Objective:The preventive and therapeutic effects of direct moxibustion on a gastric cancer rat model induced by the intragastric administration of N-methyl-N’-nitro-N-nitrosoguanidine(MNNG)were evaluated.Changes in t...Objective:The preventive and therapeutic effects of direct moxibustion on a gastric cancer rat model induced by the intragastric administration of N-methyl-N’-nitro-N-nitrosoguanidine(MNNG)were evaluated.Changes in the co-stimulatory molecules CD80 and CD86 on antigen-presenting cells in gastric tissues as well as related cytokines in serum were evaluated.The aim of the study was to explore the immunological mechanisms by which direct moxibustion may prevent gastric cancer lesions,thereby providing a basis for studies on the immunological mechanisms by which moxibustion prevents tumor development.Methods:Sixty healthy male Wistar rats were randomly divided into four groups:Control,control+moxibustion,model,and moxibustion groups.A gastric cancer rat model was induced by intragastric administration of 20 mg/mL MNNG,with a dose of 1 mL/100 g body weight,once daily for 16 weeks.The control+moxibustion and moxibustion groups received direct moxibustion simultaneously with modeling,continuing for 16 weeks.After the experiment,gastric tissue was collected,and morphological changes in the gastric mucosa in each group of rats were observed through H&E staining.Immunohistochemistry(IHC)and a western blotting were used to detect the expression levels of CD80 and CD86 in gastric tissues.Enzyme-linked immunosorbent assays(ELISA)were used to measure the levels of interleukin-12(IL-12),interferon-gamma(IFN-γ),and tumor necrosis factor-beta(TNF-β)in rat serum.Results:Upon macroscopic observation,the gastric mucosa of rats in the control and control+moxibustion groups appeared uniformly red,with a glossy mucosal surface,normal gastric wall elasticity,and clear,regular mucosal folds,without hyperplasia or bleeding points.In the model group,the gastric mucosa was reduced in volume,the gastric wall thinned,elasticity decreased,mucosal folds were disordered,and yellow-white cauliflower-like lesions and yellow-brown hyperkeratosis were observed.In the moxibustion group,the gastric mucosa showed decreased elasticity,with disordered mucosal folds and granular hyperplasia.After H&E staining,the gastric mucosal structure was clear and intact in the control and control+moxibustion groups displaying an organized and uniform arrangement of the mucosa,submucosa,and muscularis propria,without hyperplasia or keratinization.In the model group,the epithelial glands in the gastric mucosa were disordered,with varied cell morphologies,thickened submucosa,and disrupted squamous epithelium that invaded downward into the muscularis propria.In the moxibustion group,the squamous epithelium did not invade the muscularis propria.IHC results showed higher expression levels of CD80 and CD86 in the gastric mucosa of the control+moxibustion group than in the control group(P<0.05)and lower expression levels in the model group than in the control group(P<0.05).The moxibustion group showed higher CD80 and CD86 levels than those in the model group(P<0.05).Western blotting indicated that CD80 and CD86 levels were higher in the moxibustion group than in the model group(P<0.05).ELISA results showed higher IL-12 levels in the model group than in the control group(P<0.05)and higher TNF-βand IFN-γlevels in the moxibustion group than in the model group(P<0.01).Conclusion:Direct moxibustion alleviates the pathological progression of gastric cancer in an MNNGinduced rat model.Its mechanisms may involve effects on the state of antigen-presenting cells,thereby promoting T cell activation and enhancing immune function.展开更多
Objective:To develop a novel artificial antigen-presenting system for efficiently inducing melanoma-specific CD8+CD28+ cytotoxic T lymphocyte（CTL） responses.Methods:Cell-sized Dynabeads? M-450 Epoxy beads coated wit...Objective:To develop a novel artificial antigen-presenting system for efficiently inducing melanoma-specific CD8+CD28+ cytotoxic T lymphocyte（CTL） responses.Methods:Cell-sized Dynabeads? M-450 Epoxy beads coated with H-2Kb:Ig-TRP2(181111K and anti-CD28 antibody were used as artificial antigen-presenting cells（aAPCs） lo induce melanoma-specific CD8*CD28’ CTL responses with the help of IL-2I and IL-I5.Dimer staining,proliferation,ELISPOT,and cytotoxicity experiments were conducted to evaluate the frequency and activity of induced CTLs.Results:Dimer staining demonstrated that the new artificial antigen-presenting system efficiently induced melanoma TRP2-specific CD8CD28' CTLs.Proliferation and ELISPOT assays indicated that the induced CTLs rapidly proliferate and produce increased IFN- y under the slimulalion of H-2K:Ig-TRP2-aAPCs,TL-15,and IL-21.In addition,cytoloxicily experiments showed lhat induced CTLs have specific killing activity of target cells.Conclusions:The new artificial antigen-presenting system including aAPCs plus IL-21 and IL-15 can induce a large number of antigen-specific CD8+CD28+ CTLs against the melanoma.Our study provides evidence for a novel adoptive immunotherapy against tumors.展开更多
BACKGROUND:This study aimed to explore the changes of programmed death-ligand 1(PDL1)and programmed death-1(PD-1)expression on antigen-presenting cells(APCs)and evaluate their association with organ failure and mortal...BACKGROUND:This study aimed to explore the changes of programmed death-ligand 1(PDL1)and programmed death-1(PD-1)expression on antigen-presenting cells(APCs)and evaluate their association with organ failure and mortality during early sepsis.METHODS:In total,40 healthy controls and 198 patients with sepsis were included in this study.Peripheral blood was collected within the first 24 h after the diagnosis of sepsis.The expression of PDL1 and PD-1 was determined on APCs,such as B cells,monocytes,and dendritic cells(DCs),by flow cytometry.Cytokines in plasma,such as interferon-γ(IFN-γ),tumor necrosis factor-α(TNF-α),interleukin-4(IL-4),IL-6,IL-10,and IL-17A were determined by Luminex assay.RESULTS:PD-1 expression decreased significantly on B cells,monocytes,myeloid DCs(mDCs),and plasmacytoid DCs(pDCs)as the severity of sepsis increased.PD-1 expression was also markedly decreased in non-survivors compared with survivors.In contrast,PD-L1 expression was markedly higher on mDCs,pDCs,and monocytes in patients with sepsis than in healthy controls and in non-survivors than in survivors.The PD-L1 expression on APCs(monocytes and DCs)was weakly related to organ dysfunction and infl ammation.The area under the receiver operating characteristic curve(AUC)of the PD-1 percentage of monocytes(monocyte PD-1%)+APACHE II model(0.823)and monocyte PD-1%+SOFA model(0.816)had higher prognostic value than other parameters alone.Monocyte PD-1%was an independent risk factor for 28-day mortality.CONCLUSION:The severity of sepsis was correlated with PD-L1 or PD-1 over-expression on APCs.PD-L1 in monocytes and DCs was weakly correlated with infl ammation and organ dysfunction during early sepsis.The combination of SOFA or APACHE II scores with monocyte PD-1%could improve the prediction ability for mortality.展开更多
The route of vaccine administration is associated with various immune outcomes,and the relationship between the route of administration and broad protection against heterologous pathogens remains unclear.Here,we found...The route of vaccine administration is associated with various immune outcomes,and the relationship between the route of administration and broad protection against heterologous pathogens remains unclear.Here,we found that subcutaneous vaccination with Bacillus Calmette-Guérin(BCG)promotes respiratory influenza clearance and T-cell responses.Group 1 innate lymphoid cells(ILC1s)express MHCII molecules and engage in antigen processing and presentation after BCG vaccination.During influenza virus infection,ILC1s in the lungs of BCG-vaccinated mice can present influenza virus antigens and prime Th1 cells.After subcutaneous vaccination with BCG,MHCII^(+)ILC1s migrate from the skin to the lungs and play an antigen-presenting role in influenza infection.Both the BCG and the BCG component lipomannan can induce MHCII expression and skin-to-lung migration of ILC1s via TLR2 signaling.Our study revealed an important regulatory mechanism by which subcutaneous vaccination with BCG promotes respiratory antiviral immune responses via the skin‒lung axis.展开更多
Rheumatoid arthritis is an autoimmune disease that primarily affects the limbs, but the pathogenic mechanism remains unclear. 78 T cells, a T-cell subpopulation, are characterized by multiple biological functions and ...Rheumatoid arthritis is an autoimmune disease that primarily affects the limbs, but the pathogenic mechanism remains unclear. 78 T cells, a T-cell subpopulation, are characterized by multiple biological functions and associated with a variety of diseases. This study investigated the antigen-presenting effects of γδ2 cells and their relationship with rheumatoid arthritis development. We found that Vγ9Vδ2 T cells （the predominant subtype of γδ T cells in peripheral blood） were activated by isopentenyl pyrophosphate to continuously proliferate and differentiate into effector memory cells. The effector memory Vγ9Vδ2 T cells exhibited phenotypic characteristics of specific antigen-presenting cells, including high HLA-DR and CD80/86 expression. These Vγ9Vδ2 T cells could present soluble antigens and synthetic peptides to CD4＋ T cells. Vγ9Vδ2 T cells with different phenotypes showed different cytokine secretion patterns. Effector memoryVγ9Vδ2 T cells simultaneously secreted not only interferon （IFN）-γbut also IL-17. The peripheral blood and joint synovial fluid from RA patients contained numerous heterogeneous γδ T cells that were predominantly effector memory Vγ9Vδ2 T cells with the ability to secrete inflammatory factors. We also found that γδ T cells had a similar antigen-presenting capability to B cells. These results suggest that during the development of rheumatoid arthritis, 78 T cells can aggravate immune dysfunction and produce abnormal immune damage by secreting cytokines and inducing inflammatory cells to participate in synergistic inflammatory responses. Furthermore, γδ T cells can behave similarly to B cells to present viral peptides and autoantigen peptides to CD4＋ T cells, thus sustaining CD4＋ T-cell activation.展开更多
Artificial antigen-presenting cells are expected to stimulate the expansion and acquisition of optimal therapeutic features of T cells before infusion. Here CD32 that binds to a crystallizable fragment of IgG monoclon...Artificial antigen-presenting cells are expected to stimulate the expansion and acquisition of optimal therapeutic features of T cells before infusion. Here CD32 that binds to a crystallizable fragment of IgG monoclonal antibody was genetically expressed on human K562 leukemia cells to provide a ligand for T-cell receptor. CD86 and 4-1BBL, which are ligands of co-stimulating receptors of CD28 and 4-1BB, respectively, were also expressed on K562 cells. Then we accomplished the artificial antigen-presenting cells by coupling K32/CD86/4-1BBL cell with OKT3 monoclonal antibody against CD3, named K32/CD86/4-1BBL/OKT3 cells. These artificial modified cells had the abilities of inducing CD8^＋ T cell activation, promoting CD8^＋ T cell proliferation, division, and long-term growth, inhibiting CD8^＋ T cell apoptosis, and enhancing CD8^＋ T cell secretion of IFN-T and perforin. Furthermore, antigen-specific cytotoxic T lymphocytes could be retained in the culture stimulated with K32/CD86/4-1BBL/OKT3 cells at least within 28 days. This approach was robust, simple, reproducible and economical for expansion and activation of CD8^＋ T cells and may have important therapeutic implications for adoptive immunotherapy. Cellular ＆ Molecular Immunology.展开更多
Fibrocytes are bone marrow-derived mesenchymal progenitors that co-express hematopoietic cell antigens and markers of monocytic lineage as well as fibroblast products. During wound healing, fibrocytes have been found ...Fibrocytes are bone marrow-derived mesenchymal progenitors that co-express hematopoietic cell antigens and markers of monocytic lineage as well as fibroblast products. During wound healing, fibrocytes have been found to possess the ability of antigen-presentation to naive T cells in the inflammatory phase. Moreover, they can promote the endothelial cell proliferation, migration and angiogenesis by secreting several proteins. Fibrocytes can further differentiate into mature mesenchymocyte lineage, such as fibroblasts, myofibroblasts and adipocytes, and they may represent the systemic source of myofibroblasts that exert a contractile force required to close tissue wounds. A deep understanding of the mechanism involved in fibrocyte migration and differentiation may lead to the development of a novel theory of normal physiology and pathology.展开更多
Stimulator of interferon genes(STING)-mediated innate immune activation plays a key role in tumor-and self-DNA-elicited antitumor immunity and autoimmunity.However,STING can also suppress tumor immunity and autoimmuni...Stimulator of interferon genes(STING)-mediated innate immune activation plays a key role in tumor-and self-DNA-elicited antitumor immunity and autoimmunity.However,STING can also suppress tumor immunity and autoimmunity.STING signaling In host nonhematopoietic cells was reported to either protect against or promote graft-versus-host disease(GVHD),a major complication of allogeneic hematopoietic cell transplantation(allo-HCT).Host hematopoietic antigen-presenting cells(APCs)play key roles in donor T-cell priming during GVHD initiation.However,how STING regulates host hematopoietic APCs after allo-HCT remains unknown.We utilized murine models of allo-HCT to assess the role of STING in hematopoietic APCs.STING-deficient recipients developed more severe GVHD after major histocompatibility complex-mismatched allo-HCT.Using bone marrow chimeras,we found that STING deficiency in host hematopoietic cells was primarily responsible for exacerbating the disease.Furthermore,STING on host CD11c+cells played a dominant role in suppressing allogeneic T-cell responses.Mechanistically,STING deficiency resulted in increased survival,activation,and function of APCs,including macrophages and dendritic cells.Consistently,constitutive activation of STING attenuated the survival,activation,and function of APCs isolated from STING V154M knock-in mice.STING-deficient APCs augmented donor T-cell expansion,chemokine receptor expression,and migration into intestinal tissues,resulting in accelerated/exacerbated GVHD.Using pharmacologic approaches,we demonstrated that systemic administration of a STING agonist(bis-(3'-5')-cyclic dimeric guanosine monophosphate)to recipient mice before transplantation significantly reduced GVHD mortality.In conclusion,we revealed a novel role of STING in APC activity that dictates T-cell allogeneic responses and validated STING as a potential therapeutic target for controlling GVHD after allo-HCT.展开更多
Pathogenic African swine fever virus(ASFV)remains a lethal causative agent in the domestic pig industry,which poses a burden on the swine market and causes substantial socioeconomic losses worldwide.Currently,there ar...Pathogenic African swine fever virus(ASFV)remains a lethal causative agent in the domestic pig industry,which poses a burden on the swine market and causes substantial socioeconomic losses worldwide.Currently,there are no commercially efcacious vaccines or specifc treatments available for ASF prevention and control.Unfortunately,little is known about the swine immune response upon ASFV infection.Here,we investigated the host immune response discrepancy induced by the feld moderately virulent strain ASFV HB-2208 among healthy,diseased and asymptomatic pigs.In the peripheral blood of diseased swine,lymphopenia is caused by the massive loss of bystander lymphocytes,such asγδT cells,B cells and CD4^(+)T cells.Conversely,ASFV has a strong tropism for the mononuclear phagocyte system(MPS)and partial dendritic cells(DCs),whose antigen-presenting ability is impeded by the downregulation of CD80 and MHC I.However,no signifcant diference in the number of CD8α^(high) T cells was detected,whereas the frequencies of NK cells,NKT cells,and regulatory T cells(Tregs)were signifcantly increased.Additionally,an in vitro model was established with a coculture of primary pulmonary alveolar macrophages(PAMs)and peripheral blood mononuclear cells(PBMCs),which signifcantly reducedγδT cells,B cells and CD4^(+)T cells and increased Tregs.The diferentiated immune response might aid in enhancing the understanding of ASFV pathogenesis in suids and provide insights into the mechanism of ASFV-induced lymphopenia for further studies.展开更多
The onslaught of foreign antigens carried by spermatozoa into the epididymis, an organ that has not demonstrated immune privilege, a decade or more after the establishment of central immune tolerance presents a unique...The onslaught of foreign antigens carried by spermatozoa into the epididymis, an organ that has not demonstrated immune privilege, a decade or more after the establishment of central immune tolerance presents a unique biological challenge. Historically, the physical confinement of spermatozoa to the epididymal tubule enforced by a tightly interwoven wall of epithelial cells was considered sufficient enough to prevent cross talk between gametes and the immune system and, ultimately, autoimmune destruction. The discovery of an intricate arrangement of mononuclear phagocytes （MPs） comprising dendritic cells and macrophages in the murine epididymis suggests that we may have underestimated the existence of a sophisticated mucosal immune system in the posttesticular environment. This review consolidates our current knowledge of the physiology of MPs in the steady state epididymis and speculates on possible interactions between auto-antigenic spermatozoa, pathogens and the immune system by drawing on what is known about the immune system in the intestinal mucosa. Ultimately, further investigation will provide valuable information regarding the origins of pathologies arising as a result of autoimmune or inflammatory responses in the epididymis, including epididymitis and infertility.展开更多
Immune reactions to foreign or self-antigens lead to protective immunity and, sometimes, immune disorders such as allergies and autoimmune diseases. Antigen presenting cells (APC) including epidermal Langerhans cells ...Immune reactions to foreign or self-antigens lead to protective immunity and, sometimes, immune disorders such as allergies and autoimmune diseases. Antigen presenting cells (APC) including epidermal Langerhans cells (LCs) play an important role in the course and outcome of the immune reactions. Epidermal powder immunization (EPI) is a technology that offers a tool to manipulate the LCs and the potential to harness the immune reactions towards prevention and treatment of infectious diseases and immune disorders.展开更多
Bone marrow precursor cells were extracted from C57BL/6J mice aged 7-8 weeks, and dendritic cells were purified using anti-CD1 lc （a specific marker for dendritic cells） antibody-coated magnetic beads. Immunofluores...Bone marrow precursor cells were extracted from C57BL/6J mice aged 7-8 weeks, and dendritic cells were purified using anti-CD1 lc （a specific marker for dendritic cells） antibody-coated magnetic beads. Immunofluorescence staining revealed that the expression levels of endomorphin-1 and endomorphin-2 were upregulated in dendritic cells activated by lipopolysaccharide. An enzyme Jmmunoassay showed that lipopolysaccharide and other Toll-like receptor ligands promoted the secretion of endomorphin-1 and endomorphin-2 from activated dendritic cells. [3H]-thymidine incorporation demonstrated that endomorphin-1 and endomorphin-2 both inhibited the proliferation of T lymphocyte induced by activated dendritic cells. Furthermore, this immunosuppressive effect was blocked by CTOP, a specific antagonist of IJ-opioid receptors. Our experimental findings indicate that activated dendritic cells can induce the expression and secretion of endomorphins, and that endomorphins suppress T lymphocyte proliferation through activation of iJ-opioid receptors.展开更多
Membrane-associated RING-CH-1 (MARCH1) is an E3 ubiquitin ligase which targets MHC-II, CD86 and various other molecules for degradation. It is one of the most efficient post-translational regulators of antigen present...Membrane-associated RING-CH-1 (MARCH1) is an E3 ubiquitin ligase which targets MHC-II, CD86 and various other molecules for degradation. It is one of the most efficient post-translational regulators of antigen presentation. MARCH1 is expressed in resting immature dendritic cells and B cells but can be induced in other cell types. While activation of most immune cells results in a reduction in MARCH1 gene expression, its anti-inflammatory properties are highlighted by its induction in response to IL-10. Here, we review what is known about the regulation of MARCH1 gene expression in response to IL-10 by various immune cells. We speculate on the role of MARCH1 ininfection, its differential expression pattern and the promise that this E3 ubiquitin ligase holds to influence immune responses and mitigate immune pathologies.展开更多
<p style="text-align:justify;"> <span>Following organ transplantation</span><span>,</span><span> the outcome of the encounter between an APC and a T lymphocyte is str...<p style="text-align:justify;"> <span>Following organ transplantation</span><span>,</span><span> the outcome of the encounter between an APC and a T lymphocyte is strongly dependent on the presence of costimulatory and co-inhibitory molecules, the former associated with allograft rejection and the latter with allograft acceptance. We evaluated the expression of PD-L2, GITR, ILT-2/3/5, and ILT-4 on graft-infiltrating cells procured by Fnab from human KTx under different immunosuppressive regimens. Methods: Fnab biopsies were performed on days 7 or 14</span><span> </span><span>-</span><span> </span><span>30 in stable KTx and on the day of acute rejection diagnosis. Cytopreparations were studied by the enzymatic avidin biotin complex staining. Results: Acute rejection group </span><span>showed a significant down-regulated expression of PD-L2, GITR, and ILT-2/3/5 </span><span>as compared to stable group, while for ILT-4 we did not find significant difference. Anti-IL2</span><i><span>α</span></i><span>R and rapamicyn treatment trend to down-regulate ILT-4 expression, although meaningless. A significant</span><span>ly</span><span> positive correlation was observed between PD-L2 and GITR expression in Fnab. The PPV for acute rejection diagnosis for both PD-L2 and GITR w</span><span>as</span><span> clearly above 0.8. Conclusions: Our findings point to an early entrance of cells expressing PD-L2, GITR and ILT-2/3/5 inside human KTx who are going to remain rejection-free. Both PD-L2 and GITR shared a high ability to rule-in and rule-out acute rejection.</span> </p>展开更多
While immunotherapy with immune checkpoint inhibitors(ICIs)has revolutionized the clinical management of various malignancies,a large fraction of patients are refractory to ICIs employed as standalone therapeutics,nec...While immunotherapy with immune checkpoint inhibitors(ICIs)has revolutionized the clinical management of various malignancies,a large fraction of patients are refractory to ICIs employed as standalone therapeutics,necessitating the development of combinatorial treatment strategies.Immunogenic cell death(ICD)inducers have attracted considerable interest as combinatorial partners for ICIs,at least in part owing to their ability to initiate a tumor-targeting adaptive immune response.However,compared with either approach alone,combinatorial regimens involving ICD inducers and ICIs have not always shown superior clinical activity.Here,we discuss accumulating evidence on the therapeutic interactions between ICD inducers and immunotherapy with ICIs in oncological settings,identify key factors that may explain discrepancies between preclinical and clinical findings,and propose strategies that address existing challenges to increase the efficacy of these combinations in patients with cancer.展开更多
Recently,nanovaccine-based immunotherapy has been robustly investigated due to its potential in governing the immune response and generating long-term protective immunity.However,the presentation of a tumor peptide-ma...Recently,nanovaccine-based immunotherapy has been robustly investigated due to its potential in governing the immune response and generating long-term protective immunity.However,the presentation of a tumor peptide-major histocompatibility complex to T lymphocytes is still a challenge that needs to be addressed for eliciting potent antitumor immunity.Type 1 conventional dendritic cell(cDC1)subset is of particular interest due to its pivotal contribution in the cross-presentation of exogenous antigens to CD8+T cells.Here,the DC-derived nanovaccine(denoted as Si9GM)selectively targets cDC1s with marginal loss of premature antigen release for effective stimulator of interferon genes(STING)-mediated antigen cross-presentation.Bone marrow dendritic cell(BMDC)-derived membranes,conjugated to cDC1-specific antibody(αCLEC9A)and binding to tumor peptide(OVA257-264),are coated onto dendrimer-like polyethylenimine(PEI)-grafted silica nanoparticles.Distinct molecular weight-cargos(αCLEC9A-OVA257-264 conjugates and 2′3′-cGAMP STING agonists)are loaded in hierarchical center-radial pores that enables lysosome escape for potent antigen-cross presentation and activates interferon type I,respectively.Impressively,Si9GM vaccination leads to the upregulation of cytotoxic T cells,a reduction in tumor regulatory T cells(Tregs),M1/M2 macrophage polarization,and immune response that synergizes with αPD-1 immune checkpoint blockade.This nanovaccine fulfills a dual role for both direct T cell activation as an artificial antigen-presenting cell and DC subset maturation,indicating its utility in clinical therapy and precision medicine.展开更多
Background:Pancreatic ductal adenocarcinoma(PDAC)is one of the main types of malignant tumor of the digestive system,and patient prognosis is affected by difficulties in early diagnosis,poor treatment response,and a h...Background:Pancreatic ductal adenocarcinoma(PDAC)is one of the main types of malignant tumor of the digestive system,and patient prognosis is affected by difficulties in early diagnosis,poor treatment response,and a high postoperative recurrence rate.Carbohydrate antigen 19-9(CA19-9)has been widely used as a biomarker for the diagnosis and postoperative follow-up of PDAC patients.Nevertheless,the production mechanism and potential role of CA19-9 in PDAC progression have not yet been elucidated.Methods:We performed single-cell RNA sequencing on six samples pathologically diagnosed as PDAC(three CA19-9-positive and three CA19-9-negative PDAC samples)and two paracarcinoma samples.We also downloaded and integrated PDAC samples(each from three CA19-9-positive and CA19-9-negative patients)from an online database.The dynamics of the proportion and potential function of each cell type were verified through immunofluorescence.Moreover,we built an in vitro coculture cellular model to confirm the potential function of CA19-9.Results:Three subtypes of cancer cells with a high ability to produce CA19-9 were identified by the markers TOP2A,AQP5,and MUC5AC.CA19-9 production bypass was discovered on antigen-presenting cancer-associated fibroblasts(apCAFs).Importantly,the proportion of immature ficolin-1 positive(FCN1+)macrophages was high in the CA19-9-negative group,and the proportion of mature M2-like macrophages was high in the CA19-9-positive group.High proportions of these two macrophage subtypes were associated with an unfavourable clinical prognosis.Further experiments indicated that CA19-9 could facilitate the transformation of M0 macrophages into M2 macrophages in the tumor microenvironment.Conclusions:Our study described CA19-9 production at single-cell resolution and the dynamics of the immune atlas in CA19-9-positive and CA19-9-negative PDAC.CA19-9 could promote M2 polarization of macrophage in the pancreatic tumor microenvironment.展开更多
Chronic hepatitis B(CHB)is consistently challenging to conquer with numerous complications and fatalities.Despite the effectiveness of antiviral therapies in suppressing hepatitis B virus(HBV)replication,there is an u...Chronic hepatitis B(CHB)is consistently challenging to conquer with numerous complications and fatalities.Despite the effectiveness of antiviral therapies in suppressing hepatitis B virus(HBV)replication,there is an urgent need for novel and more effective treatment modalities.Current strategies predominantly emphasize immune activation but still face challenges in sufficiently eliciting T cell responses.Taking into account the targeted delivery of nanoparticles to the liver and spleen via intravenous injection,we have proposed a dual-pronged therapeutic strategy based on antigen-presenting cells(APCs)-derived exosomes.Specifically,exosomes targeted to the spleen can activate specific immune responses,while those targeted to the liver can modulate or reverse the liver’s immunosuppressive microenvironment.After immunization,exosome formulations exhibit the remarkable ability to effectively activate APCs,thereby triggering the proliferation of CD8^(+)T cells.Simultaneously,they also play an immunoregulatory role by converting M2 macrophages into M1 macrophages.This two-pronged therapeutic strategy precisely addresses the issues of T cell dysfunction and immune suppression,both characteristic features of CHB patients.When combined with Aluminum(Alum)-adjuvanted vaccine,these exosome formulations not only demonstrate a high level of cellular immune response but also secrete specific antibodies comparable to those induced by Alum adjuvant.This combined approach effectively enhances both cellular and humoral immunity,offering a promising avenue for the development of therapeutic hepatitis B vaccines based on exosome formulations.展开更多
Preterm birth （PTB） is the leading cause of neonatal morbidity and mortality worldwide. A transition from an anti-inflammatory state to a pro-inflammatory state in the mother and at the maternal-fetal interface has ...Preterm birth （PTB） is the leading cause of neonatal morbidity and mortality worldwide. A transition from an anti-inflammatory state to a pro-inflammatory state in the mother and at the maternal-fetal interface has been implicated in the pathophysiology of microbial-induced preterm labor. However, it is unclear which immune cells mediate this transition. We hypothesized that an imbalance between innate and adaptive immune cells at the maternal-fetal interface will occur prior to microbial-induced preterm labor. Using an established murine model of endotoxin-induced PTB, our results demonstrate that prior to delivery there is a reduction of CD4 ＋ regulatory T cells （Tregs） in the uterine tissues. This reduction is neither linked to a diminished number of Tregs in the spleen, nor to an impaired production of ILIO, CCL17, or CCL22 by the uterine tissues. Endotoxin administration to pregnant mice does not alter effector CD4＋ T cells at the maternal-fetal interface. However, it causes an imbalance between Tregs （CD4＋ and CD8＋）, effector CD8＋ T cells, and Th17 cells in the spleen. In addition, endotoxin administration to pregnant mice leads to an excessive production of CCL2, CCL3, CCL17, and CCL22 by the uterine tissues as well as abundant neutrophils. This imbalance in the uterine microenvironment is accompanied by scarce APC-like cells such as macrophages and MHC II ＋ neutrophils. Collectively, these results demonstrate that endotoxin administration to pregnant mice causes an imbalance between innate and adaptive immune cells at the maternal-fetal interface.展开更多
Primary immune thrombocytopenia(ITP)is an autoimmune disorder characterized by immune-mediated accelerated platelet destruction and/or suppressed platelet production.Although the development of autoantibodies against ...Primary immune thrombocytopenia(ITP)is an autoimmune disorder characterized by immune-mediated accelerated platelet destruction and/or suppressed platelet production.Although the development of autoantibodies against platelet glycoproteins remains central in the pathophysiology of ITP,several abnormalities involving the cellular mechanisms of immune modulation have been identified,and the pathways behind the immune-mediated destruction of platelets have opened new avenues for the design of specific immunotherapies in an attempt to reduce the platelet destruction.This review is primarily focused on the recent literature with respect to immunopathological mechanisms in patients with ITP.展开更多
基金Supported by the National Natural Science Foundation of China:81173342Scientific Research Ability Improvement Projects of Hebei College of Traditional Chinese Medicine(now known as Hebei University of Chinese Medicine):KTZ2019012Scientific Research Project of Hebei Province Administration of Traditional Chinese Medicine:2022361.2021095。
文摘Objective:The preventive and therapeutic effects of direct moxibustion on a gastric cancer rat model induced by the intragastric administration of N-methyl-N’-nitro-N-nitrosoguanidine(MNNG)were evaluated.Changes in the co-stimulatory molecules CD80 and CD86 on antigen-presenting cells in gastric tissues as well as related cytokines in serum were evaluated.The aim of the study was to explore the immunological mechanisms by which direct moxibustion may prevent gastric cancer lesions,thereby providing a basis for studies on the immunological mechanisms by which moxibustion prevents tumor development.Methods:Sixty healthy male Wistar rats were randomly divided into four groups:Control,control+moxibustion,model,and moxibustion groups.A gastric cancer rat model was induced by intragastric administration of 20 mg/mL MNNG,with a dose of 1 mL/100 g body weight,once daily for 16 weeks.The control+moxibustion and moxibustion groups received direct moxibustion simultaneously with modeling,continuing for 16 weeks.After the experiment,gastric tissue was collected,and morphological changes in the gastric mucosa in each group of rats were observed through H&E staining.Immunohistochemistry(IHC)and a western blotting were used to detect the expression levels of CD80 and CD86 in gastric tissues.Enzyme-linked immunosorbent assays(ELISA)were used to measure the levels of interleukin-12(IL-12),interferon-gamma(IFN-γ),and tumor necrosis factor-beta(TNF-β)in rat serum.Results:Upon macroscopic observation,the gastric mucosa of rats in the control and control+moxibustion groups appeared uniformly red,with a glossy mucosal surface,normal gastric wall elasticity,and clear,regular mucosal folds,without hyperplasia or bleeding points.In the model group,the gastric mucosa was reduced in volume,the gastric wall thinned,elasticity decreased,mucosal folds were disordered,and yellow-white cauliflower-like lesions and yellow-brown hyperkeratosis were observed.In the moxibustion group,the gastric mucosa showed decreased elasticity,with disordered mucosal folds and granular hyperplasia.After H&E staining,the gastric mucosal structure was clear and intact in the control and control+moxibustion groups displaying an organized and uniform arrangement of the mucosa,submucosa,and muscularis propria,without hyperplasia or keratinization.In the model group,the epithelial glands in the gastric mucosa were disordered,with varied cell morphologies,thickened submucosa,and disrupted squamous epithelium that invaded downward into the muscularis propria.In the moxibustion group,the squamous epithelium did not invade the muscularis propria.IHC results showed higher expression levels of CD80 and CD86 in the gastric mucosa of the control+moxibustion group than in the control group(P<0.05)and lower expression levels in the model group than in the control group(P<0.05).The moxibustion group showed higher CD80 and CD86 levels than those in the model group(P<0.05).Western blotting indicated that CD80 and CD86 levels were higher in the moxibustion group than in the model group(P<0.05).ELISA results showed higher IL-12 levels in the model group than in the control group(P<0.05)and higher TNF-βand IFN-γlevels in the moxibustion group than in the model group(P<0.01).Conclusion:Direct moxibustion alleviates the pathological progression of gastric cancer in an MNNGinduced rat model.Its mechanisms may involve effects on the state of antigen-presenting cells,thereby promoting T cell activation and enhancing immune function.
基金supported,in part,by grants from the Program for New Century Excellent Talents in University(NECT-10-0098)the National Natural Scientific Foundation of China(Nos.81072161.81000769.81172139.and 81060183)+3 种基金Programs for Changjiang Scholars and Innovative Research Team in University(No. IRT1119)Innovative Research Team in Guangxi Natural Science Foundation (No.2011-18-5)Fund for Distinguished Young Scholars in Guangxi Natural Science Foundation(2012jjFA40005)Project of science and technology of Guangxi (1140003A-17)
文摘Objective:To develop a novel artificial antigen-presenting system for efficiently inducing melanoma-specific CD8+CD28+ cytotoxic T lymphocyte（CTL） responses.Methods:Cell-sized Dynabeads? M-450 Epoxy beads coated with H-2Kb:Ig-TRP2(181111K and anti-CD28 antibody were used as artificial antigen-presenting cells（aAPCs） lo induce melanoma-specific CD8*CD28’ CTL responses with the help of IL-2I and IL-I5.Dimer staining,proliferation,ELISPOT,and cytotoxicity experiments were conducted to evaluate the frequency and activity of induced CTLs.Results:Dimer staining demonstrated that the new artificial antigen-presenting system efficiently induced melanoma TRP2-specific CD8CD28' CTLs.Proliferation and ELISPOT assays indicated that the induced CTLs rapidly proliferate and produce increased IFN- y under the slimulalion of H-2K:Ig-TRP2-aAPCs,TL-15,and IL-21.In addition,cytoloxicily experiments showed lhat induced CTLs have specific killing activity of target cells.Conclusions:The new artificial antigen-presenting system including aAPCs plus IL-21 and IL-15 can induce a large number of antigen-specific CD8+CD28+ CTLs against the melanoma.Our study provides evidence for a novel adoptive immunotherapy against tumors.
文摘BACKGROUND:This study aimed to explore the changes of programmed death-ligand 1(PDL1)and programmed death-1(PD-1)expression on antigen-presenting cells(APCs)and evaluate their association with organ failure and mortality during early sepsis.METHODS:In total,40 healthy controls and 198 patients with sepsis were included in this study.Peripheral blood was collected within the first 24 h after the diagnosis of sepsis.The expression of PDL1 and PD-1 was determined on APCs,such as B cells,monocytes,and dendritic cells(DCs),by flow cytometry.Cytokines in plasma,such as interferon-γ(IFN-γ),tumor necrosis factor-α(TNF-α),interleukin-4(IL-4),IL-6,IL-10,and IL-17A were determined by Luminex assay.RESULTS:PD-1 expression decreased significantly on B cells,monocytes,myeloid DCs(mDCs),and plasmacytoid DCs(pDCs)as the severity of sepsis increased.PD-1 expression was also markedly decreased in non-survivors compared with survivors.In contrast,PD-L1 expression was markedly higher on mDCs,pDCs,and monocytes in patients with sepsis than in healthy controls and in non-survivors than in survivors.The PD-L1 expression on APCs(monocytes and DCs)was weakly related to organ dysfunction and infl ammation.The area under the receiver operating characteristic curve(AUC)of the PD-1 percentage of monocytes(monocyte PD-1%)+APACHE II model(0.823)and monocyte PD-1%+SOFA model(0.816)had higher prognostic value than other parameters alone.Monocyte PD-1%was an independent risk factor for 28-day mortality.CONCLUSION:The severity of sepsis was correlated with PD-L1 or PD-1 over-expression on APCs.PD-L1 in monocytes and DCs was weakly correlated with infl ammation and organ dysfunction during early sepsis.The combination of SOFA or APACHE II scores with monocyte PD-1%could improve the prediction ability for mortality.
基金supported by the National Key R&D Program of China(2022YFC2302900,2021YFA1300202,2023YFC2306204)the Beijing Natural Science Foundation(JQ24043)the CAS Project for Young Scientists in Basic Research(YSBR-010).
文摘The route of vaccine administration is associated with various immune outcomes,and the relationship between the route of administration and broad protection against heterologous pathogens remains unclear.Here,we found that subcutaneous vaccination with Bacillus Calmette-Guérin(BCG)promotes respiratory influenza clearance and T-cell responses.Group 1 innate lymphoid cells(ILC1s)express MHCII molecules and engage in antigen processing and presentation after BCG vaccination.During influenza virus infection,ILC1s in the lungs of BCG-vaccinated mice can present influenza virus antigens and prime Th1 cells.After subcutaneous vaccination with BCG,MHCII^(+)ILC1s migrate from the skin to the lungs and play an antigen-presenting role in influenza infection.Both the BCG and the BCG component lipomannan can induce MHCII expression and skin-to-lung migration of ILC1s via TLR2 signaling.Our study revealed an important regulatory mechanism by which subcutaneous vaccination with BCG promotes respiratory antiviral immune responses via the skin‒lung axis.
基金ACKNOWLEGEMENTS This work was supported by the grants from the following： National Natural Science Foundation of China （no. 30471593, 30872304 and 81072470）, Shanghai Commission of Science and Technology （no. 10IC14 08500 and 10ZR1426100）, Shanghai Leading Academic Discipline-Surgery （no. $30204- K01）, Shanghai Municipal education Commission （no. 150207 and 09YZ102）, Shanghai Institute of Immunology （no. 08-A04）, Clinical Medicine Technology Development Foundation of Jiangsu University （no. ILY2010091） and Foundation of Shanghai Xuhui Central Hospital （no. 2011XHCH07）.
文摘Rheumatoid arthritis is an autoimmune disease that primarily affects the limbs, but the pathogenic mechanism remains unclear. 78 T cells, a T-cell subpopulation, are characterized by multiple biological functions and associated with a variety of diseases. This study investigated the antigen-presenting effects of γδ2 cells and their relationship with rheumatoid arthritis development. We found that Vγ9Vδ2 T cells （the predominant subtype of γδ T cells in peripheral blood） were activated by isopentenyl pyrophosphate to continuously proliferate and differentiate into effector memory cells. The effector memory Vγ9Vδ2 T cells exhibited phenotypic characteristics of specific antigen-presenting cells, including high HLA-DR and CD80/86 expression. These Vγ9Vδ2 T cells could present soluble antigens and synthetic peptides to CD4＋ T cells. Vγ9Vδ2 T cells with different phenotypes showed different cytokine secretion patterns. Effector memoryVγ9Vδ2 T cells simultaneously secreted not only interferon （IFN）-γbut also IL-17. The peripheral blood and joint synovial fluid from RA patients contained numerous heterogeneous γδ T cells that were predominantly effector memory Vγ9Vδ2 T cells with the ability to secrete inflammatory factors. We also found that γδ T cells had a similar antigen-presenting capability to B cells. These results suggest that during the development of rheumatoid arthritis, 78 T cells can aggravate immune dysfunction and produce abnormal immune damage by secreting cytokines and inducing inflammatory cells to participate in synergistic inflammatory responses. Furthermore, γδ T cells can behave similarly to B cells to present viral peptides and autoantigen peptides to CD4＋ T cells, thus sustaining CD4＋ T-cell activation.
基金the National Natural Science Foundation of China（No.30400399,No.30671917）the Natural Science Fund of Jiangsu Province（BK2004404） the Natural Science Fund of the Educational Committee of Jiangsu Province（04KJB320162） in China.
文摘Artificial antigen-presenting cells are expected to stimulate the expansion and acquisition of optimal therapeutic features of T cells before infusion. Here CD32 that binds to a crystallizable fragment of IgG monoclonal antibody was genetically expressed on human K562 leukemia cells to provide a ligand for T-cell receptor. CD86 and 4-1BBL, which are ligands of co-stimulating receptors of CD28 and 4-1BB, respectively, were also expressed on K562 cells. Then we accomplished the artificial antigen-presenting cells by coupling K32/CD86/4-1BBL cell with OKT3 monoclonal antibody against CD3, named K32/CD86/4-1BBL/OKT3 cells. These artificial modified cells had the abilities of inducing CD8^＋ T cell activation, promoting CD8^＋ T cell proliferation, division, and long-term growth, inhibiting CD8^＋ T cell apoptosis, and enhancing CD8^＋ T cell secretion of IFN-T and perforin. Furthermore, antigen-specific cytotoxic T lymphocytes could be retained in the culture stimulated with K32/CD86/4-1BBL/OKT3 cells at least within 28 days. This approach was robust, simple, reproducible and economical for expansion and activation of CD8^＋ T cells and may have important therapeutic implications for adoptive immunotherapy. Cellular ＆ Molecular Immunology.
文摘Fibrocytes are bone marrow-derived mesenchymal progenitors that co-express hematopoietic cell antigens and markers of monocytic lineage as well as fibroblast products. During wound healing, fibrocytes have been found to possess the ability of antigen-presentation to naive T cells in the inflammatory phase. Moreover, they can promote the endothelial cell proliferation, migration and angiogenesis by secreting several proteins. Fibrocytes can further differentiate into mature mesenchymocyte lineage, such as fibroblasts, myofibroblasts and adipocytes, and they may represent the systemic source of myofibroblasts that exert a contractile force required to close tissue wounds. A deep understanding of the mechanism involved in fibrocyte migration and differentiation may lead to the development of a novel theory of normal physiology and pathology.
基金supported in part by the Hollings Cancer Center Fellowship(to V.W.)NIH Grant R01CA163910(to C.-CAH.)NIH ROIs AI118305,HL137373,and HL140953(to X.-Z.Y.).
文摘Stimulator of interferon genes(STING)-mediated innate immune activation plays a key role in tumor-and self-DNA-elicited antitumor immunity and autoimmunity.However,STING can also suppress tumor immunity and autoimmunity.STING signaling In host nonhematopoietic cells was reported to either protect against or promote graft-versus-host disease(GVHD),a major complication of allogeneic hematopoietic cell transplantation(allo-HCT).Host hematopoietic antigen-presenting cells(APCs)play key roles in donor T-cell priming during GVHD initiation.However,how STING regulates host hematopoietic APCs after allo-HCT remains unknown.We utilized murine models of allo-HCT to assess the role of STING in hematopoietic APCs.STING-deficient recipients developed more severe GVHD after major histocompatibility complex-mismatched allo-HCT.Using bone marrow chimeras,we found that STING deficiency in host hematopoietic cells was primarily responsible for exacerbating the disease.Furthermore,STING on host CD11c+cells played a dominant role in suppressing allogeneic T-cell responses.Mechanistically,STING deficiency resulted in increased survival,activation,and function of APCs,including macrophages and dendritic cells.Consistently,constitutive activation of STING attenuated the survival,activation,and function of APCs isolated from STING V154M knock-in mice.STING-deficient APCs augmented donor T-cell expansion,chemokine receptor expression,and migration into intestinal tissues,resulting in accelerated/exacerbated GVHD.Using pharmacologic approaches,we demonstrated that systemic administration of a STING agonist(bis-(3'-5')-cyclic dimeric guanosine monophosphate)to recipient mice before transplantation significantly reduced GVHD mortality.In conclusion,we revealed a novel role of STING in APC activity that dictates T-cell allogeneic responses and validated STING as a potential therapeutic target for controlling GVHD after allo-HCT.
基金support provided by the National Natural Sciences Foundation of China(Grant Nos.32172873 and 31941005)the National Programme on Key Research Project of China(2021YFD1800105-2)National Natural Sciences Foundation of China,32172873,Min Cui,31941005,Min Cui,National Programme on Key Research Project of China,2021YFD1800105-2,Min Cui。
文摘Pathogenic African swine fever virus(ASFV)remains a lethal causative agent in the domestic pig industry,which poses a burden on the swine market and causes substantial socioeconomic losses worldwide.Currently,there are no commercially efcacious vaccines or specifc treatments available for ASF prevention and control.Unfortunately,little is known about the swine immune response upon ASFV infection.Here,we investigated the host immune response discrepancy induced by the feld moderately virulent strain ASFV HB-2208 among healthy,diseased and asymptomatic pigs.In the peripheral blood of diseased swine,lymphopenia is caused by the massive loss of bystander lymphocytes,such asγδT cells,B cells and CD4^(+)T cells.Conversely,ASFV has a strong tropism for the mononuclear phagocyte system(MPS)and partial dendritic cells(DCs),whose antigen-presenting ability is impeded by the downregulation of CD80 and MHC I.However,no signifcant diference in the number of CD8α^(high) T cells was detected,whereas the frequencies of NK cells,NKT cells,and regulatory T cells(Tregs)were signifcantly increased.Additionally,an in vitro model was established with a coculture of primary pulmonary alveolar macrophages(PAMs)and peripheral blood mononuclear cells(PBMCs),which signifcantly reducedγδT cells,B cells and CD4^(+)T cells and increased Tregs.The diferentiated immune response might aid in enhancing the understanding of ASFV pathogenesis in suids and provide insights into the mechanism of ASFV-induced lymphopenia for further studies.
文摘The onslaught of foreign antigens carried by spermatozoa into the epididymis, an organ that has not demonstrated immune privilege, a decade or more after the establishment of central immune tolerance presents a unique biological challenge. Historically, the physical confinement of spermatozoa to the epididymal tubule enforced by a tightly interwoven wall of epithelial cells was considered sufficient enough to prevent cross talk between gametes and the immune system and, ultimately, autoimmune destruction. The discovery of an intricate arrangement of mononuclear phagocytes （MPs） comprising dendritic cells and macrophages in the murine epididymis suggests that we may have underestimated the existence of a sophisticated mucosal immune system in the posttesticular environment. This review consolidates our current knowledge of the physiology of MPs in the steady state epididymis and speculates on possible interactions between auto-antigenic spermatozoa, pathogens and the immune system by drawing on what is known about the immune system in the intestinal mucosa. Ultimately, further investigation will provide valuable information regarding the origins of pathologies arising as a result of autoimmune or inflammatory responses in the epididymis, including epididymitis and infertility.
文摘Immune reactions to foreign or self-antigens lead to protective immunity and, sometimes, immune disorders such as allergies and autoimmune diseases. Antigen presenting cells (APC) including epidermal Langerhans cells (LCs) play an important role in the course and outcome of the immune reactions. Epidermal powder immunization (EPI) is a technology that offers a tool to manipulate the LCs and the potential to harness the immune reactions towards prevention and treatment of infectious diseases and immune disorders.
基金supported by the Natural Science Research Foundation of Anhui Province Universities,No.KJ2011A202the National Natural Science Foundation of China,No.81000074
文摘Bone marrow precursor cells were extracted from C57BL/6J mice aged 7-8 weeks, and dendritic cells were purified using anti-CD1 lc （a specific marker for dendritic cells） antibody-coated magnetic beads. Immunofluorescence staining revealed that the expression levels of endomorphin-1 and endomorphin-2 were upregulated in dendritic cells activated by lipopolysaccharide. An enzyme Jmmunoassay showed that lipopolysaccharide and other Toll-like receptor ligands promoted the secretion of endomorphin-1 and endomorphin-2 from activated dendritic cells. [3H]-thymidine incorporation demonstrated that endomorphin-1 and endomorphin-2 both inhibited the proliferation of T lymphocyte induced by activated dendritic cells. Furthermore, this immunosuppressive effect was blocked by CTOP, a specific antagonist of IJ-opioid receptors. Our experimental findings indicate that activated dendritic cells can induce the expression and secretion of endomorphins, and that endomorphins suppress T lymphocyte proliferation through activation of iJ-opioid receptors.
文摘Membrane-associated RING-CH-1 (MARCH1) is an E3 ubiquitin ligase which targets MHC-II, CD86 and various other molecules for degradation. It is one of the most efficient post-translational regulators of antigen presentation. MARCH1 is expressed in resting immature dendritic cells and B cells but can be induced in other cell types. While activation of most immune cells results in a reduction in MARCH1 gene expression, its anti-inflammatory properties are highlighted by its induction in response to IL-10. Here, we review what is known about the regulation of MARCH1 gene expression in response to IL-10 by various immune cells. We speculate on the role of MARCH1 ininfection, its differential expression pattern and the promise that this E3 ubiquitin ligase holds to influence immune responses and mitigate immune pathologies.
文摘<p style="text-align:justify;"> <span>Following organ transplantation</span><span>,</span><span> the outcome of the encounter between an APC and a T lymphocyte is strongly dependent on the presence of costimulatory and co-inhibitory molecules, the former associated with allograft rejection and the latter with allograft acceptance. We evaluated the expression of PD-L2, GITR, ILT-2/3/5, and ILT-4 on graft-infiltrating cells procured by Fnab from human KTx under different immunosuppressive regimens. Methods: Fnab biopsies were performed on days 7 or 14</span><span> </span><span>-</span><span> </span><span>30 in stable KTx and on the day of acute rejection diagnosis. Cytopreparations were studied by the enzymatic avidin biotin complex staining. Results: Acute rejection group </span><span>showed a significant down-regulated expression of PD-L2, GITR, and ILT-2/3/5 </span><span>as compared to stable group, while for ILT-4 we did not find significant difference. Anti-IL2</span><i><span>α</span></i><span>R and rapamicyn treatment trend to down-regulate ILT-4 expression, although meaningless. A significant</span><span>ly</span><span> positive correlation was observed between PD-L2 and GITR expression in Fnab. The PPV for acute rejection diagnosis for both PD-L2 and GITR w</span><span>as</span><span> clearly above 0.8. Conclusions: Our findings point to an early entrance of cells expressing PD-L2, GITR and ILT-2/3/5 inside human KTx who are going to remain rejection-free. Both PD-L2 and GITR shared a high ability to rule-in and rule-out acute rejection.</span> </p>
基金supported(as a PI unless otherwise indicated)by one R01 grant from the NIH/NCI(#CA271915)by two Breakthrough Level 2 grants from the US DoD BCRP(#BC180476P1,#BC210945)+11 种基金by a grant from the STARR Cancer Consortium(#I16--0064)by a Transformative Breast Cancer Consortium Grant from the US DoD BCRP(#W81XWH2120034,PI:Formenti)by a U54 grant from NIH/NCI(#CA274291)from the Leukemia and Lymphoma Society(LLS),by the 2019 Laura Ziskin Prize in Translational Research(#ZP--6177,PI:Formenti)from the Stand Up to Cancer(SU2C)by a Mantle Cell Lymphoma Research Initiative(MCL-RI,PI:Chen-Kiang)grant from the Leukemia and Lymphoma Society(LLS)by a Rapid Response Grant from the Functional Genomics Initiative(New York,US)by a pre-SPORE grant(PI:Demaria,Formenti)and a Clinical Trials Innovation Grant from the Sandra and Edward Meyer of Radiation Oncology at Weill Cornell Medicine(New York,US)and Fox Chase Cancer Center(Philadelphia,US)by industrial collaborations with Lytix Biopharma(Oslo,Norway),Promontory(New York,US)and Onxeo(Paris,France)by donations from Promontory(New York,US),the Luke Heller TECPR2 Foundation(Boston,US),Sotio a.s.(Prague,Czech Republic),Lytix Biopharma(Oslo,Norway),Onxeo(Paris,France),Ricerchiamo(Brescia,Italy),and Noxopharm(Chatswood,Australia)supported by the Flanders Research Foundation(FWO)and the Belgian National Fund for Scientific Research(F.R.S.-FNRS)under the Excellence of Science(EOS)program(#40007488),FWO grant(#G016221N)two Special Research Fund(BOF)grants from Ghent University(#BOF/IOP/2022/033,#BOF23/GOA/029)IOF“PULSE”grant(#F2023/IOF-ConcepTT/033)and IOF“IMMUNO-FER-GUARD”grant(#F2023/IOF-ConcepTT/106)from Ghent UniversityEC holds a Marie Sklodowska Curie(MSCA)postdoctoral fellowship(HORIZON-MSCA-2022 PF-01).
文摘While immunotherapy with immune checkpoint inhibitors(ICIs)has revolutionized the clinical management of various malignancies,a large fraction of patients are refractory to ICIs employed as standalone therapeutics,necessitating the development of combinatorial treatment strategies.Immunogenic cell death(ICD)inducers have attracted considerable interest as combinatorial partners for ICIs,at least in part owing to their ability to initiate a tumor-targeting adaptive immune response.However,compared with either approach alone,combinatorial regimens involving ICD inducers and ICIs have not always shown superior clinical activity.Here,we discuss accumulating evidence on the therapeutic interactions between ICD inducers and immunotherapy with ICIs in oncological settings,identify key factors that may explain discrepancies between preclinical and clinical findings,and propose strategies that address existing challenges to increase the efficacy of these combinations in patients with cancer.
基金supported by a National Research Foundation of Korea(NRF)grant funded by the Korean government(MSIT,No.RS-2024-00352440 and No.NRF-2019R1A5A2027340).
文摘Recently,nanovaccine-based immunotherapy has been robustly investigated due to its potential in governing the immune response and generating long-term protective immunity.However,the presentation of a tumor peptide-major histocompatibility complex to T lymphocytes is still a challenge that needs to be addressed for eliciting potent antitumor immunity.Type 1 conventional dendritic cell(cDC1)subset is of particular interest due to its pivotal contribution in the cross-presentation of exogenous antigens to CD8+T cells.Here,the DC-derived nanovaccine(denoted as Si9GM)selectively targets cDC1s with marginal loss of premature antigen release for effective stimulator of interferon genes(STING)-mediated antigen cross-presentation.Bone marrow dendritic cell(BMDC)-derived membranes,conjugated to cDC1-specific antibody(αCLEC9A)and binding to tumor peptide(OVA257-264),are coated onto dendrimer-like polyethylenimine(PEI)-grafted silica nanoparticles.Distinct molecular weight-cargos(αCLEC9A-OVA257-264 conjugates and 2′3′-cGAMP STING agonists)are loaded in hierarchical center-radial pores that enables lysosome escape for potent antigen-cross presentation and activates interferon type I,respectively.Impressively,Si9GM vaccination leads to the upregulation of cytotoxic T cells,a reduction in tumor regulatory T cells(Tregs),M1/M2 macrophage polarization,and immune response that synergizes with αPD-1 immune checkpoint blockade.This nanovaccine fulfills a dual role for both direct T cell activation as an artificial antigen-presenting cell and DC subset maturation,indicating its utility in clinical therapy and precision medicine.
基金supported by grants from the National Natural Science Foundation.The project was supported by the Major International(Regional)Joint Research Program of China(Grant No.82020108005)the Science Fund for Outstanding Young Scholars of China(Grant No.82022008).
文摘Background:Pancreatic ductal adenocarcinoma(PDAC)is one of the main types of malignant tumor of the digestive system,and patient prognosis is affected by difficulties in early diagnosis,poor treatment response,and a high postoperative recurrence rate.Carbohydrate antigen 19-9(CA19-9)has been widely used as a biomarker for the diagnosis and postoperative follow-up of PDAC patients.Nevertheless,the production mechanism and potential role of CA19-9 in PDAC progression have not yet been elucidated.Methods:We performed single-cell RNA sequencing on six samples pathologically diagnosed as PDAC(three CA19-9-positive and three CA19-9-negative PDAC samples)and two paracarcinoma samples.We also downloaded and integrated PDAC samples(each from three CA19-9-positive and CA19-9-negative patients)from an online database.The dynamics of the proportion and potential function of each cell type were verified through immunofluorescence.Moreover,we built an in vitro coculture cellular model to confirm the potential function of CA19-9.Results:Three subtypes of cancer cells with a high ability to produce CA19-9 were identified by the markers TOP2A,AQP5,and MUC5AC.CA19-9 production bypass was discovered on antigen-presenting cancer-associated fibroblasts(apCAFs).Importantly,the proportion of immature ficolin-1 positive(FCN1+)macrophages was high in the CA19-9-negative group,and the proportion of mature M2-like macrophages was high in the CA19-9-positive group.High proportions of these two macrophage subtypes were associated with an unfavourable clinical prognosis.Further experiments indicated that CA19-9 could facilitate the transformation of M0 macrophages into M2 macrophages in the tumor microenvironment.Conclusions:Our study described CA19-9 production at single-cell resolution and the dynamics of the immune atlas in CA19-9-positive and CA19-9-negative PDAC.CA19-9 could promote M2 polarization of macrophage in the pancreatic tumor microenvironment.
基金supported by National Key Research and Development Program of China(Nos.2023YFC2307704,and 2021YFC2302603)National Natural Science Foundation of China(Nos.82341405,and 32030062)+1 种基金CAS Project for Young Scientists in Basic Research(No.YSBR-083)IPE Project for Frontier Basic Research(No.QYJC-2022-012).
文摘Chronic hepatitis B(CHB)is consistently challenging to conquer with numerous complications and fatalities.Despite the effectiveness of antiviral therapies in suppressing hepatitis B virus(HBV)replication,there is an urgent need for novel and more effective treatment modalities.Current strategies predominantly emphasize immune activation but still face challenges in sufficiently eliciting T cell responses.Taking into account the targeted delivery of nanoparticles to the liver and spleen via intravenous injection,we have proposed a dual-pronged therapeutic strategy based on antigen-presenting cells(APCs)-derived exosomes.Specifically,exosomes targeted to the spleen can activate specific immune responses,while those targeted to the liver can modulate or reverse the liver’s immunosuppressive microenvironment.After immunization,exosome formulations exhibit the remarkable ability to effectively activate APCs,thereby triggering the proliferation of CD8^(+)T cells.Simultaneously,they also play an immunoregulatory role by converting M2 macrophages into M1 macrophages.This two-pronged therapeutic strategy precisely addresses the issues of T cell dysfunction and immune suppression,both characteristic features of CHB patients.When combined with Aluminum(Alum)-adjuvanted vaccine,these exosome formulations not only demonstrate a high level of cellular immune response but also secrete specific antibodies comparable to those induced by Alum adjuvant.This combined approach effectively enhances both cellular and humoral immunity,offering a promising avenue for the development of therapeutic hepatitis B vaccines based on exosome formulations.
文摘Preterm birth （PTB） is the leading cause of neonatal morbidity and mortality worldwide. A transition from an anti-inflammatory state to a pro-inflammatory state in the mother and at the maternal-fetal interface has been implicated in the pathophysiology of microbial-induced preterm labor. However, it is unclear which immune cells mediate this transition. We hypothesized that an imbalance between innate and adaptive immune cells at the maternal-fetal interface will occur prior to microbial-induced preterm labor. Using an established murine model of endotoxin-induced PTB, our results demonstrate that prior to delivery there is a reduction of CD4 ＋ regulatory T cells （Tregs） in the uterine tissues. This reduction is neither linked to a diminished number of Tregs in the spleen, nor to an impaired production of ILIO, CCL17, or CCL22 by the uterine tissues. Endotoxin administration to pregnant mice does not alter effector CD4＋ T cells at the maternal-fetal interface. However, it causes an imbalance between Tregs （CD4＋ and CD8＋）, effector CD8＋ T cells, and Th17 cells in the spleen. In addition, endotoxin administration to pregnant mice leads to an excessive production of CCL2, CCL3, CCL17, and CCL22 by the uterine tissues as well as abundant neutrophils. This imbalance in the uterine microenvironment is accompanied by scarce APC-like cells such as macrophages and MHC II ＋ neutrophils. Collectively, these results demonstrate that endotoxin administration to pregnant mice causes an imbalance between innate and adaptive immune cells at the maternal-fetal interface.
基金supported by grants from Independent Innovation Foundation of Shandong University(No.2082012TS134)National Natural Science Foundation of China(No.81200344,No.81070411)National Science Fund for Distinguished Young Scholars(No.81125002).
文摘Primary immune thrombocytopenia(ITP)is an autoimmune disorder characterized by immune-mediated accelerated platelet destruction and/or suppressed platelet production.Although the development of autoantibodies against platelet glycoproteins remains central in the pathophysiology of ITP,several abnormalities involving the cellular mechanisms of immune modulation have been identified,and the pathways behind the immune-mediated destruction of platelets have opened new avenues for the design of specific immunotherapies in an attempt to reduce the platelet destruction.This review is primarily focused on the recent literature with respect to immunopathological mechanisms in patients with ITP.
