DLA genotyping (DQA1, DQB1, and DRB1), peripheral blood mononuclear cells (PBMCs) from two dogs (Dogs 1 and 2) were analyzed by direct sequencing of polymerase chain reaction (PCR) products. The cA-MSCs were co-cultured at a 1:10 ratio with activated PBMCs (DLA matching or mismatching) for 3 days and analyzed for immunosuppressive (IDO, PTGS2, and PTGES), inflammatory (IL6 and IL10), and apoptotic genes (CASP8, BAX, TP53, and BCL2) by quantitative real-time reverse transcriptase-PCR. Results cA-MSCs were expressed cell surface markers such as CD90⁺/44⁺/29⁺/45⁻ and differentiated into osteocytes, chondrocytes, and adipocytes in vitro. According to the Immuno Polymorphism Database, DLA genotyping comparisons of Dogs 1 and 2 revealed complete differences in genes DQA1, DQB1, and DRB1. In the co-culturing of cA-MSCs and PBMCs, DLA mismatch between the two cell types induced a significant increase in the expression of immunosuppressive (IDO/PTGS2) and apoptotic (CASP8/BAX) genes. Conclusions The administration of cA-MSCs matching the recipient DLA type can alleviate the need to regulate excessive immunosuppressive responses associated with genes, such as IDO and PTGES. Furthermore, easy and reliable DLA genotyping technology is required because of the high degree of genetic polymorphisms of DQA1, DQB1, and DRB1 and the low readability of DLA 88.

İmmunomodülatörler, bağışıklık sistemini etkileyerek immun sistem üzerinde uyarıcı veya baskılayıcı etki gösteren veya bu sistem üzerinde regüle edici özelliklere sahip maddeler olarak tanımlanmaktadır. Bu maddeler arasında, bakteri ve bakteriyel ürünler, bitkisel immunmodülatörler, hayvansal ekstraktlar, aşılar, kompleks karbonhidratlar, besinsel faktörler, sitokinler ve sentetik bir kısım kimyasal bileşikler sayılabilir. Doğada aynı zamanda immunmodülatör etkili birçok bitki de bulunmaktadır. Bu derleme çalışmasında, immunmodülatör etkili bitkiler, bunların içerdikleri etkin maddeler ile bu maddelerin etki şekilleri detaylı olarak incelenmiştir. Çalışmanın amacı, söz konusu bitkisel immunmodulatörlerin pet hayvanlarının, ruminantların ve atların tedavilerinde kullanım olanaklarının araştırılmasıdır., Immunomodulators are defined as substances that stimulate or suppress the immune system by affecting the immune system, or have regulatory properties on this system. These substances include some bacterial and bacterial products, plant-derived immunomodulators, animal extracts, vaccines, complex carbohydrates, nutritional factors, cytokines and some synthetic chemical compounds. In nature, there are also many plants with immunomodulatory effects. In this review study, plants with immunomodulatory effects, their active ingredients and their mode of action were examined in detail. In addition, results of the studies regarding with possibilities of using these herbal immunomodulators in the treatment of pet animals, ruminants as well as horses were evaluated.

SARS-CoV-2 infections are rising at an alarming rate and various aspects of this pandemic must be quickly and adequately addressed in order to enhance effective healthcare delivery and protect at risk populations such as cancer patients. Preventing Covid-19 infection must be a top system wide priority to avoid mortality, and considerable financial and disease burden. Most cancer patients, and in particular those with tumors resistant to chemotherapy are particularly vulnerable to infection. In this review, we connect potential viral infection of patients with lung tumors that have somewhat quiescence the immune response in the tumor microenvironment and categorize target molecules in metabolism that may be used to identify at risk patients leading to more effective treatment regimens; keeping continuity of therapy and disease prevention during a very tumultuous period of time surrounding the pandemic.

Endoplasmic reticulum (ER) stress has considerable impact on cell growth, proliferation, metastasis, invasion, angiogenesis and chemoradiotherapy resistance in various cancers. However, the effect of ER stress on the outcomes of glioma patients remains unclear. In this study, we established an ER stress risk model based on The Cancer Genome Atlas (TCGA) glioma data set to reflect immune characteristics and predict the prognosis of glioma patients. Survival analysis indicated that there were significant differences in the overall survival (OS) of glioma patients with different ER stress‐related risk scores. Moreover, the ER stress‐related risk signature, which was markedly associated with the clinicopathological properties of glioma patients, could serve as an independent prognostic indicator. Functional enrichment analysis revealed that the risk model correlated with immune and inflammation responses, as well as biosynthesis and degradation. In addition, the ER stress‐related risk model indicated an immunosuppressive microenvironment. In conclusion, we present an ER stress risk model that is an independent prognostic factor and indicates the general immune characteristics in the glioma microenvironment.

In immunological responses, controlling excessive T cell activity is critical for immunological homeostasis maintenance. Diketoacetonylphenalenone, derived from Hawaiian volcanic soil-associated fungus Penicillium herquei FT729, possesses moderate anti-inflammatory activity in RAW 264.7 cells but its immunosuppressive effect on T cell activation is unknown. In the present study, diketoacetonylphenalenone (up to 40 &mu, M) did not show cytotoxicity in T cells. Western blot analysis showed treatment with diketoacetonylphenalenone did not alter the expression of anti-apoptotic proteins. Pretreatment with diketoacetonylphenalenone suppressed the interleukin-2 production in activated T cells induced by T cell receptor-mediated stimulation and PMA/A23187. The CFSE-proliferation assay revealed the inhibitory effect of diketoacetonylphenalenone on the proliferation of T cells. The expression of surface molecules on activated T cells was also reduced. We discovered the suppression of the TAK1-IKK&alpha, NF-&kappa, B pathway by pretreatment with diketoacetonylphenalenone abrogated mitogen-activated protein kinase (MAPK) signaling in activated T cells. These results suggest that diketoacetonylphenalenone effectively downregulates T cell activity via the MAPK pathway and provides insight into the therapeutic potential of immunosuppressive reagents.

Background: Glioblastoma multiforme is a malignant intracranial neoplasm that constitutes a therapeutic challenge because of the associated high morbidity and mortality given the lack of effective approved medication and aggressive nature of the tumor. However, there has been extensive research recently to address the reasons implicated in the resistant nature of the tumor to pharmaceutical compounds, which have resulted in several clinical trials investigating promising treatment approaches. Methods: We reviewed literature published since 2010 from PUBMED and several annual meeting abstracts through 15 September 2020. Selected articles included those relevant to topics of glioblastoma tumor biology, original basic research, clinical trials, seminal reviews, and meta-analyses. We provide a discussion based on the collected evidence regarding the challenging factors encountered during treatment, and we highlighted the relevant trials of novel therapies including immunotherapy and targeted medication. Results: Selected literature revealed four main factors implicated in the low efficacy encountered with investigational treatments which included: (1) blood-brain barrier; (2) immunosuppressive microenvironment; (3) genetic heterogeneity; (4) external factors related to previous systemic treatment that can modulate tumor microenvironment. Investigational therapies discussed in this review were classified as immunotherapy and targeted therapy. Immunotherapy included: (1) immune checkpoint inhibitors; (2) adoptive cell transfer therapy; (3) therapeutic vaccines; (4) oncolytic virus therapy. Targeted therapy included tyrosine kinase inhibitors and other receptor inhibitors. Finally, we provide our perspective on future directions in treatment of glioblastoma. Conclusion: Despite the limited success in development of effective therapeutics in glioblastoma, many treatment approaches hold potential promise including immunotherapy and novel combinational drugs. Addressing the molecular landscape and resistant immunosuppressive nature of glioblastoma are imperative in further development of effective treatments.

Gout is an inflammatory joint disease caused by monosodium urate (MSU) crystals; however, the mechanism underlying MSU-induced inflammation is unclear. Previous research has suggested that inflammation or cancer can drive the expansion of myeloid-derived suppressor cells (MDSCs). In this study, the role of MDSCs in MSU-induced gout inflammation was evaluated. A total of 28 patients with gout, and 20 healthy controls were recruited for the study. MDSCs, and their functions, were analyzed by flow cytometry and a T cell co-culture assay, respectively. We observed a higher frequency of PMN-MDSCs, and a stronger immunosuppressive function, in patients with gout compared to the controls. Moreover, circulating PMN-MDSCs were positively correlated with pathological indicators, including uric acid and C-reactive protein levels. We also demonstrated that MSU can induce significant PMN-MDSC expansion, using in vivo and in vitro experiments. Finally, MSU-induced PMN-MDSCs produced higher levels of IL-1β, which mediated gout inflammatory progression. Our results demonstrate that MSU modulates the expansion and suppressive function of PMN-MDSCs, providing insights into a novel mechanism underlying the pathogenesis of MSU-induced gout. Thus, MDSCs may be useful for the development of novel therapeutic strategies for the prevention and treatment of gout.

Toll-like receptor (TLR) signaling is an indispensable factor in immune cells activation. Many TLR ligands have been identified, and were characterized the immunological functions such as inflammatory cytokine production in immune cells. However, the anti-inflammatory response in TLR ligand-mediated manner is poorly understood. In this report, we show that bacterial lipoteichoic acid (LTA), which is a TLR2 ligand from gram-positive bacteria including Staphylococcus aureus (S. aureus), suppresses TLR-mediated inflammatory response in dendritic cells (DCs). The TLR ligand-induced Tumor Necrosis Factor-alpha (TNF-&alpha, ) production was suppressed in the bone marrow derived dendritic cells (BMDCs) by co-treatment of LTA. The cellular activation, which was characterized as upregulations of CD80, CD86 and major histocompatibility complex II (MHC II) expression, was also suppressed in the TLR ligand stimulated BMDCs in the presence of LTA. While LTA itself didn&rsquo, t induced both TNF-&alpha, production and upregulation of cell surface markers. The LTA mediated immunosuppressive function was abolished by TLR2 blocking in lipopolysaccharide (LPS)-stimulated BMDCs. Furthermore, LTA also showed the immunosuppressive function in the generation of IFN-&gamma, +CD4+ T (Th1) cells by attenuation of antigen presenting activity in the BMDCs. In the imiquimod (IMQ)-induced acute skin inflammation, LTA suppressed the inflammation by downregulation of the activation in skin accumulated DCs. Thus, LTA is a TLR2 dependent immunological suppressor against inflammatory response induced by other TLR ligands in the DCs.

INTRODUCTION: Lactate secreted by tumors is not just a byproduct, but rather an active modulator of immune cells. There are few studies aimed at investigating the true effect of lactate, which is normally confounded by pH. Such a knowledge gap needs to be addressed. Herein, we studied the immunomodulatory effects of lactate on dendritic cells (DCs) and macrophages (MΦs). METHODS: Bone marrow-derived innate immune cells were treated with 50 mM sodium lactate (sLA) and incubated for 2 days or 5 days at 37 °C. Controls included media, lipopolysaccharide (LPS), MCT inhibitors (α-cyano-4-hydroxycinnamic acid and AR-C15585). Flow cytometric analysis of immune phenotypes were performed by incubating cells with specific marker antibodies and viability dye. Differential expression analyses were conducted on R using limma-voom and adjusted p-values were generated using the Bejamini-Hochberg Procedure. RESULTS: Lactate exposure attenuated DC maturation through the downregulation of CD80 and MHCII expression under LPS stimulation. For MΦs, lactate exposure resulted in M2 polarization as evidenced by the reduction of M1 markers (CD38 and iNOS), and the increase in expression of CD163 and Arg1. We also revealed the role of monocarboxylate transporters (MCTs) in mediating lactate effect in MΦs. MCT4 inhibition significantly boosted lactate M2 polarization, while blocking of MCT1/2 failed to reverse the immunosuppressive effect of lactate, correlating with the result of gene expression that lactate increased MCT4 expression, but downregulated the expression of MCT1/2. CONCLUSIONS: This research provides valuable insight on the influence of metabolic products on tumor immunity and will help to identify novel metabolic targets for augmenting cancer immunotherapies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12195-020-00652-x) contains supplementary material, which is available to authorized users.

Background Despite improvements in antimicrobial therapy and supportive care, sepsis is still a major public health issue. Recently, CD100 and its receptor in the immune system CD72 were shown to play a major role in immune regulation. The purpose of this study was to investigate the expression and clinical correlations of CD72 and CD100 on circulating lymphocytes of septic patients. Methods In total, 24 healthy controls and 54 septic patients were enrolled in this study. Considering the focus of the current study was on the immunosuppressive phase of sepsis, blood samples of patients were collected at days 3–4 after the onset of sepsis. The levels of CD72 and CD100 expression on circulating lymphocytes were measured by flow cytometry and serum IL-6, IL-10, and immunoglobulin M levels were determined by enzyme-linked immunosorbent assay. Results Our results showed that the levels of CD100 expression on T cells and CD72 expression on B cells were significantly lower in septic patients. Similarly, a significant decrease in the expression levels of CD72 and CD100 was observed in non-survivors compared with survivors. In addition, the reduction of immunoglobulin M levels and lymphocyte counts were correlated with the low CD72 and CD100 expression levels. Multivariate logistic regression analysis showed that the percentage of CD100+/CD8+ T cells and CD72+/CD19+ B cells were independent predictors of 28-day mortality in septic patients. Simultaneously, the receiver operating characteristic curve analysis showed that the combination of the percentage of CD100+/CD8+ T cells and sequential organ failure assessment score had the best predictive value of mortality risk. Conclusions Our study demonstrated that the decrease of the levels of CD72 and CD100 expression on circulating lymphocytes after 3–4 days of sepsis had a close correlation of the 28-day mortality of septic patients. Thus, CD72 and CD100 are promising biomarkers for assessing the prognosis of patients with sepsis. Trial registration Peripheral blood lymphocytes analysis detects CD72 and CD100 alteration in trauma patients; ChiCTR1900026367; Registered 4 October 2019; http://www.chictr.org.cn.