Effects of Rosa roxburghii&edible fungus fermentation broth on immune response and gut microbiota in immunosuppressed mice

With the rise of probiotics fermentation in food industry,fermented foods have attracted worldwide attention.In this study,protective effects of Rosa roxburghii&edible fungus fermentation broth(REFB)on immune function and gut health in Cyclophosphamide induced immunosuppressed mice were investigated.Results showed that REFB could improve the immune organ index,and promote the proliferation and differentiation of splenic T lymphocytes.In addition,it attenuated intestinal mucosal damage and improved intestinal cellular immunity.REFB administration also up-regulated the expression of IL-4,INF-γ,TNF-α,T-bet and GATA-3 mRNA in small intestine.Furthermore,administration of REFB modulated gut microbiota composition and increased the relative abundance of beneficial genus,such as Bacteroides.It also increased the production of fecal short-chain fatty acids.These indicate that REFB has the potential to improve immunity,alleviate intestinal injury and regulate gut microbiota in immunosuppressed mice.

Mechanisms of tumor immunosuppressive microenvironment formation in esophageal cancer

As a highly invasive malignancy,esophageal cancer(EC)is a global health issue,and was the eighth most prevalent cancer and the sixth leading cause of cancerrelated death worldwide in 2020.Due to its highly immunogenic nature,emerging immunotherapy approaches,such as immune checkpoint blockade,have demonstrated promising efficacy in treating EC;however,certain limitations and challenges still exist.In addition,tumors may exhibit primary or acquired resistance to immunotherapy in the tumor immune microenvironment(TIME);thus,understanding the TIME is urgent and crucial,especially given the importance of an immunosuppressive microenvironment in tumor progression.The aim of this review was to better elucidate the mechanisms of the suppressive TIME,including cell infiltration,immune cell subsets,cytokines and signaling pathways in the tumor microenvironment of EC patients,as well as the downregulated expression of major histocompatibility complex molecules in tumor cells,to obtain a better understanding of the differences in EC patient responses to immunotherapeutic strategies and accurately predict the efficacy of immunotherapies.Therefore,personalized treatments could be developed to maximize the advantages of immunotherapy.

27-Hydroxycholesterol/liver X receptor/apolipoprotein E mediates zearalenone-induced intestinal immunosuppression:A key target potentially linking zearalenone and cancer

Zearalenone(ZEN)is a mycotoxin that extensively contaminates food and feed,posing a significant threat to public health.However,the mechanisms behind ZEN-induced intestinal immunotoxicity remain unclear.In this study,Sprague-Dawley(SD)rats were exposed to ZEN at a dosage of 5 mg/kg/day b.w.for a duration of 14 days.The results demonstrated that ZEN exposure led to notable pathological alterations and immunosuppression within the intestine.Furthermore,ZEN exposure caused a significant reduction in the levels of apolipoprotein E(ApoE)and liver X receptor(LXR)(P<0.05).Conversely,it upregulated the levels of myeloid-derived suppressor cells(MDSCs)markers(P<0.05)and decreased the presence of 27-hydroxycholesterol(27-HC)in the intestine(P<0.05).It was observed that ApoE or LXR agonists were able to mitigate the immunosuppressive effects induced by ZEN.Additionally,a bioinformatics analysis highlighted that the downregulation of ApoE might elevate the susceptibility to colorectal,breast,and lung cancers.These findings underscore the crucial role of the 27-HC/LXR/ApoE axis disruption in ZEN-induced MDSCs proliferation and subsequent inhibition of T lymphocyte activation within the rat intestine.Notably,ApoE may emerge as a pivotal target linking ZEN exposure to cancer development.

Advancing immunosuppression in liver transplantation: A narrative review

Immunosuppression is essential to ensure recipient and graft survivals after liver transplantation(LT). However, our understanding and management of the immune system remain suboptimal. Current immunosuppressive therapy cannot selectively inhibit the graft-specific immune response and entails a significant risk of serious side effects, i.e., among others, de novo cancers, infections, cardiovascular events, renal failure, metabolic syndrome, and late graft fibrosis, with progressive loss of graft function. Pharmacological research, aimed to develop alternative immunosuppressive agents in LT, is behind other solidorgan transplantation subspecialties, and, therefore, the development of new compounds and strategies should get priority in LT. The research trajectories cover mechanisms to induce T-cell exhaustion, to inhibit co-stimulation, to mitigate non-antigen-specific inflammatory response, and, lastly, to minimize the development and action of donor-specific antibodies. Moreover, while cellular modulation techniques are complex, active research is underway to foster the action of T-regulatory cells, to induce tolerogenic dendritic cells, and to promote the function of B-regulatory cells. We herein discuss current lines of research in clinical immunosuppression, particularly focusing on possible applications in the LT setting.

Mechanisms of myeloid-derived suppressor cell-mediated immunosuppression in colorectal cancer and related therapies

Severe immunosuppression is a hallmark of colorectal cancer(CRC).Myeloid-derived suppressor cells(MDSCs),one of the most abundant components of the tumor stroma,play an important role in the invasion,metastasis,and immune escape of CRC.MDSCs create an immunosuppressive microenvironment by inhibiting the proliferation and activation of immunoreactive cells,including T and natural killer cells,as well as by inducing the proliferation of immunosuppressive cells,such as regulatory T cells and tumor-associated macrophages,which,in turn,promote the growth of cancer cells.Thus,MDSCs are key contributors to the emergence of an immunosup-pressive microenvironment in CRC and play an important role in the breakdown of antitumor immunity.In this narrative review,we explore the mechanisms through which MDSCs contribute to the immunosuppressive microenvironment,the current therapeutic approaches and technologies targeting MDSCs,and the therapeutic potential of modulating MDSCs in CRC treatment.This study provides ideas and methods to enhance survival rates in patients with CRC.

Impact of STAT-signaling pathway on cancer-associated fibroblasts in colorectal cancer and its role in immunosuppression

Colorectal cancer(CRC)remains one of the most commonly diagnosed and deadliest types of cancer worldwide.CRC displays a desmoplastic reaction(DR)that has been inversely associated with poor prognosis;less DR is associated with a better prognosis.This reaction generates excessive connective tissue,in which cancer-associated fibroblasts(CAFs)are critical cells that form a part of the tumor microenvironment.CAFs are directly involved in tumorigenesis through different mechanisms.However,their role in immunosuppression in CRC is not well understood,and the precise role of signal transducers and activators of transcription(STATs)in mediating CAF activity in CRC remains unclear.Among the myriad chemical and biological factors that affect CAFs,different cytokines mediate their function by activating STAT signaling pathways.Thus,the harmful effects of CAFs in favoring tumor growth and invasion may be modulated using STAT inhibitors.Here,we analyze the impact of different STATs on CAF activity and their immunoregulatory role.

Colon signet-ring cell carcinoma with chylous ascites caused by immunosuppressants following liver transplantation:A case report

BACKGROUND Chylous ascites is caused by disruption of the lymphatic system,which is characterized by the accumulation of a turbid fluid containing high levels of triglycerides within the abdominal cavity.The two most common causes are cirrhosis and tuberculosis,and colon signer ring cell carcinoma(SRCC)due to the use of immunosuppressants is extremely rare in cirrhotic patients after liver transplantation,making it prone to misdiagnosis and missed diagnosis.CASE SUMMARY A 52-year-old man who underwent liver transplantation and was administered with immunosuppressants for 8 months was admitted with a 3-month history of progressive abdominal distention.Initially,based on lymphoscintigraphy and lymphangiography,lymphatic obstruction was considered,and cystellar chyli decompression with band lysis and external membrane stripping of the lymphatic duct was performed.However,his abdominal distention was persistent without resolution.Abdominal paracentesis revealed allogenic cells in the ascites,and immunohistochemistry analysis revealed adenocarcinoma cells with phenotypic features suggestive of a gastrointestinal origin.Gastrointestinal endoscopy was performed,and biopsy showed atypical signet ring cells in the ileocecal valve.The patient eventually died after a three-month follow-up due to progression of the tumor.CONCLUSION Colon SRCC,caused by immunosuppressants,is an unusual but un-neglected cause of chylous ascites.

Update on the reciprocal interference between immunosuppressive therapy and gut microbiota after kidney transplantation

Gut microbiota is often modified after kidney transplantation.This principally happens in the first period after transplantation.Antibiotics and,most of all,immunosuppressive drugs are the main responsible.The relationship between immunosuppressive drugs and the gut microbiota is bilateral.From one side immunosuppressive drugs modify the gut microbiota,often generating dysbiosis;from the other side microbiota may interfere with the immunosuppressant pharmacokinetics,producing products more or less active with respect to the original drug.These phenomena have influence over the graft outcomes and clinical consequences as rejections,infections,diarrhea may be caused by the dysbiotic condition.Corticosteroids,calcineurin inhibitors such as tacrolimus and cyclosporine,mycophenolate mofetil and mTOR inhibitors are the immunosuppressive drugs whose effect on the gut microbiota is better known.In contrast is well known how the gut microbiota may interfere with glucocorticoids,which may be transformed into androgens.Tacrolimus may be transformed by microbiota into a product called M1 that is 15-fold less active with respect to tacrolimus.The pro-drug mycophenolate mofetil is normally transformed in mycophenolic acid that according the presence or not of microbes producing the enzyme glucuronidase,may be transformed into the inactive product.

Immunosuppressive tumor microenvironment in gastric signet-ring cell carcinoma

Gastric signet-ring cell carcinoma(GSRCC)is a subtype of gastric cancer with distinct phenotype and high risk of peritoneal metastasis.Studies have shown that early GSRCC has a good prognosis,while advanced GSRCC is insensitive to radiotherapy,chemotherapy or immune checkpoint blockade therapy.With technological advancement of single-cell RNA sequencing analysis and cytometry by time of flight mass cytometry,more detailed atlas of tumor microenvironment(TME)in GSRCC and its association with prognosis could be investigated extensively.Recently,two single-cell RNA sequencing studies revealed that GSRCC harbored a unique TME,manifested as highly immunosuppressive,leading to high immune escape.The TME of advanced GSRCC was enriched for immunosuppressive factors,including the loss of CXCL13+-cluster of differentiation 8+-Tex cells and declined clonal crosstalk among populations of T and B cells.In addition,GSRCC was mainly infiltrated by follicular B cells.The increased proportion of SRCC was accompanied by a decrease in mucosaassociated lymphoid tissue-derived B cells and a significant increase in follicular B cells,which may be one of the reasons for the poor prognosis of GSRCC.By understanding the relationship between immunosuppressive TME and poor prognosis in GSRCC and the underlying mechanism,more effective immunotherapy strategies and improved treatment outcomes of GSRCC can be anticipated.

Clinical Exploration of Immunosuppressants Combined with Abiraterone in the Treatment of Metastatic Castration-Resistant Prostate Cancer

Prostate cancer is a malignant tumor with a high incidence in elderly men.In recent years,with the improvement of people’s living standards and the advancement of detection technology,the incidence of prostate cancer has been increasing year by year.Castration-resistant prostate cancer(CRPC)is a highly challenging type of advanced prostate cancer treatment,which clinically shows resistance to hormonal deprivation therapy.The overall treatment efficacy of CRPC is currently poor and further relevant therapeutic studies are needed to improve patient survival and quality of life.Immunosuppressants can play a role in combating the immune system of tumors,and abiraterone has also achieved remarkable results in prostate cancer treatment.This study will investigate the possible clinical effects and safety of immunosuppressants combined with abiraterone in the treatment of metastatic CRPC.The population-based study will provide clinicians with more effective treatment options,as well as enhance the understanding of novel combination therapy strategies to be implemented in the future for such patients.

Pharmacogenetics of immunosuppressant drugs:A new aspect for individualized therapy

In recent years,pharmacogenetics has emerged as an important tool for choosing the right immunosuppressant drug and its appropriate dose.Indeed,pharmacogenetics may exert its action on immunosuppressant drugs at three levels.Pharmacogenetics identifies and studies the genes involved in encoding the proteins involved in drug pharmacokinetics and in encoding the enzymes involved in drug degradation.Pharmacogenetics is also relevant in encoding the enzymes and proteins involved in codifying the transmembrane proteins involved in transmembrane passage favoring the absorption and intracellular action of several immunosuppressants.Pharmacogenetics concern the variability of genes encoding the proteins involved as immunosuppressant triggers in the pharmacodynamic pathways.Of course,not all genes have been discovered and studied,but some of them have been clearly examined and their relevance together with other factors such as age and race has been defined.Other genes on the basis of relevant studies have been proposed as good candidates for future studies.Unfortunately,to date,clear conclusions may be drawn only for those drugs that are metabolized by CYP3A5 and its genotyping before kidney,heart and lung transplantation is recommended.The conclusions of the studies on the recommended candidate genes,together with the development of omics techniques could in the future allow us to choose the right dose of the right immunosuppressant for the right patient.

Molecular chaperones in stroke-induced immunosuppression

Stroke-induced immunosuppression is a process that leads to peripheral suppression of the immune system after a stroke and belongs to the central nervous system injury-induced immunosuppressive syndrome.Stroke-induced immunosuppression leads to increased susceptibility to post-stroke infections,such as urinary tract infections and stroke-associated pneumonia,worsening prognosis.Molecular chaperones are a large class of proteins that are able to maintain proteostasis by directing the folding of nascent polypeptide chains,refolding misfolded proteins,and targeting misfolded proteins for degradation.Various molecular chaperones have been shown to play roles in stroke-induced immunosuppression by modulating the activity of other molecular chaperones,cochaperones,and their associated pathways.This review summarizes the role of molecular chaperones in stroke-induced immunosuppression and discusses new approaches to restore host immune defense after stroke.

Single-cell transcriptome profiling of sepsis identifies HLA-DR^(low)S100A^(high)monocytes with immunosuppressive function

Background Sustained yet intractable immunosuppression is commonly observed in septic patients,resulting in aggravated clinical outcomes.However,due to the substantial heterogeneity within septic patients,precise indicators in deciphering clinical trajectories and immunological alterations for septic patients remain largely lacking.Methods We adopted cross-species,single-cell RNA sequencing(scRNA-seq)analysis based on two published datasets containing circulating immune cell profile of septic patients as well as immune cell atlas of murine model of sepsis.Flow cytometry,laser scanning confocal microscopy(LSCM)imaging and Western blotting were applied to identify the presence of S100A9^(+)monocytes at protein level.To interrogate the immunosuppressive function of this subset,splenic monocytes isolated from septic wild-type or S100a9^(–/–)mice were co-cultured with naive CD4^(+)T cells,followed by proliferative assay.Pharmacological inhibition of S100A9 was implemented using Paquinimod via oral gavage.Results scRNA-seq analysis of human sepsis revealed substantial heterogeneity in monocyte compartments following the onset of sepsis,for which distinct monocyte subsets were enriched in disparate subclusters of septic patients.We identified a unique monocyte subset characterized by high expression of S100A family genes and low expression of human leukocyte antigen DR(HLA-DR),which were prominently enriched in septic patients and might exert immunosuppressive function.By combining single-cell transcriptomics of murine model of sepsis with in vivo experiments,we uncovered a similar subtype of monocyte significantly associated with late sepsis and immunocompromised status of septic mice,corresponding to HLA-DR^(low)S100A^(high)monocytes in human sepsis.Moreover,we found that S100A9^(+)monocytes exhibited profound immunosuppressive function on CD4^(+)T cell immune response and blockade of S100A9 using Paquinimod could partially reverse sepsis-induced immunosuppression.Conclusions This study identifies HLA-DR^(low)S100A^(high)monocytes correlated with immunosuppressive state upon septic challenge,inhibition of which can markedly mitigate sepsis-induced immune depression,thereby providing a novel therapeutic strategy for the management of sepsis.

Sepsis-induced immunosuppression:mechanisms,diagnosis and current treatment options

Sepsis is a common complication of combat injuries and trauma,and is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection.It is also one of the significant causes of death and increased health care costs in modern intensive care units.The use of antibiotics,fluid resuscitation,and organ support therapy have limited prognostic impact in patients with sepsis.Although its pathophysiology remains elusive,immunosuppression is now recognized as one of the major causes of septic death.Sepsis-induced immunosuppression is resulted from disruption of immune homeostasis.It is characterized by the release of antiinflammatory cytokines,abnormal death of immune effector cells,hyperproliferation of immune suppressor cells,and expression of immune checkpoints.By targeting immunosuppression,especially with immune checkpoint inhibitors,preclinical studies have demonstrated the reversal of immunocyte dysfunctions and established host resistance.Here,we comprehensively discuss recent findings on the mechanisms,regulation and biomarkers of sepsis-induced immunosuppression and highlight their implications for developing effective strategies to treat patients with septic shock.

Expert consensus on the monitoring and treatment of sepsis-induced immunosuppression

Emerged evidence has indicated that immunosuppression is involved in the occurrence and development of sepsis.To provide clinical practice recommendations on the immune function in sepsis,an expert consensus focusing on the monitoring and treatment of sepsis-induced immunosuppression was developed.Literature related to the immune monitoring and treatment of sepsis were retrieved from PubMed,Web of Science,and Chinese National Knowledge Infrastructure to design items and expert opinions were collected through an online questionnaire.Then,the Delphi method was used to form consensus opinions,and RAND appropriateness method was developed to provide consistency evaluation and recommendation levels for consensus opinions.This consensus achieved satisfactory results through two rounds of questionnaire survey,with 2 statements rated as perfect consistency,13 as very good consistency,and 9 as good consistency.After summarizing the results,a total of 14 strong recommended opinions,8 weak recommended opinions and 2 non-recommended opinions were produced.Finally,a face-to-face discussion of the consensus opinions was performed through an online meeting,and all judges unanimously agreed on the content of this consensus.In summary,this expert consensus provides a preliminary guidance for the monitoring and treatment of immunosuppression in patients with sepsis.

Compound fufangteng mixture affects the expression of CD69 on CD11b^(+) monocytes in immunosuppressed mice

Objective:To investigate the effects of Compound Fufangteng Mixture(CFM)on the expression levels of CD11b^(+)monocytes surface activation molecules CD2,CD69 and depleted molecules PD-1 and CD95 in spleen and peripheral blood of immunosuppressed mice.Methods:30 healthy SPF Balb/c male mice were randomly divided into Control,immunosuppressive model group(CTX group),high,medium and low dose intervention group(CTX+CFM-H group,CTX+CFM-M group,CTX+CFM-L group),Astragalus particles(AP)intervention group(CTX+AP group).The mice in each intervention group were injected intraperitoneally with cyclophosphamide(CTX)70 mg/kg for 3 consecutive days,and then administered for 10 d according to the group regimen,and the materials were taken 24 h after the last dose.Flow cytometry detected the expression of CD11b^(+)monocytes surface activation molecules(CD2,CD69)and depleting molecules(PD-1,CD95)in mouse peripheral blood.Results:Compared with the control group,the expression levels of CD11b^(+)and CD69+in the spleen of CTX+CFM-H,CTX+CFM-M and CTX+CFM-L groups showed an improvement trend,and decreased with the dose gradient of CFM.Conclusion:CFM could regulate the immune function of splenic CD11b+ CD69 cells in immunosuppressed mice.

Advances in glucocorticoid-mediated stroke-associated immunosuppression

Acute ischemic stroke is often accompanied by complications such as infection.After acute isch-emic stroke,immunosuppression can occur as a mechanism to prevent an excessive inflammatory response. Glucocorticoid,an important product of the hypothalamic-pituitary-adrenal axis,plays a crucial role in inducing immunosuppression in the early stage of acute cerebral infarction. Glucocorticoid not only affects the secretion of inflammatory cytokines but also influences the function of immune cells,ultimately leading to an increased risk of infection.

Review on immunosuppression in liver transplantation

The optimal level of immunosuppression in solid organ transplantation,in particular for the liver,is a delicate balance between the benefit of preventing rejection and the adverse side effects of immunosuppression. There is uncertainty about when this level is achieved in any individual recipient. Immunosuppression regimens vary between individual centers and changes with time asnew agents and data are available. Presently concerns about the adverse side effects of calcineurin inhibitor,the main class of immunosuppressive agents used in liver transplantation(LT),has led to consideration of the use of antibody induction therapies for patients at higher risk of developing adverse side effects. The longevity of the transplanted organ is potentially improved by better management of rejection episodes and special consideration for tailoring of immunosuppression to the individual with viral hepatitis C,hepatocellular carcinoma or pregnancy. This review provides an overview of the current strategies for post LT immunosuppression and discusses modifications to consider for special patient populations.

Impact of immunosuppression minimization and withdrawal in long-term hepatitis C virus liver transplant recipients

AIM: To investigate the effects of different immunosuppressive regimens and avoidance on fibrosis progression in hepatitis C virus (HCV) liver transplant (LT) recipients.

Reversing effects of traditional Chinese antitumor medicines on colorectal tumor immunosuppression of natural killer cell and T lymphocyte in vitro

Objective： Reversing effects of traditional Chinese medicines on colorectal tumor immunosuppressions of natural killer （NK） cell and T lymphocyte were analyzed to provide evidence on selecting medicines for patients according to the differ- ent types of tumor immunosuppression. Methods： Six traditional Chinese medicines, including Arsenious acid （AS）, Ligustra- zine hydrochloride （LHC）, Astragalus mongholicus bge （AMB）, Matrine N-oxide （MOX）, Polyporus umbellatus polysaccharide （PUPS） and Artesunate （ART）, were enrolled. The reversing effects on suppression of murine splenocyte transformation and NK killing activity were measured by 3-{4,5-dimethyl-2-thiazolyl}-2,5-diphenyl tetrazolium （MTT）, and the effects on the suppressed expression of intefieukin 2 receptor a （IL-2R（I）, CD3E＊~,＊ and CD3~.-~＊ were detected by flow cytometry （FCM）. The effects on immunosuppressive molecules were measured by enzyme linked immunosorbent assay （ELISA）, including transforming growth factor ~1 （TGF-~I）, vascular endothelial growth factor （VEGF）, interleukin 4 （IL-4）, IL-6, IL-10 and pros- taglandin （PG） E2. Results： （1） The reversing effects of AMB on the inhibition of NK killing and CD3 expression were the most significant; the effect of LHC on inhibition of CD3 expression was the strongest; the effects of AMB, PUPS and ART on inhibition of transformation were the greatest; and the effect of ART on inhibition of IL-2Ra expression was the strongest. （2） The correlated molecules of these medicines that exerted reversing effects on colorectal tumor immunosuppression were TGF-~I and IL-10. AMB had the highest down-regulating effect on the secretion of TGF-~I. AS and ART had the highest effects on IL-10. Conclusion： Reversing tumor immunosuppression through the down-regulation of immunosuppressive molecules is one of the novel antitumor mechanisms of traditional Chinese medicines. The clinical use of compounded prescriptions of ART combined with AMB and LHC should be considered to avoid the reduced treatment efficiency caused by tumor im- munosuppression.