Research progress of ICOSL/ICOS pathway in maternal-fetal immune tolerance

Co-signaling molecules are molecules whose ligands on the surface of cells interact with receptors on the surface of T cells to convey stimulatory or inhibitory signals to regulate immune responses.Co-signaling molecules play an important role in tumor and autoimmune diseases.Lately,studies have shown that co-signaling molecules are also involved in the regulation of maternal-fetal immune tolerance,and abnormalities of co-signaling molecules may lead to the imbalance of maternal-fetal immune tolerance,resulting in recurrent abortion,eclampsia and other pregnancy complications.ICOSL/ICOS is a ligand and receptor of costimulatory signals,which regulates maternal and fetal immune tolerance by participating in T cell differentiation and Th1 and Th2 cytokine secretion.Therefore,this article reviews the structure of ICOSL/ICOS,the distribution of ICOSL/ICOS at the maternal-fetal interface and its immune regulation during pregnancy,in order to provide new ideas for the future study of immunotherapy of pregnancy complications caused by abnormal co-signaling molecules.

IMMUNE TOLERANCE INDUCED BY GAMMA-RAY IRRADIATION

Objective: To detect the existence of immune tolerance induced by gamma-ray irradiation. Methods: Peritoneal cells were harvested from mice subjected to 5 Gy 60Co gamma-ray total body irradiation at 3d, 7d, 15d and 30d, then their counts, morphological changes and IL-12 gene expression were investigated. Results: After irradiation, the peritoneal cells were sharply reduced, the cell morphology shifted from round-like to polymorphic and fusiform with some processes, expression of IL-12 p35 was seriously suppressed, while that of IL-12 p40 greatly enhanced. Conclusion: Our data highly suggest that the gamma-ray irradiation could potentially induce dendritic cell (DC) commitment and immune tolerance.

Diverse Roles of Immune Cells in Transplant Rejection and Immune Tolerance

Organ transplant rejection(OTR)is a complex immune reaction involving multiple cells,and it determines graft survival and patient prognosis.At present,most transplant recipients are administered a combination of immunosuppressive and biological agents to protect them from OTR.However,immunosuppressive agents negatively impact the immune system of the patients,causing them to suffer from serious complications,such as chronic infection and malignant tumors.Therefore,a thorough understanding of the mechanisms involved in immune tolerance and immune rejection with regard to organ transplant(OT)is essential for developing better treatment options and improving patient outcomes.This article reviews the role of immune cells in OTR and organ transplant tolerance(OTT),including the novel cell therapies that are currently under clinical trials for transplant recipients.

Ragweed pollen induces allergic conjunctivitis immune tolerance in mice via regulation of the NF-κB signal pathway

AIM:To investigate the feasibility and mechanism of immune tolerance in allergic conjunctivitis.METHODS:The allergic conjunctivitis immune tolerance mice model was established by ragweed pollen(RW)and the related cytokines were detected.The mice were divided into 9 groups and the maslinic acid(MA)or PBS were given for different group after modeling.The expression levels of chemokine ligand 5(CCL5)and P-65 in the conjunctival tissue were analyzed by immunohistochemistry,quantitative reverse transcription polymerase chain reaction(q RT-PCR)and Western blot.The percentage of interleukin-17(IL-17)and CD4+CD25+in the splenocyte supernatant was analyzed by flow cytometry.Fur thermore,the serum and splenocyte supernatant concentration of total-IgE,interleukin-10(IL-10),and IL-17 was analyzed by enzyme linked immune response(ELISA).RESULTS:After the model was established,symptoms of conjunctivitis were alleviated,the level of P-65,CCL5,IL-17,and total-IgE was raised,while the expression of IL-10,CD4+CD25+was decreased.This result fully demonstrated that a typical IL-17/regulatory-T-cells(Treg cells)imbalance and NF-κB activation.When the NF-κB signal pathway was suppressed,it showed that there was a further relief of conjunctivitis in mice.At the same time,the expression of total-IgE,IL-17,and CCL5 was decreased and the expression of anti-inflammatory factor(IL-10,CD4+CD25+)was increased.CONCLUSION:In the state of immune tolerance,symptoms of conjunctivitis in mice are alleviated,the Th-17 cells of allergic conjunctivitis mice are inhibited,and Treg cells activity is enhanced.

Sinomenine promotes differentiation of induced pluripotent stem cells into immature dendritic cells with high induction of immune tolerance

BACKGROUND Immature dendritic cells(imDCs)play an important role in the induction of donor-specific transplant immunotolerance.However,these cells have limitations,such as rapid maturation and a short lifespan in vivo.In previous studies,induced pluripotent stem cells(iPSCs)differentiated into imDCs,and sinomenine(SN)was used to inhibit the maturation of imDCs.AIM To study the capacity of SN to maintain iPSC-derived imDCs(SN-iPSCs-imDCs)in an immature state and the mechanism by which SN-iPSCs-imDCs induce immunotolerance.METHODS In this study,mouse iPSCs were induced to differentiate into imDCs in culture medium without or with SN(iPSCs-imDCs and SN-iPSCs-imDCs).The imDCrelated surface markers,endocytotic capacity of fluorescein isothiocyanate Dextran and apoptosis were analyzed by flow cytometry.The effects of iPSCs-imDCs and SNiPSCs-imDCs on T-cell stimulatory function,and regulatory T(Treg)cell proliferative function in vitro were analyzed by mixed lymphocyte reaction.Cytokine expression was detected by ELISA.The apoptosis-related proteins of iPSCs-DCs and SN-iPSCs-DCs were analyzed by western blotting.The induced immunotolerance of SN-iPSCs-DCs was evaluated by treating recipient Balb/c skin graft mice.Statistical evaluation of graft survival was performed using Kaplan–Meier curves.RESULTS Both iPSCs-imDCs and SN-iPSCs-imDCs were successfully obtained,and their biological characteristics and ability to induce immunotolerance were compared.SN-iPSCs-imDCs exhibited higher CD11c levels and lower CD80 and CD86 levels compared with iPSCs-imDCs.Reduced major histocompatibility complex II expression,worse T-cell stimulatory function,higher Treg cell proliferative function and stronger endocytotic capacity were observed with SN-iPSCs-imDCs(P<0.05).The levels of interleukin(IL)-2,IL-12,interferon-γin SN-iPSCs-imDCs were lower than those in iPSCs-imDCs,whereas IL-10 and transforming growth factor-βlevels were higher(P<0.05).The apoptosis rate of these cells was significantly higher(P<0.05),and the expression levels of cleaved caspase3,Bax and cleaved poly(ADP-ribose)polymerase were higher after treatment with lipopolysaccharides,but Bcl-2 was reduced.In Balb/c mice recipients immunized with iPSCsimDCs or SN-iPSCs-imDCs 7 d before skin grafting,the SN-iPSCs-imDCs group showed lower ability to inhibit donor-specific CD4+T-cell proliferation(P<0.05)and a higher capacity to induce CD4+CD25+FoxP3+Treg cell proliferation in the spleen(P<0.05).The survival span of C57bl/6 skin grafts was significantly prolonged in immunized Balb/c recipients with a donor-specific pattern.CONCLUSION This study demonstrated that SN-iPSCs-imDCs have potential applications in vitro and in vivo for induction of immunotolerance following organ transplantation.

Complex regulatory effects of gut microbial short-chain fatty acids on immune tolerance and autoimmunity

Immune tolerance deletes or suppresses autoreactive lymphocytes and is established at multiple levels during the development,activation and effector phases of T and B cells.These mechanisms are cell-intrinsically programmed and critical in preventing autoimmune diseases.We have witnessed the existence of another type of immune tolerance mechanism that is shaped by lifestyle choices,such as diet,microbiome and microbial metabolites.Short-chain fatty acids(SCFAs)are the most abundant microbial metabolites in the colonic lumen and are mainly produced by the microbial fermentation of prebiotics,such as dietary fiber.This review focuses on the preventive and immunomodulatory effects of SCFAs on autoimmunity.The tissue-and disease-specific effects of dietary fiber,SCFAs and SCFA-producing microbes on major types of autoimmune diseases,including type I diabetes,multiple sclerosis,rheumatoid arthritis and lupus,are discussed.Additionally,their key regulatory mechanisms for lymphocyte development,tissue barrier function,host metabolism,immunity,autoantibody production,and inflammatory effector and regulatory lymphocytes are discussed.The shared and differential effects of SCFAs on different types and stages of autoimmune diseases are discussed.

Mechanisms of Immune Tolerance and Inflammation via Gonadal Steroid Hormones in Preterm Birth

In 2019,preterm births(PTB)accounted for approximately 0.66 million deaths globally.PTB is also associated with a significantly higher risk of mortality and long-term complications for newborns.Long-term studies associated several factors,including disruption of immune tolerance and inflammation,with PTB.However,the pathogenesis of PTB remains unclear.Gonadal steroid hormones are critical for pregnancy maintenance and regulation of immune and inflammatory responses.However,it is not clear how unbalanced gonadal steroid hormones,such as imbalanced estrogen/androgen or estrogen/progesterone contribute to PTB.In this review,we discuss how gonadal steroid hormones mediate dysfunction in immune tolerance and inflammatory responses,which are known to promote the occurrence of PTB,and provide insight into PTB prediction.

Increased leakage of brain antigens after traumatic brain injury and effect of immune tolerance induced by cells on traumatic brain injury

Background Although traumatic brain injury can lead to opening the blood-brain barrier and leaking of blood substances （including water） into brain tissue, few studies of brain antigens leaking into the blood and the pathways have been reported. Brain antigens result in damage to brain tissues by stimulating the immune system to produce anti-brain antibodies, but no treatment has been reported to reduce the production of anti-brain antibodies and protect the brain tissue. The aim of the study is to confirm the relationship between immune injury and arachnoid granulations following traumatic brain injury, and provide some new methods to inhibit the immune injury.Methods In part one, methylene blue was injected into the rabbits’ cisterna magna after traumatic brain injury, and concentrations of methylene blue and tumor necrosis factor （TNF）-α in blood were detected to determine the permeability of arachnoid granulations. In part two, umbilical cord mesenchymal stem cells and immature dendritic cells were injected into veins, and concentrations of interleukin 1 （IL-1）, IL-10, interferon （IFN）-γ, transforming growth factor （TGF）-β, anti-brain antibodies （ABAb）, and IL-12 were measured by ELISA on days 1, 3, 7, 14 and 21 after injury, and the numbers of leukocytes in the blood were counted. Twenty-one days after injury, expression of glutamate in brain tissue was determined by immunohistochemical staining, and neuronal degeneration was detected by H＆E staining. Results In part one, blood concentrations of methylene blue and TNF-α in the traumatic brain injury group were higher than in the control group （P 〈0.05）. Concentrations of methylene blue and TNF-α in the trauma cerebrospinal fluid （CSF） injected group were higher than in the control cerebrospinal fluid injected group （P 〈0.05）. In part two, concentrations of IL-1, IFN-γ, ABAb, IL-12, expression of glutamate （Glu）, neuronal degeneration and number of peripheral blood leukocytes were lower in the group with cell treatment compared to the control group. IL-10 and TGF-β were elevated compared to the control group. Conclusions Traumatic brain injury can lead to stronger arachnoid granulations （AGs） permeability; umbilical cord mesenchymal stem cells and immature dendritic cells can induce immune tolerance and reduce inflammation and anti-brain antibodies to protect the brain tissue.

An experimental study on thymus immune tolerance to treat surgical brain injury

Background Many researches demonstrate that the secondary brain injury which is caused by autoimmune attack toward brain antigens plays an important role in surgical brain injury （SBI）.Although traditional immunosuppression can reduce autoimmune attack,it will lower the body immunity.Immune tolerance,by contrast,not only does not lower the body immunity,but also could lighten autoimmunity.This study used thymus tolerance to develop an immune system that is tolerant to autologous cerebrospinal fluid （CSF） and autologous brain tissue so that autoimmune injury can be suppressed following the disruption of the blood-brain barrier,thereby reducing brain damage.Methods Eighty experimental rabbits were divided into five groups by random number table method：16 in SBI group （group A）,16 in SBI＋CSF drainage group （group B）,16 in SBI＋CSF drainage＋PBS injection group （group C）,16 in SBI＋CSF drainage＋CSF intrathymic injection group （group D）,and 16 in SBl＋brain homogenate intrathymic injection group （group E）.Rabbits＆#39; CSF was drained in group B; was drained and injected PBS into thymus in group C; was drained and injected CSF into thymus in group D; and was injected brain homogenate in group E.Half of the rabbits in each group were phlebotomized on 1st,3rd,7th,and 14th days to observe the changes in IL-I,TGF-β by ELISA test,and CD4CD25 regulatory T cells ratio by flow cytometry,and in other animals brain tissues were taken on 7th day for exploring FasL expression by RT-PCR.The least significant difference （LSD） test was used to make paired comparisons; P ＜0.05 was considered statistically significant.Results The levels of FasL,TGF-β,and the ratios of CD4CD25 regulatory T cells in groups D and E were apparently higher than those in other three groups （P ＜0.05）.Likewise,the levels of IL-1 in these two groups were lower than the other three groups （P ＜0.05）.Moreover,the ratios of CD4CD25 regulatory T cells and the levels of TGF-β in groups B and C were higher than those in group A,but the level of IL-1 was lower than that in group A （P ＜0.05）.There was no significant difference between groups B and C,and groups D and E.Conclusion Thymic injection of CSF and brain homogenate may be able to reduce inflammation after SBI,so thymus immune tolerance may be a useful therapy to treat SBI.

Transcriptional and epigenetic regulation of immune tolerance:roles of the NF-κB family members

Immune tolerance is a highly regulated state and involves diverse mechanisms.Central to the induction of tolerance is the targeted modulation of T-cell activities(both effector and regulatory),in which transcription factors play a significant role.The nuclear factor kappa-B(NF-κB)family is a family of transcription factors that not only are critically involved in diverse T-cell responses but also are regulated by many mechanisms to maintain tolerance and T-cell homeostasis.NF-κB,as a transcription factor,has been extensively studied in recent decades,and the molecular mechanisms that regulate NF-κB activities have been well documented.However,recent studies have revealed exciting new roles for NF-κB;in addition to its transcriptional activity,NF-κB can also activate diverse epigenetic mechanisms that mediate extensive chromatin remodeling of target genes to regulate T-cell activities.In this review article,we highlight recent discoveries and emerging opportunities in targeting NF-κB family members as well as their associated chromatin modifiers in the induction of immune tolerance and in the clinical treatment of immune diseases.

Immune Tolerance Therapy： A New Method for Treatment of Traumatic Brain Injury

Objective： Due to the special anatomical structure and pathophysiological mechanism of the central nervous system （CNS）, there is a big difference between the repair of brain injury and other systems of the body. More and more evidence shows that targetedly reducing the autoimmune response of brain tissue without affecting the immune function in other parts of the body will be the best optimized treatment for brain injury. Data Sources： This review was based on data in articles published in PubMed up to June 5,2017, with the following keywords： ＂immune tolerance＂, ＂traumatic brain injury＂, and ＂central nervous system＂. Study Selection： Original articles and critical reviews on immune tolerance and brain damage were selected for this review. References of the retrieved articles were also screened to search for potentially relevant papers. Results： The CNS is isolated from the immune system through the blood-brain barrier. After brain injury, brain antigens are released into the systemic circulation to induce damaging immune responses. Immune tolerance can effectively reduce the brain edema and neurological inflammatory response after brain injury, which is beneficial to the recovery of neurological function. The clinical application prospect and theoretical research value of the treatment of immune tolerance on traumatic brain inj ury （TBi） is worth attention. Conclusions： The establishment of immune tolerance mechanism has a high clinical value in the treatment of TBI. It opens up new opportunities for the treatment of brain damage.

Cytokine regulation of immune tolerance

The immune system provides defenses against invading pathogens while maintaining immune tolerance to self-antigens.This immune homeostasis is harmonized by the direct interactions between immune cells and the cytokine environment in which immune cells develop and function.Herein,we discuss three non-redundant paradigms by which cytokines maintain or break immune tolerance.We firstly describe how anti-inflammatory cytokines exert direct inhibitory effects on immune cells to enforce immune tolerance,followed by discussing other cytokines that maintain immune tolerance through inducing CD_(4)^(+) Foxp_(3)^(+) regulatory T cells(Tregs),which negatively control immune cells.Interleukin(IL)-2 is the most potent cytokine in promoting the development and survival of Tregs,thereby mediating immune tolerance.IL-35 is mainly produced by Tregs,but its biology function remains to be defi ned.Finally,we discuss the actions of proinflammatory cytokines that breach immune tolerance and induce autoimmunity,which include IL-7,IL-12,IL-21,and IL-23.Recent genetic studies have revealed the role of these cytokines(or their cognate receptors)in susceptibility to autoimmune diseases.Taken together,we highlight in this review the cytokine regulation of immune tolerance,which will help in further understanding of human diseases that are caused by dysregulated immune system.

Histone methyltransferase Nsd2 ensures maternal-fetal immune tolerance by promoting regulatory T-cell recruitment

Regulatory T cells(Tregs)are fundamentally important for maintaining systemic immune homeostasis and are also required for immune tolerance at the maternal-fetal interface during pregnancy.Recent studies have suggested that epigenetic regulation is critically involved in Treg development and function.However,the role of H3K36me has not yet been investigated.Here,we found that the H3K36me2 methyltransferase Nsd2 was highly expressed in Tregs.Although loss of Nsd2 did not impair systemic Treg development or function,the level of Tregs at the maternal-fetal interface was significantly decreased in pregnant Nsd2 conditional knockout mice.Consequently,maternal-fetal immune tolerance was disrupted in the absence of Nsd2 in Tregs,and the pregnant mice showed severe fetal loss.Mechanistically,Nsd2 was found to upregulate CXCR4 expression via H3K36me2 modification to promote Treg cell recruitment into the decidua and suppress the anti-fetal immune response.Overall,our data identified Nsd2 as a critical epigenetic regulator of Treg recruitment for maternal-fetal tolerance.

Facing challenges with hope:universal immune cells for hematologic malignancies

Many patients have achieved a favorable overall survival rate since allogenic hematopoietic stem cell transplantation(allo-HSCT)has been widely implemented to treat hematologic malignancies.However,graft-versus-host disease(GVHD)and complications of immunosuppressive drugs after allo-HSCT are the main causes of non-relapse mortality and a poor quality of life.In addition,GVHD and infusion-induced toxicity still occur with donor lymphocyte infusions(DLIs)and chimeric antigen receptor(CAR)T-cell therapy.Because of the special immune tolerance characteristics and anti-tumor ability of universal immune cells,universal immune cell therapy may strongly reduce GVHD,while simultaneously reducing tumor burden.Nevertheless,widespread application of universal immune cell therapy is mainly restricted by poor expansion and persistence efficacy.Many strategies have been applied to improve universal immune cell proliferation and persistence efficacy,including the use of universal cell lines,signaling regulation and CAR technology.In this review we have summarized current advances in universal immune cell therapy for hematologic malignancies with a discussion of future perspectives.

Immune tolerance induced by immune-homeostatic particles

Autoimmune diseases,induced by dysfunction of the adaptive immune system,are the common disease categories worldwide.Recently,regulatory T cells(Tregs)enhancing therapies have been demonstrated to treat autoimmune diseases,which could induce immune tolerance to protect cells and tissues from self-attacking of the immune system.However,their widespread application is limited by complex manufacturing process,long production period and high cost.Herein,we give a perspective of immune-homeostatic particles as immune regulators to induce antigen-specific Tregs for treating autoimmune diseases.Disease-specific autoantigen is loaded into the particle to induce Tregs differentiation after release.In addition,the surface of the particles is decorated by specific ligands that could bind and trigger apoptosis of activated T cells,thereby impressing the overreacted immune system.Furthermore,liver sinusoidal endothelial cells(LSEC)-targeting particles are developed to stimulate CD4^(+)T cells differentiation into Tregs.We believe that the immune-homeostatic particles have great potential in autoimmune diseases treatment and are valuable in various immune-related disease treatments.

Immunology demystified: A guide for transplant hepatologists

Liver transplantation has become standard practice for treating end-stage liver disease.The success of the procedure relies on effective immunosuppressive medications to control the host's immune response.Despite the liver's inherent capacity to foster tolerance,the early post-transplant period is marked by significant immune reactivity.To ensure favorable outcomes,it is imperative to identify and manage various rejection types,encompassing T-cell-mediated,antibody-mediated,and chronic rejection.However,the approach to prescribing immunosuppressants relies heavily on clinical judgment rather than evidencebased criteria.Given that the majority of patients will require lifelong immunosuppression as the mechanisms underlying operational tolerance are still being investigated,healthcare providers must possess an understanding of immune responses,rejection mechanisms,and the pathways targeted by immunosuppressive drugs.This knowledge enables customization of treatments and improved patient care,even though a consensus on an optimal immunosuppressive regimen remains elusive.

Hepatitis B:Who should be treated?-managing patients with chronic hepatitis B during the immune-tolerant and immunoactive phases

New hepatitis B virus(HBV)infections are decreasing owing to improved antiviral therapy and increased HBV vaccination worldwide;however,the number of HBV infections remains a major cause of liver carcinogenesis.HBV triggers cytotoxic immunity to eliminate HBV-infected cells.Therefore,the HBV pathophysiology changes in persistently infected individuals depending on host immune responses and HBV DNA proliferation state.To prevent liver cirrhosis and carcinogenesis caused by HBV,it is important to treat HBV infection at an early stage.Active treatment is recommended for the immunoactive hepatitis B surface-antigen-positive and-negative phase,but not during the immune-inactive phase or immune-tolerant phase;instead,follow-up is recommended.However,these patients should be monitored through regular blood tests to accurately diagnose the immune-inactive or-tolerant phases.The treatment regimen should be determined based on the age,sex,family history of liver cancer,and liver fibrosis status of patients.Early treatment is often recommended due to various problems during the immune-tolerant phase.This review compares the four major international practice guidelines,including those from the Japanese Society of Hepatology,and discusses strategies for chronic hepatitis B treatment during the immune-tolerant,immune-inactive,and resolved phases.Finally,recommended hepatitis B antiviral therapy and follow-up protocols are discussed.

Establishment of Nasal Tolerance to Heat Shock Protein-60 Alleviates Atherosclerosis by Inducing TGF-β-dependent Regulatory T Cells

Mounting evidence supports that a newly identified regulatory T cell (Treg),CD4+LAP+ Treg,is associated with oral tolerance induction and following inhibition of atherosclerosis,but little is described about whether nasal tolerance to antigen likewise induces the novel Tregs production and the relevant antiatherosclerotic benefit.We investigated the effect of nasal administration of heat shock protein-60 (HSP60) on atherogenesis.HSP60 or phosphate buffer solution (PBS) was nasally adminis-tered to six-week-old male ApoE-/-mice.At the 10th week after the nasal administration,there was a significant decrease in atherosclerotic plaque areas of aortic roots in the HSP60-treated mice as com-pared with those in the PBS-treated mice.Atherosclerosis suppression was accompanied with a signifi-cant increase in CD4+LAP+ and CD4+CD25+Foxp3+ Tregs and a concurrently increased production of TGF-β in the HSP60-treated mice.The protective effect of HSP60 was offset by injection of anti-TGF-βantibody.It is concluded that nasal administration of HSP60 can inhibit atherosclerotic formation through immune tolerance which is established by Tregs depending on the induction of anti-inflammatory cytokine TGF-β.Immune tolerance induced by nasal administration of HSP60 may provide an alternative therapeutic method for atherosclerosis.

Clinical operational tolerance in liver transplantation:state-of-the-art perspective and future prospects

BACKGROUND:Liver transplantation is the definite treatment for end-stage liver diseases with satisfactory results.However,untoward effects of life-long immunosuppression prevent the development of alternative strategies to achieve better longterm outcome.Achieving clinical operational tolerance is the ultimate goal.DATA SOURCES:A PubMed and Google Scholar search using terms:"immune tolerance","liver transplantation","clinical trial","operational tolerance" and "immunosuppression withdrawal" was performed,and relevant articles published in English in the past decade were reviewed.Full-text publications relevant to the field were selected and relevant articles from reference lists were also included.Priority was given to those articles which are relevant to the review.RESULTS:Because of the inherent tolerogenic property,around 20%-30% of liver transplantation recipients develop spontaneous operational tolerance after immunosuppression withdrawal,and the percentage may be even higher in pediatric living donor liver transplantation recipients.Several natural killer and γδT cell related markers have been identified to be associated with the tolerant state in liver transplantation patients.Despite the progress,clinical operational tolerance is still rare in liver transplantation.Reprogramming the recipient immune system by creating chimerism and regulatory cell therapies is among newer promising means to achieve clinical liver transplantation tolerance in the future.CONCLUSION:Although clinical operational tolerance is still rare in liver transplantation recipients,ongoing basic research and collaborative clinical trials may help to decipher the mystery of transplantation tolerance and extend the potential benefits of drug withdrawal to an increasing number of patients in a more predictable fashion.

Innate and adaptive immune escape mechanisms of hepatitis B virus

Chronic hepatitis B virus(HBV)infection is an international health problem with extremely high mortality and morbidity rates.Although current clinical chronic hepatitis B(CHB)treatment strategies can partly inhibit and eliminate HBV,viral breakthrough may result due to non-adherence to treatment,the emergence of viral resistance,and a long treatment cycle.Persistent CHB infection arises as a consequence of complex interactions between the virus and the host innate and adaptive immune systems.Therefore,understanding the immune escape mechanisms involved in persistent HBV infection is important for designing novel CHB treatment strategies to clear HBV and achieve long-lasting immune control.This review details the immunological and biological characteristics and escape mechanisms of HBV and the novel immune-based therapies that are currently used for treating HBV.