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.

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.

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.

Immunosuppressive terpenoids from Tripterygium wilfordii

Two new terpenes,triptobenzene P（1）and wilforone（2）were isolated from Tripterygium wilfordii,as well as 10 known terpenes.Their structures were elucidated by spectroscopic methods.Compounds 2-4,8,10,and 11 showed significant immunosuppressive activities.

Immunosuppressive Treatment of Non-infectious Uveitis:History and Current Choices

Non-infectious uveitis is one of the leading causes of preventable blindness worldwide. Long-term immunosuppressive treatment is generally required to achieve durable control of inflammation in posterior and panuveitis. Although systemic corticosteroids have been the gold standard of immunosuppressive treatment for uveitis since first introduced in 1950 s,its side effects of long-term use often warrant an adjuvant treatment to reduce the dosage/duration of corticosteroids needed to maintain disease control. Conventional immunosuppressive drugs,classified into alkylating agent,antimetabolites and T cell inhibitors,have been widely used as corticosteroid-sparing agents,each with characteristic safety/tolerance profiles on different uveitis entities. Recently,biologic agents,which target specific molecules in immunopathogenesis of uveitis,have gained great interest as alternative treatments for refractory uveitis based on their favorable safety and effectiveness in a variety of uveitis entities. However,lack of large randomized controlled clinical trials,concerns about efficacy and safety of long-term usage,and economic burden are limiting the use of biologics in non-infectious uveitis. Local administration of immunosuppressive drugs(from corticosteroids to biologics) through intraocular drug delivery systems represent another direction for drug development and is now under intense investigation,but more evidences are needed to support their use as regular alternative treatments for uveitis. With the numerous choices belonging to different treatment modalities(conventional immunosuppressive agents,biologics and local drug delivery systems) on hand,the practice patterns have been reported to vary greatly from center to center. Factors influence uveitis specialists' choices of immunosuppressive agents may be complex and may include personal familiarity,treatment availability,safety/tolerability,effectiveness,patient compliance,cost concerns and suggestions from related specialists such as rheumatologists and pediatricians. The focus of this review is to provide an overview of each treatment modality on safety/tolerability and effectiveness,which are believed to be the two most important factors affecting treatment decision making.

Protective effect of glucocorticoid-free immunosuppressive regimen in allogenic islet transplantation

BACKGROUND: The most common complication after allogenic islet transplantation is rejection. This study was to evaluate the effect of anti-rejection of glucocorticoid-free immunosuppressive regimen on allogenic islet transplantation. METHODS: Tacrolimus(FK506)+mycophenolate mofetil (MMF) and FK506+MMF+prednisone (Pred) were administered respectively for 2 weeks to inhibit rejection after allogenic islet transplantation in rats, which were compared with the control group. The concentrations of blood glucose, insulin and C-peptide were determined dynamically in recipients and the sites of transplantation were observed morphologically. RESULTS: As compared with the control group without immunosuppressive agents, FK506+MMF and FK506+MMF+Pred could prolong the survival time of grafts significantly. There were many morphologically intact islets in the liver of recipients 2 months after transplantation. Group FK506+MMF kept normal levels of blood glucose, insulin and C-peptide beyond 60 days after transplantation. In contrast, group FK506+MMF+Pred secreted less C-peptide(P<0.05) and maintained a higher level of blood glucose concentration (P<0.01) after the operation. There was no significant difference in insulin concentrations between the two groups. The level of blood glucose beyond the first 2 weeks after drug withdrawal in group FK506+MMF+Pred decreased obviously (P<0.05), and the secretion of insulin and C-peptide increased. These results were compared with those the first 2 weeks after transplantation and the first 2 weeks after drug withdrawal. CONCLUSIONS: Both regimens of FK506+MMF and FK506+MMF+Pred could provide effective immunosup-pression. Moreover the combined glucocorticoid-free immunosuppressive strategy of low-dose FK506 and MMF could protect islet grafts in islet transplantation without diabetogenic side-effects.

BRAF_(V600E)mutant colorectal cancer cells mediate local immunosuppressive microenvironment through exosomal long noncoding RNAs

BACKGROUND BRAF^(V600E) mutated colorectal cancer(CRC)is prone to peritoneal and distant lymph node metastasis and this correlates with a poor prognosis.The BRAF^(V600E) mutation is closely related to the formation of an immunosuppressive microenvironment.However,the correlation between BRAF^(V600E) mutation and changes in local immune microenvironment of CRC is not clear.AIM To explore the effect and mechanism of BRAF^(V600E) mutant on the immune microenvironment of CRC.METHODS Thirty patients with CRC were included in this study:20 in a control group and 10 in a treatment group.The density of microvessels and microlymphatic vessels,and M2 subtype macrophages in tumor tissues were detected by immunohistochemistry.Screening and functional analysis of exosomal long noncoding RNAs(lncRNAs)were performed by transcriptomics.The proliferation and migration of human umbilical vein endothelial cells(HUVECs)and human lymphatic endothelial cells(HLECs)were detected by CCK-8 assay and scratch test,respectively.The tube-forming ability of endothelial cells was detected by tube formation assay.The macrophage subtypes were obtained by flow cytometry.The expression of vascular endothelial growth factor(VEGF)-A,basic fibroblast growth factor(bFGF),transforming growth factor(TGF)-β1,VEGF-C,claudin-5,occludin,zonula occludens(ZO)-1,fibroblast activation protein,andα-smooth muscle actin was assessed by western blot analysis.The levels of cytokines interleukin(IL)-6,TGF-β1,and VEGF were assessed by enzyme-linked immunosorbent assay.RESULTS BRAF^(V600E) mutation was positively correlated with the increase of preoperative serum carbohydrate antigen 19-9(P<0.05),and with poor tumor tissue differentiation in CRC(P<0.01).Microvascular density and microlymphatic vessel density in BRAF^(V600E) mutant CRC tissues were higher than those in BRAF wildtype CRC(P<0.05).The number of CD163+M2 macrophages in BRAF^(V600E) mutant CRC tumor tissue was markedly increased(P<0.05).Compared with exosomes from CRC cells with BRAF gene silencing,the expression of 13 lncRNAs and 192 mRNAs in the exosomes from BRAF^(V600E) mutant CRC cells was upregulated,and the expression of 22 lncRNAs and 236 mRNAs was downregulated(P<0.05).The biological functions and signaling pathways predicted by differential lncRNA target genes and differential mRNAs were closely related to angiogenesis,tumor cell proliferation,differentiation,metabolism,and changes in the microenvironment.The proliferation,migration,and tube formation ability of HUVECs and HLECs induced by exosomes in the 1627 cell group(HT29 cells with BRAF gene silencing)was greatly reduced compared with the HT29 cell group(P<0.05).Compared with the HT29 cell group,the expression levels of VEGF-A,bFGF,TGF-β1,and VEGF-C in the exosomes derived from 1627 cells were reduced.The expression of ZO-1 in HUVECs,and claudin-5,occludin,and ZO-1 in HLECs of the 1627 cell group was higher.Compared with the 1627 cell group,the exosomes of the HT29 cell group promoted the expression of CD163 in macrophages(P<0.05).IL-6 secretion by macrophages in the HT29 cell group was markedly elevated(P<0.05),whereas TGF-β1 was decreased(P<0.05).The levels of IL-6,TGF-β1,and VEGF secreted by fibroblasts in the 1627 cell group decreased,compared with the HT29 cell group(P<0.05).CONCLUSION BRAF^(V600E) mutant CRC cells can reach the tumor microenvironment by releasing exosomal lncRNAs,and induce the formation of an immunosuppressive microenvironment.

Effects of an immunosuppressive active component of Periplocae Cortex (Periploca sepium Bge.) on positive selection of thymocytes in vitro

Objective:To determine the effect of an immunosuppressive active component (periploside A) isolated from the stem bark of Periplocae Cortex (Periploca sepium Bge.),a Chinese medicinal herb used in the treatment of rheumatoid arthritis for centuries in China,on positive selection of thymocytes in vitro.Methods:Female C57BL/6 mice at 6 weeks of age were housed in specific pathogen-free conditions.Double-positive thymocytes from C57BL/6 mice were induced into positive selection in vitro with or without periploside A treatment.Cell viability and expression of CD69,CD4,and CD8 were analyzed by flow cytometry.Results:Flow cytometric examination of thymocyte populations revealed that the percentage of CD8+ single-positive thymocytes was decreased by periploside A upon differentiation induced by an anti-CD3 antibody.However,the percentage of CD4+ single-positive thymocytes was decreased by periploside A upon differentiation induced by phorbol 12-myristate 13-acetate/ionomycin.Expression of CD69 plays a major role in prohibiting differentiation of thymocytes.Treatment with periploside A decreased CD69 expression in thymocytes.Conclusion:These results demonstrate that periploside A influences positive selection of thymocytes in vitro.

Immunosuppressive and antibacterial activities of dihydromorin and norartocarpetin isolated from Artocarpus heterophyllus heartwoods

Objective:To evaluate the immunosuppressive effect on human phagocytes and antibacterial activity of dihydromorin and norartocarpetin isolated from Artocarpus heterophyllus heartwoods.Methods:Dihydromorin and norartocarpetin were isolated from Artocarpus heterophyllus heartwoods.A modified Boyden chamber was used to determine the chemotactic activity of human phagocyte.The respiratory burst was evaluated by chemiluminescence assay.Myeloperoxidase(MPO)activity was quantified using a colorimetric assay.The broth microdilution method was performed to assess their antibacterial activity.Results:Dihydromorin exhibited potent inhibitory effect on the chemotactic activity of polymorphonuclear neutrophils(PMNs)with an IC50 value of 5.03μg/mL.Dihydromorin also inhibited reactive oxygen species production of whole blood cells,PMNs,and monocytes with IC50 values of 7.88,7.59 and 7.24μg/mL,respectively.Interestingly,dihydromorin also strongly inhibited the MPO activity of PMNs with an IC50 value of 5.24μg/mL,which was lower than indomethacin(24.6μg/mL).Molecular docking of dihydromorin and crystal structure of MPO showed that dihydromorin had close interaction with key amino acid residues such as Arg239 and Gln91.Antibacterial activity assay showed that only dihydromorin had a strong effect against Streptococcus pyogenes with MIC and MBC values of 15.62 and 31.25μg/mL,respectively.Conclusions:The results suggest that dihydromorin could be developed as an anti-inflammatory and antibacterial agent.

A New Immunosuppressive Therapy for Very Severe Aplastic Anemia in Children with Autoantibodies

Objective At present,a number of very severe aplastic anemia(VSAA)patients cannot receive hematopoietic stem cell transplantation(HSCT)or standard immunosuppressive therapy(IST)due to the high cost of therapy,shortage of sibling donors,and lack of resources to support the HSCT.In addition,some VSAA patients with autoantibodies have no life-threatening infections or bleeding at the time of initial diagnosis.Considering the disease condition,economics and other factors,the present study designed a new and relatively mild treatment strategy:cyclosporine A plus pulsed high-dose prednisone(CsA+HDP).Methods The present study retrospectively analyzed 11 VSAA patients,who were treated with CsA+HDP in our hospital from August 2017 to August 2019.Results The median follow-up time for these patients was 24.9 months.The overall response rate was 54.5%(6/11)at six months after the initiation of IST and 81.8%(9/11)at deadline.Five patients achieved complete remission and four patients met the criteria for partial response at the last follow-up.The median time to response for responders was 110 days.Three patients underwent HSCT due to the poor effect of CsA+HDP or to find a suitable transplant donor.Recurrence and clonal evolution were not found in any of these patients.The estimated 3-year overall survival rate and 3-year failure-free survival rate were 100.0%and 72.7%,respectively.In addition,the results revealed that the cyclosporine-prednisone-associated toxicity was mild and well-tolerated by most patients.Conclusion The novel CsA+HDP regimen has good therapeutic effect and safety for VSAA patients with autoantibodies,who have no serious life-threatening infections or bleeding at the time of initial diagnosis.

Determinantion and evaluation of antisperm antibodies and seminal immunosuppressive material in recurrent aborting couples

Circulating antisperm antibodies (AsAb) and immunosuppressive material in seminal plasma (SPIM)were determined by solid-phase enzyme staining assay and anticomplement test respectively in 686 patients with abortion (including 285 couples) . 241 fertile couple served as control. It’s found that the positive rate of AsAb in infertile patients was significantly higher than that in fertile control,being 36.6% vs 3.3% (P【0.001). AsAb was even more offen detected in recurrent aborting patients. Male patients whose spouses aborted 2-6 fetuses had significantly less SPIM than control, sperm count and sperm motility were also significantly decreased. But the incidence of pyospermia was significantly greater than that in control. It is concluded that AsAb and SPIM have played an important role in the development of recurrent abortions.

Research progress on the correlation between immunosuppressive population and SARS-CoV-2 variation

Recently,some severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants represented by B.1.7(Alpha),B.1.351(Beta),P1(Gamma),B.1.617(Delta)and B.1.529(Omicron)have higher transmission and pathogenicity.Especially,Omicron causes global panic because of its high mutation in infectivity and vaccine escape,and their emergence makes the epidemic more difficult to control.The latest research reports indicate that these new corona mutants may first be mutated in the special population of immunosuppressive patients,and long-term infection and artificial immunotherapy may promote the variation of SARS-CoV-2.Not only that,there are a large number of congenital or acquired immunosuppressive patients worldwide,and immunosuppressive patients infected with SARS-CoV-2 will also have different impacts on social public health security.Therefore,we should pay more attention to the immunosuppressive population.This paper will briefly analyze the correlation between immunosuppressive population and SARS-CoV-2 variation in the form of review.

A New Immunosuppressive Protein in Pig Spleen

Chronic stress has been the popular phenomenon in the modern society. But we have not yet resolved the problem effectively. A novel protein in pig spleen, which possesses immunosuppressive activity, has been purified in this study. Its molecular weight about 200 kDa and three subunits composition were fractionated by SDS-PAGE. The protein inhibited mouse T-lymphocyte proliferation by the induced concanavalin A (ConA) and regulatory volume decrease (RVD), which may be due to the decreased Kv1.3 expression and activity. In addition, we have raised successfully its polyclonal antibody, which could reverse the inhibited lymphocyte proliferation by the immuno-suppressive protein. And the antibody could be used to coat plate for ELISA assay. Therefore, the antibody will have the potential to provide a basis for applying to clinical stress diseases in the future.

Immunosuppressive Treatment of Connective Tissue Disease and Occurrence of Tuberculosis

Introduction: The occurrence of tuberculosis (TB) during the follow-up of Connective tissue diseases (CTD) is a particular situation often posing real diagnostic problems. This is an association described in the literature. Patients and methods: We conducted a retrospective and descriptive study at the internal medicine department of Aristide Le Dantec Hospital. The purpose of this study was to determine the treatment that patients followed for CTD and suffering from TB took before the occurrence of this one. Results: During a study period of 11 years and 6 months, 21 cases of TB were diagnosed in 602 cases of CTD (0.03%). The predominance was female with a sex ratio (H/F) of 0.6. The median age was 42 years old. The majority of cases originated from the Dakar region (13 patients or 61.9%) and 85.7% had previous follow-up exclusively in modern medicine and 21 cases (95%) received the CTD’s treatment. This consisted of prednisone (90.5%) combined with methotrexate (52.4%), azathioprine (23.8%) or cyclophosphamide (19.4%). The respective medians doses of these drugs were 12.5 mg per day for prednisone, 13.5 mg per week for methotrexate and 100 mg per day for azathioprine. The median duration of patient follow-up was 36 months. The cumulative dose of prednisone during this period was 23.6 g and that of methotrexate 2.25 g. CTD were dominated by rheumatoid arthritis (RA) (57.1%), and systemic lupus (19%). Isolated cases of systemic scleroderma, primary Sj&#244;gren, SHARP syndrom, mixed connective tissue disease, and multiple autoimmune syndrom were noted. TB was localized in 95% of cases, readily bilateral and poorly disseminated. The respective medians diagnostic delays for systemic disease and TB were 21 months and 5 months. Tuberculin intradermal reaction was performed in 16 cases and was positive in 9 cases, sputum bacilli was performed in 19 cases and was positive in 15 cases. Conclusion: The association of TB and CTD was characterized by its rarity, its poorly disseminated character and its frequency on RA field.

Breast and Ovarian Carcinoma Overexpress HLA-G, a Neglected Cancer Immunosuppressive Protein

Purpose: HLA-G binds to the inhibitory receptors of uterine NK cells and plays an important role in protection of fetal cells from maternal NK lysis. HLA-G also mediates tumor escape, but the immunosuppressive role is often neglected. These studies have focused on the examination of HLA-G expression in human breast and ovarian carcinoma and HLA-G immunosuppressive role in NK cytolysis. Methods: We examined HLA-G expression in breast and ovarian carcinoma cell lines by real time PCR, ELISA and immunofluorescent staining, and in frozen breast and ovarian carcinoma tissues by immunohistochemistry (IHC). We treated the breast cancer cell lines with anti-human HLA-G antibody or progesterone. Then, NK cytolysis was measured by using MTT assay. Results: We find breast and ovarian cancer cell lines increase the expression of HLA-G mRNA and protein, compared to normal cells. IHC shows that 100% of frozen breast and ovarian carcinoma tissues overexpress HLA-G protein. HLA-G IHC scores of breast and ovarian carcinoma are significantly higher than normal breast and ovarian tissues, respectively (both p < 0.01). Blocking HLA-G of the breast cancer cells by the antibody increases NK cytolysis. Progesterone upregulates HLA-G mRNA and protein of human breast cancer cell lines. The increased HLA-G expression by progesterone suppresses the NK cytolysis. Conclusion: Human breast and ovarian carcinoma overexpress HLA-G immunosuppressive molecules. Blocking HLA-G protein by antibody improves the cytolysis of NK cells against human breast cancer cell lines. In contrast, upregulation of HLA-G expression by progesterone impairs NK cytolytic function. Thus, HLA-G is a new immune checkpoint protein and potential cancer immunotherapeutic target.

Systematic Review and Meta-analysis:Immunosuppressive Agents for the Treatment of Primary Biliary Cholangitis

Background and aim:There are still no clinically satisfactory therapy for PBC.This study was performed to assess the safety and efficacy of IAs for the therapy of PBC.Methods:Relevant studies were identified and selected by searching PubMed,Web of Science and Cochrane Library databases.The primary outcome was defined as the need for mortality or liver transplantation.Adverse effects and liver biochemical variables were a secondary outcome.Results:Nine randomized controlled trials,involving six different treatment regimens with a total of 996 patients,were included in the analysis.On meta-analysis,IAs was not associated with a reduction in risk of mortality or liver transplantation(risk ratio[RR]:0.92,95% confidence interval[CI]:0.69-1.22,P=0.57,P=0%),and have resulted in more adverse effects(RR:1.44,95%CI:1.08-1.92,P=0.01,P=19%).Subgroup analysis showed that IAs monotherapy caused adverse effects such as diarrthea,abdominal pain,and renal insufficiency(RR:1.36,95% CI:1.01-1.82,P=0.04,P=48%).IAs therapy did not prominently improve markers of liver function except for alkaline phosphatases(weighted mean difference[WMD]:-0.38,95% CI:-0.62 to-0.14,P=0.002).Conclusions:IAs cannot reduce the risk of mortality or liver transplantation,whether in IAs monotherapy or combination therapy,and even be associated with more adverse effects.

Individual immunosuppressive protocol after liver transplantation in benign end-stage liver disease:a single-center experience of 645 cases

Objective To analyze individual immunosuppressive protocol ( IP) after liver transplantation ( LT) in benign end - stage liver disease. Methods The clinical data of 645 patients with benign end - stage liver disease undergoing LT in our institute from April 2002 to Aug 2010 were analyzed retrospectively. 146 cases from Apr.

Follow-up and surveillance of immunosuppressive treatment in intestinal transplantation

Objective To evaluate the efficiency of monitoring parameters and methods of immunosuppresive treatment in intestinal transplantation and to provide scientific evidence for establishment of Intestinal Transplant Registry.

Application of donor dendric cell mediated recipieut lymphocyte reaction after related kidney transplantation in individualized immunosuppressive therapy

Objective To explore the feasibility of mediating recipient lymphocyte reaction with donor dendritic cells ( Dcs) in renal allograft recipients to guide individualized immunosuppressive therapy. Methods From Jan. 2008 to Jan. 2010,30 recipients received living related kidney transplantation were successively and divided into

Overexpression and Immunosuppressive Functions of Transforming Growth Factor 1,Vascular Endothelial Growth Factor and Interleukin-10 in Epithelial Ovarian Cancer

Objective： Transforming growth factor-1 （TGF-βI）, vascular endothelial growth factor （VEGF）, and interleukin-lO （IL-10） may be critical cytokines in the microenvironment of a tumor, playing roles in immune suppression. This study was conducted to elucidate the roles and immunosuppressive functions of these cytokines in epithelial ovarian cancer （EOC）. Methods： The expression levels of TGF-β1, VEGF and IL-10 in malignant tissue were evaluated by immune- histochemistry and compared with corresponding borderline, benign, and tumor-free tissues. Moreover, relationships among the levels of these cytokines and correlations between expression and the prognosis of EOC were analyzed by Pearson rank correlations and multi-factor Logistic regression. The roles of TGF-βI, VEGF, and IL-lO in the immunosuppressive microenvironment of ovarian cancer were studied through dendritic cell （DC） maturation and CD4＋CD25＋FoxP3＋ Treg generation in vitro experiments. Results： TGF-β1, VEGF, and IL-IO were expressed TGF-β1 was an independent prognostic factor for EOC n 100%, 74.69%, and 54.96% of EOC patients, respectively. L-IO was significantly co-expressed with VEGF. In vitro, VEGF and TGF-β31 strongly interfered with DC maturation and consequently led to immature DCs, which secreted high levels of IL-IO that accumulated around the tumor site. TGF-β1 and IL-10 induced Treg generation without antigen presentation in DCs. Conclusions： TGF-βI, VEGF and IL-IO play important roles in EOC and can lead to frequent immune evasion events.