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.

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.

Immunological tolerance of human hepatocyte xenograft induced by adenovirus vector-mediated CTLA4Ig gene transfer

BACKGROUND:Systemic administration of CTLA4Ig has been applied in inducing immunological tolerance of hepatocyte implants,but has potential for systemic immune inhibition.This study was designed to induce hepatocyte immunological tolerance by locally expressing CTLA4Ig in an attempt to improve the effectiveness of cell transplantation.METHODS:A normal human liver cell line(L02) was transfected with adenovirus vector containing the CTLA4Ig gene(Ad-CTLA4Ig-EGFP) in vitro,and the expression of CTLA4Ig by transfected cells was assessed by fluorescent imaging and immunocytochemical staining.Transfected cells then were injected into the spleen of Sprague-Dawley rats,the survival of cells was determined by immunohistochemistry,and the immune status was examined through CD4 + and CD69 + T cellcounts and ELISA detection of IL-2 in peripheral blood.RESULTS:L02 cells expressed CTLA4Ig in the cytoplasm for >4 weeks.Surviving L02 cells were observed in the experimental group at 3 and 4 weeks post-transplantation,while none was detected in the control group.Furthermore,the percentages of CD4 + and CD4 + CD69 + T cells in the CTLA4-transfected group were 24.5% and 45.1%,markedly lower than those in the control group at 4 weeks post-transplantation(P<0.01).Furthermore,the IL-2 level was also lower in the CTLA4transfected group than in the control group.CONCLUSION:Adenovirus-mediated CTLA4Ig gene transfer into human hepatocytes has the potential to become an effective method of inducing immunological tolerance in hepatocyte transplantation.

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.

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 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.

Nerve allograft regeneration and immunological tolerance of rats with sciatic nerve transplantation after intragastric pretreatment with ultraviolet B-irradiated donor splenocytes

BACKGROUND： Nerve allograft rejection is an unavoidable problem for nerve allografts. Traumatic peripheral nerve injuries are commonly reconstructed using autogenous nerve grafts. However, this form of reconstruction is limited by insufficient autologous nerves for large gap repairs and by morbidity at the nerve donor site. OBJECTIVE： To examine sciatic nerve regeneration and immune tolerance reaction after intragastric administration of ultraviolet B-irradiated （UVB） donor splenocytes. DESIGN, TIME AND SETTING： A complete randomized grouping design and controlled experiment. The experiments were conducted in the Department of Orthopedics, the First Affiliated Hospital to Shanxi Medical University, China, between March and October 2007. MATERIALS： Fourteen adult male SD rats and fourteen male Wistar rats, weighing 250-300 g, were randomly matched as donors and acceptors. A further seven male SD rats （weight 250-300 g, age 12-16 weeks） were used for nerve isografts. Immune preparations and the Epics XL flow cytometer were purchased from B-D Company, USA. A computer-assisted electromyograph machine was provided by Keypoint P, Dantel Company, Denmark. METHODS： Splenocytes from Wistar rats were isolated, purified, and cultured, and then irradiated with ultraviolet B. In the first control group （Group 1）, the SD rats received a syngeneic SD nerve isograft. In the second control group （Group 2）, the SD rats received a nerve allograft from Wistar rats without pretreatment. In the oral-tolerance treated group （Group 3）, the SD recipient rats were inoculated with 2.5×10^7 Lewis UVB-irradiated donor splenocyte cells by intestinal tract administration at seven days before transplantation. MAIN OUTCOME MEASURES： （1） The recent end and the middle and distal end of the transplanted nerve were cut at 8 and 12 weeks after operation. Recovery of nerve regeneration was measured with HE staining using the total number, density, and diameter of the nerve fibers. （2） The level of CD25＋T lymphocytes in peripheral blood was detected with the Epics XL flow cytometer at one week after operation. （3） The bilateral sciatic nerves were exposed from the sciatic notch up to 0.5 mm beyond the distal graft site at eight weeks post-engraftment. Bipolar platinum stimulating electrodes were placed under the sciatic nerve proximally and the mean conduction velocity was recorded with recording electrodes on the posterior tibial nerve at 0.3 cm distal to the nerve graft. RESULTS： Eight weeks after operation, total axon number and fiber density in Group 3 were higher than that in Group 1 （P 〈 0.05）, neural regeneration in Group 3 was lower than that in Group 1 （P 〈 0.05） , The level of CD25＋T lymphocytes in peripheral blood of Group 3 was significantly lower than that of Group 2 （P 〈 0.05）. There was no significant difference between Group 3 and Group 1 （P 〉 0.05）. At eight weeks post-engraftment the mean conduction velocity of Group 3 approximated that of Group 1. The untreated allografts in Group 2 demonstrated no measurable recovery of conduction velocity. CONCLUSION： Pretreatment with a single intragastric dose of UVB-modified donor antigen specifically induced tolerance to peripheral nerve allografts in rats.

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.

Islet transplantation-immunological challenges and current perspectives

Pancreatic islet transplantation is a minimally invasive procedure aiming to reverse the effects of insulin deficiency in patients with type 1 diabetes(T1D)by transplanting pancreatic beta cells.Overall,pancreatic islet transplantation has improved to a great extent,and cellular replacement will likely become the mainstay treatment.We review pancreatic islet transplantation as a treatment for T1D and the immunological challenges faced.Published data demonstrated that the time for islet cell transfusion varied between 2 and 10 h.Approximately 54%of the patients gained insulin independence at the end of the first year,while only 20%remained insulin-free at the end of the second year.Eventually,most transplanted patients return to using some form of exogenous insulin within a few years after the transplantation,which imposed the need to improve immunological factors before transplantation.We also discuss the immunosuppressive regimens,apoptotic donor lymphocytes,anti-TIM-1 antibodies,mixed chimerism-based tolerance induction,induction of antigen-specific tolerance utilizing ethylene carbodiimide-fixed splenocytes,pretransplant infusions of donor apoptotic cells,B cell depletion,preconditioning of isolated islets,inducing local immunotolerance,cell encapsulation and immunoisolation,using of biomaterials,immunomodulatory cells,etc.

Liver immunity,autoimmunity,and inborn errors of immunity

The liver is the front line organ of the immune system.The liver contains the largest collection of phagocytic cells in the body that detect both pathogens that enter through the gut and endogenously produced antigens.This is possible by the highly developed differentiation capacity of the liver immune system between self-antigens or non-self-antigens,such as food antigens or pathogens.As an immune active organ,the liver functions as a gatekeeping barrier from the outside world,and it can create a rapid and strong immune response,under unfavorable conditions.However,the liver's assumed immune status is anti-inflammatory or immuno-tolerant.Dynamic interactions between the numerous populations of immune cells in the liver are key for maintaining the delicate balance between immune screening and immune tolerance.The anatomical structure of the liver can facilitate the preparation of lymphocytes,modulate the immune response against hepatotropic pathogens,and contribute to some of its unique immunological properties,particularly its capacity to induce antigen-specific tolerance.Since liver sinusoidal endothelial cell is fenestrated and lacks a basement membrane,circulating lymphocytes can closely contact with antigens,displayed by endothelial cells,Kupffer cells,and dendritic cells while passing through the sinusoids.Loss of immune tolerance,leading to an autoaggressive immune response in the liver,if not controlled,can lead to the induction of autoimmune or autoinflammatory diseases.This review mentions the unique features of liver immunity,and dysregulated immune responses in patients with autoimmune liver diseases who have a close association with inborn errors of immunity have also been the emphases.

Role of maternal-fetal immune tolerance in the establishment and maintenance of pregnancy

Normal pregnancy is a contradictory and complicated physiological process.Although the fetus carries the human leukocyte antigen(HLA)inherited from the paternal line,it does not cause maternal immune rejection.As the only exception to immunological principles,maternal-fetal immune tolerance has been a reproductive immunology focus.In early pregnancy,fetal extravillous trophoblast cells(EVTs)invade decidual tissues and come into direct contact with maternal decidual immune cells(DICs)and decidual stromal cells(DSCs)to establish a sophisticated maternal-fetal crosstalk.This study reviews previous research results and focuses on the establishment and maintenance mechanism of maternal-fetal tolerance based on maternal-fetal crosstalk.Insights into maternal-fetal tolerance will not only improve understanding of normal pregnancy but will also contribute to novel therapeutic strategies for recurrent spontaneous abortion,pre-eclampsia,and premature birth.

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.

Investigation on the Effects of Soluble Programmed Death-1 (sPD-1) Enhancing Anti-tumor Immune Response

Summary: By using semi-quantitative RT-PCR method, it was found that PD-L1 mRNA but not PD-L2 mRNA was expressed in H22 hepatoma cells and both PD-L1 and PD-L2 mRNAs were expressed in tumor tissues of tumor-bearing mice and upregulated as compared with muscle tissues in normal mice and H22 hepatoma cells. PD-L1 and PD-L2 were also expressed on the surface of the activated T cells. The soluble recombinant sPD-1 expressed from the constructed eukaryotic expression vector could enhance the lysis of tumor cells by lymphocytes stimulated specifically with antigen. The expresssion of sPD-1 by local gene therapy on the inoculation site of H22 hepatoma cells could inhibit the growth of tumor. The results of this study indicate that expression of soluble receptor of negative costimulatory molecules could reduce the inhibitory effect on T cells in tumor microenvironment and enhance the cytotoxicity of T cells on tumor cells. This possibly provides a new method of improving efficacy of tumor gene therapy.

Immunometabolism: A target for the comprehension of immune response toward transplantation

Organ transplantation is a life-saving procedure, however predicting graft survival is still challenging. Understanding immune-cell pathobiology is critical to the development of effective therapies to prevent rejection. Over the recent years it has become progressively evident that the complex nature of immune cell behavioral dynamics is strongly dependent on cellular metabolism, which in turn, relies on competition for nutrients, oxygen and metabolites with other immune cells and microbiota. Furthermore, the influence of the inflammatory state can lead to substantial changes in conditions within the tissue microenvironment. Considering the context of immunity, alterations in metabolic pathways (glycolysis, the tricarboxylic acid cycle, the pentose phosphate pathway, the fatty acid oxidation and synthesis, and the amino acid metabolic pathways) will influence the production of different sets of cytokines and affect transplantation outcome. It is now known that na?ve, resting and effector cells acquire different metabolic profiles and studies have shown that specifically targeting some of these metabolic routes can prevent differentiation of effector T cells in favor of Tregs. Ultimately, to develop effective therapies that will prevent graft loss and understanding how cell metabolism impacts the fate and function of immune cells is now a critical point of discussion. The distinct metabolic features and requirements observed in effector and suppressive cell subsets offer promising opportunities for selective regulation of the immune responses in transplantation and will be discussed in this review.

Anti-tumor Immunity Elicited by Adenovirus Encoding AdhTrp2 or AdmTrp2 without Vitiligo

To compare the difference in tumor immunity and autoimmunity elicited by adenovirus （Ad） encoding human or murine tyrosinase-related protein 2 （AdhTRP2 or AdmTRP2）, and to find the most effective way to induce immunity by AdhTRP2 or AdmTRP2, C57BL/6 mice were immunized with AdhTRP2 or AdmTRP2 intramuscularly at different doses of 10^5, 10^6, 10^7 and 10^8 separately （ 10 mice for each dose）. Two weeks after the immunization, in vivo CTL assay and intracellular staining （ICS） of IFN-γ were carried out to analyze the dose-effect relationship. Tumor growth and vitiligo （as an sign of autoimmunity） were observed until 3 months after challenge with 10^5 B 16F10 tumor cells. The results showed that Ad encoding AdmTrp2 induced weak tumor immune response. Similar immunization with AdhTrp-2 elicited stronger protective immunity. CTL activity and IFN-γ-produced CD8＋T cells were directly proportional to dose of AdhTrp2 or AdmTrp2. Moreover, AdhTrp2 group showed tumor rejection in 100% of challenged mice till the end of 3rd month while 60% of mice immunized with AdmTrp2 were protected against tumor. In the whole process of this experiment, no vitiligo was observed in mice immunized either with AdhTrp2 or AdmTrp2. It is concluded that anti-melanoma responses induced by genetic vaccination expressing xenoantigens breaks immune tolerance effectively and is able to elicit strong antigen-specific cytotoxic T cell response without vitiligo.

Interactions between human microbiome,liver diseases,and immunosuppression after liver transplant

In liver transplant patients,solid tumors and post-transplant lymphoproliferative disorders have emerged as significant long-term mortality causes.In addition,it is assumed that de novo malignancy after liver transplantation(LT)is the secondleading cause of death after cardiovascular complications.Well-established risk factors for post-transplant lymphoproliferative disorders and solid tumors are calcineurin inhibitors,tacrolimus,and cyclosporine,the cornerstones of all immunosuppressive therapies used after LT.The loss of immunocompetence facilitated by the host immune system due to prolonged immunosuppressive therapy leads to cancer development,including LT patients.Furthermore,various mechanisms such as bacterial dysbiosis,activation through microbe-associated molecular patterns,leaky gut,and bacterial metabolites can drive cancerpromoting liver inflammation,fibrosis,and genotoxicity.Therefore,changes in human microbiota composition may contribute further to de novo carcinogenesis associated with the severe immunosuppression after LT.