Effect of Astragalus Polysaccharide on the Cell-mediated Immunity of Traumatic Stress Mice

To investigate the changes of immune functions and the effects of Astragalus polysaccharide (ASP) on the cell-mediated immunity of the traumatic stress model of mouse by amputation, 50 mice were randomly divided into 5 groups for study, in which the group A and B served as the normal control (by injecton of 0.5 ml of saline intra-peritoneally daily), and as the stress control (by intra-peritoneal injecton of 0.5 ml of normal saline into mice after amputation) respectively, to the group C, D and E of mice, 1000 mg/kg (high dose), 300 mg/kg (median dose) and 250 mg/kg (low dose). The CD4 + and CD8 + T cells as well as the expression of the c-fos protein were determined by immunohistochemical techniques, and the expressions of NF-κB mRNA and IL-10 mRNA were assayed by hybridization in situ . The experimental results showed that in comparison with the normal control group of mice (group A), the expression levels of NF-κB mRNA, IL-10 mRNA and the c-fos protein in the tissues of thymus and spleen in the stress controls were significantly elevated and the CD4 + T cells and CD4/CD8 ratio were decreased. However, in comparison with the stress control of mice (group B), the expressions of NF-κB mRNA and IL-10 mRNA were inhibited by ASP, and the CD4 + T cells and CD4/CD8 ratio were increased in groups C, D and E, but the level of c-fos protein was decreased. There was no significant difference in these parameters among group C, D and E. It is concluded that the functions of cell-mediated immunity of mice were disturbed under the stress condition of the traumatic injuries after amputation. And the immune functions can be effectively restored by the use of Astragalus polysaccharide.

T cell interactions with microglia in immune-inflammatory processes of ischemic stroke

The primary mechanism of secondary injury after cerebral ischemia may be the brain inflammation that emerges after an ischemic stroke,which promotes neuronal death and inhibits nerve tissue regeneration.As the first immune cells to be activated after an ischemic stroke,microglia play an important immunomodulatory role in the progression of the condition.After an ischemic stroke,peripheral blood immune cells(mainly T cells)are recruited to the central nervous system by chemokines secreted by immune cells in the brain,where they interact with central nervous system cells(mainly microglia)to trigger a secondary neuroimmune response.This review summarizes the interactions between T cells and microglia in the immune-inflammatory processes of ischemic stroke.We found that,during ischemic stroke,T cells and microglia demonstrate a more pronounced synergistic effect.Th1,Th17,and M1 microglia can co-secrete proinflammatory factors,such as interferon-γ,tumor necrosis factor-α,and interleukin-1β,to promote neuroinflammation and exacerbate brain injury.Th2,Treg,and M2 microglia jointly secrete anti-inflammatory factors,such as interleukin-4,interleukin-10,and transforming growth factor-β,to inhibit the progression of neuroinflammation,as well as growth factors such as brain-derived neurotrophic factor to promote nerve regeneration and repair brain injury.Immune interactions between microglia and T cells influence the direction of the subsequent neuroinflammation,which in turn determines the prognosis of ischemic stroke patients.Clinical trials have been conducted on the ways to modulate the interactions between T cells and microglia toward anti-inflammatory communication using the immunosuppressant fingolimod or overdosing with Treg cells to promote neural tissue repair and reduce the damage caused by ischemic stroke.However,such studies have been relatively infrequent,and clinical experience is still insufficient.In summary,in ischemic stroke,T cell subsets and activated microglia act synergistically to regulate inflammatory progression,mainly by secreting inflammatory factors.In the future,a key research direction for ischemic stroke treatment could be rooted in the enhancement of anti-inflammatory factor secretion by promoting the generation of Th2 and Treg cells,along with the activation of M2-type microglia.These approaches may alleviate neuroinflammation and facilitate the repair of neural tissues.

Tumor-infiltrating T-Lymphocyte immunity-related immune tolerance and anti–programmed cell death protein 1/ligand of programmed cell death protein 1 therapy for advanced hepatocellular carcinoma

Systemic therapy has become the standard treatment for patients with advanced hepatocellular carcinoma(HCC)whose treatment options are limited.However,the long-term patient response to drugs and the survival outcomes remain a concern.With increasing exploration of the HCC microenvironment,particularly in terms of T lymphocyte immunity,a new era of immunomolecular targeted therapy,based on molecular signaling,has arrived for advanced HCC.In the study of immune tolerance of the intrinsic HCC microenvironment,we found that multiple immunosuppressive mechanisms and immune checkpoint inhibitors,such as anti–programmed cell death protein 1/ligand of programmed cell death protein 1 therapy,have improved clinical outcomes in some patients with advanced HCC.Furthermore,various combination therapies have been investigated,and HCC types have been categorized into different types based on anti–programmed cell death protein 1(PD-1)/ligand of programmed cell death protein 1(PD-L1)treatment.In this paper,we first discuss the tumor-infiltrating T lymphocyte immunity and immune tolerance of HCC.We then clarify the basic mechanism of anti–PD-1/PD-L1 therapy and discuss the types of HCC based on anti–PD-1/PD-L1 therapy.Thereafter,we explain the relevant studies and mechanisms of combination therapy of anti–PD-1/PD-L1 with antiangiogenesis drugs or multikinase kinase inhibitors,anti–T lymphocyte–related signaling pathways in HCC,and other anti-CD8+T cell immune checkpoints.In this way,this review offers a deeper understanding of anti–PD-1/PD-L1 immunotherapy for advanced HCC,in order to provide better individualized treatments for patients with advanced HCC.

Human immune suppression is inducible by trichosanthin via CD8 cell-mediated pathway

Thichosanthin(Tk), a polypeptide with 249 amino acid residues isolated and purified from a Chinese medicinal herb, showed the capability of inducing abortion and was able to inhibit tumor growth and HIV replication. Owing to sequence homology of the peptide with a ribosomeinactivating protein, the downward activity of Tk was suggested to be related to its cytotoxic property. We report here, however, that Tk could exert potent inhibitory effects on human lymphoproliferative responses in vitro to allogeneic, mitogenic and soluble antigens with 50% inhibition doses ranged between 0.05 and 0.5 μg/ml. The lowresponsiveness caused by Tk was not due to toxic cytolysis. Rather, evidences suggested that, in the dose range adopted, the Tk-induced inhibition was attributable, at least in part, to immune suppression, in view of (1) Tk was more effective in the early stage of alloreactivity; (2)Suppression also occurred if responder cells were pulsetreated with Tk rather than cocultured; (3) Irradiated Tk-pulsed cells were capable of inducing suppression in a Tk-free culture; (4) Suppression could also be transferred by the supernatants of Tk-pulsed cultured cells; (5) Tkinduced immune suppression was diminished by depletion of CD8+ cells from the culture, and, finally; (6) Adding CD8+ cells back to the culture could restore the suppres Trichosanthin-induced humall immune suppression sion. Thus the possibility that Tk might function as a down-regulator by immunological mechanisms in human immune responses is discussed.

Immune Control of Equine Infectious Anemia Virus Infection by Cell-Mediated and Humoral Responses

Equine Infectious Anemia Virus (EIAV) is a retrovirus that establishes a persistent infection in horses and ponies. The virus is in the same lentivirus subgroup that includes human immunodeficiency virus (HIV). The similarities between these two viruses make the study of the immune response to EIAV relevant to research on HIV. We developed a mathematical model of within-host EIAV infection dynamics that contains both humoral and cell-mediated immune responses. Analysis of the model yields results on thresholds that would be necessary for a combined immune response to successfully control infection. Numerical simulations are presented to illustrate the results. These findings have the potential to lead to immunological control measures for lentiviral infection.

Correlative factors of poor prognosis and abnormal cellular immune function in patients with Alzheimer’s disease

BACKGROUND Alzheimer’s disease(AD)is a serious disease causing human dementia and social problems.The quality of life and prognosis of AD patients have attracted much attention.The role of chronic immune inflammation in the pathogenesis of AD is becoming more and more important.AIM To study the relationship among cognitive dysfunction,abnormal cellular immune function,neuroimaging results and poor prognostic factors in patients.METHODS A retrospective analysis of 62 hospitalized patients clinical diagnosed with AD who were admitted to our hospital from November 2015 to November 2020.Collect cognitive dysfunction performance characteristics,laboratory test data and neuroimaging data from medical records within 24 h of admission,including Mini Mental State Examination Scale score,drawing clock test,blood T lymphocyte subsets,and neutrophils and lymphocyte ratio(NLR),disturbance of consciousness,extrapyramidal symptoms,electroencephalogram(EEG)and head nucleus magnetic spectroscopy(MRS)and other data.Multivariate logistic regression analysis was used to determine independent prog-nostic factors.the modified Rankin scale(mRS)was used to determine whether the prognosis was good.The correlation between drug treatment and prognostic mRS score was tested by the rank sum test.RESULTS Univariate analysis showed that abnormal cellular immune function,extrapyramidal symptoms,obvious disturbance of consciousness,abnormal EEG,increased NLR,abnormal MRS,and complicated pneumonia were related to the poor prognosis of AD patients.Multivariate logistic regression analysis showed that the decrease in the proportion of T lym-phocytes in the blood after abnormal cellular immune function(odd ratio:2.078,95%confidence interval:1.156-3.986,P<0.05)was an independent risk factor for predicting the poor prognosis of AD.The number of days of donepezil treatment to improve cognitive function was negatively correlated with mRS score(r=0.578,P<0.05).CONCLUSION The decrease in the proportion of T lymphocytes may have predictive value for the poor prognosis of AD.It is recommended that the proportion of T lymphocytes<55%is used as the cut-off threshold for predicting the poor prog-nosis of AD.The early and continuous drug treatment is associated with a good prognosis.

Revolutionizing gastric cancer treatment:The potential of immunotherapy

Gastric cancer,a prevalent malignancy worldwide,ranks sixth in terms of frequency and third in fatality,causing over a million new cases and 769000 annual deaths.Predominant in Eastern Europe and Eastern Asia,risk factors include family medical history,dietary habits,tobacco use,Helicobacter pylori,and Epstein-Barr virus infections.Unfortunately,gastric cancer is often diagnosed at an advanced stage,leading to a grim prognosis,with a 5-year overall survival rate below 5%.Surgical intervention,particularly with D2 Lymphadenectomy,is the mainstay for early-stage cases but offers limited success.For advanced cases,the National Comprehensive Cancer Network recommends chemotherapy,radiation,and targeted therapy.Emerging immunotherapy presents promise,especially for unresectable or metastatic cases,with strategies like immune checkpoint inhibitors,tumor vaccines,adoptive immunotherapy,and nonspecific immunomodulators.In this Editorial,with regards to the article“Advances and key focus areas in gastric cancer immunotherapy:A comprehensive scientometric and clinical trial review”,we address the advances in the field of immunotherapy in gastric cancer and its future prospects.

Awakening immunity against cancer:a 2017 primer for clinicians

Cancer immunotherapy has finally joined the pillars of cancer treatment-surgery, radiation, chemotherapy, hormonal therapy, and targeted therapy-in improving cancer patient lives. In the last 5 years, the development of immune checkpoint inhibitor and T cell therapy, particularly chimeric antigen receptor(CAR) T-cell therapy, has been remarkable for the speed, scale, and number of drug approvals. Still, these treatments may also bring unusual adverse effects and clinical outcomes including unprecedented long-term survival. Interrogating the tumor microenvironment and identifying better biomarkers hold the key to improving cancer immunotherapies. CAR T-cell therapy has dramatic effect on leukemias and lymphomas with significant cure rates, but has yet to show comparable effect on solid tumors. Cutting-edge technology will improve both processing and clinical effect of such therapies. Asia has the largest, most rapidly aging population and the largest number of cancer patients in the world. Research and development and clinical trial conduct of cancer immunotherapy in Asia remain nascent, but should be a crucial priority.

Viral infection parameters not nucleoside analogue itself correlates with host immunity in nucleoside analogue therapy for chronic hepatitis B

AIM: To determine the relationship between host immunity and the characteristics of viral infection or nucleoside analogues (NAs) themselves in patients with chronic hepatitis B (CHB) receiving NA therapy.

Recombinant E.coli LLO/OVA Vaccination Effectively Inhibits Murine Melanoma Metastasis to Lung by CD8^+T Cells Immunity

Objective： To construct recombinant E.coli LLO/OVA and investigate its tumor metastatic inhibition effect in B16 OVA melanoma challenged mice. Methods： Recombinant E.coli LLO/OVA was constructed and the expression of listeriolysin O （LLO） and ovalbumin （OVA） of the vaccine was determined by coomassie brilliant blue staining and western blotting, After 3 subcutaneous injections of E.coli LLO/OVA, the percentages of CD3^＋CD4^＋T, CD4^＋CD25^＋T, CD3^CD8^＋T and OVA257-264 SIINFEKL specific CD8^＋T cells were determined by flow cytomytry, and the tumor metastatic inhibition effect in B16 OVA melanoma challenged mice was observed. Results： Recombinant E.coli LLO/OVA was successfully constructed, and the expression of LLO and OVA of the vaccine was confirmed. After 3 subcutaneous injections of E.coli LLO/OVA and E.coli OVA in mice, the percentages of CD3^＋CD4^＋T, CD4^＋CD25^＋T and CD3^＋CD8^＋T cells were equivalent in the two groups of mice. However, there were significantly more OVA257-264 SIINFEKL specific CD8^＋T cells in E.coli LLO/OVA vaccinated mice than that in E.coli OVA vaccinated mice. The prophylactic E.coli LLO/OVA vaccination effectively prevented the tumor metastasis to lungs in B16 OVA melanoma challenged mice. Depletion of CD8^＋T cells significantly impaired the tumor inhibition effect of the vaccine in B16 OVA challenged mice. The therapeutic vaccination of E.coli LLO/OVA significantly prevented melanoma metastasis to lungs in B I6 OVA challenged mice too. Conclusion： Recombinant E.coli LLO/OVA vaccination is highly effective in inhibiting murine malignant melanoma metastasis by promoting CD8^＋T cell immunity.

Evaluation of antibody-dependent cell-mediatedcy totoxicity activity and cetuximab response in KRAS wildtype metastatic colorectal cancer patients

AIM:To investigate the prognostic role of invariant natural killer T(iNKT) cells and antibody-dependent cell-mediated cytotoxicity(ADCC) in wild type KRAS metastatic colorectal cancer(mC RC) patients treated with cetuximab.METHODS: Forty-one KRAS wt mC RC patients,treated with cetuximab and irinotecan-based chemotherapy in Ⅱ and Ⅲ lines were analyzed. Genotyping of single nucleotide polymorphism(SNP)s in the FCGR2A,FCGR3A and in the 3' untranslated regions of KRAS and mutational analysis for KRAS,BRAF and NRAS genes was determined either by sequencing or allelic discrimination assays. Enriched NK cells were obtained from lymphoprepperipheral blood mononuclear cell and iN KT cells were defined by co-expression of CD3,TCRVα24,TCRVβ11. ADCC was evaluated as ex vivo NK-dependent activity,measuring lactate dehydrogenase release.RESULTS: At basal,mCRC patients performing ADCC activity above the median level(71%) showed an improved overall survival(OS) compared to patients with ADCC below(median 16 vs 8 mo;P=0.026). We did not find any significant correlation of iN KT cells with OS(P=0.19),albeit we observed a trend to a longer survival after 10 mo in patients with iN KT above median basal level(0.382 cells/microliter). Correlation of OS and progression-free survival(PFS) with interesting SNPs involved in ADCC ability revealed not to be significant. Patients carrying alleles both with A in FCGR2 A and TT in FCGR3A presented a trend of longer PFS(median 9 vs 5 mo;P=0.064). Chemotherapy impacted both iN KT cells and ADCC activity. Their prognostic values get lost when we analysed them after 2 and 4 mo of treatment.CONCLUSION: Our results suggest a link between iN KT cells,basal ADCC activity,genotypes in FCGR2A and FCGR3A,and efficacy of cetuximab in KRAS wt mC RC patients.

EXPRESSION OF IL-2 AND SIL-2R AND ALTERATION OF CELL IMMUNITY IN PATIENTS WITH HYPERTENSIVE CEREBRAL HEMORRHAGE

Objective To study the expression of interleukin-2(IL-2), soluble interleukin-2 receptor (sIL-2R), determine the alteration of erythrocytic immunity and T cell subgroup in the blood of outer circulation in patients with hypertensive cerebral hemorrhage so and to probe into the relationship between them, and to explore the clinical significance. Methods Enzyme linked immnunosorbent assay (ELISA) was used to determine the content of IL-2 and sIL-2R. The immunoadsorption was employed to examine the erythrocytic immune activity and its regulating function. Streptavidin-peroxidase(S-P) was used to determine the cell number of CD3 (cluster of differentiation3), CD4 and CD8. Results The content of IL-2 in the group with hypertensive cerebral hemorrhage was significantly lower than that in the control group (P<0.01), and the content of sIL-2R increased. Red blood cell C_ 3b receptor (RBC.C_ 3b R) and RBC immune adherence enhancing factor (RFEB) dropped greatly (P<0.01), while RBC immune complex rosette (RBC.ICR) and RBC immune adherence inhibiting factor (RFIR) increased greatly. The cell number of CD3 and CD4decreased (P<0.01) and there was no obvious change in CD8 (P<0.05). Conclusion The decrease of immune function was observed in patients with hypertensive cerebral hemorrhage. The determination of the content of IL-2, sIL-2R, erythrocytic immunity and the activity of T subgroup has an important clinical significance in the occurrence, development, treatment, and prognosis of hypertensive cerebral hemorrhage.

Elimination of GGTA1,CMAH,β4GalNT2 and CIITA genes in pigs compromises human versus pig xenogeneic immune reactions

Background:Pig organ xenotransplantation is a potential solution for the severe organ shortage in clinic,while immunogenic genes need to be eliminated to improve the immune compatibility between humans and pigs.Current knockout strategies are mainly aimed at the genes causing hyperacute immune rejection(HAR)that occurs in the first few hours while adaptive immune reactions orchestrated by CD4 T cell thereafter also cause graft failure,in which process the MHCⅡmolecule plays critical roles.Methods:Thus,we generate a 4-gene(GGTA1,CMAH,β4GalNT2,and CIITA)knockout pig by CRISPR/Cas9 and somatic cell nuclear transfer to compromise HAR and CD4 T cell reactions simultaneously.Results:We successfully obtained 4KO piglets with deficiency in all alleles of genes,and at cellular and tissue levels.Additionally,the safety of our animals after gene editing was verified by using whole-genome sequencing and karyotyping.Piglets have survived for more than one year in the barrier,and also survived for more than 3 months in the conventional environment,suggesting that the piglets without MHCⅡcan be raised in the barrier and then gradually mated in the conventional environment.Conclusions:4KO piglets have lower immunogenicity,are safe in genomic level,and are easier to breed than the model with both MHCⅠandⅡdeletion.

2’-Fucosyllactose alleviate immune checkpoint blockade-associated colitis by reshaping gut microbiota and activating AHR pathway

Immune checkpoint blockade(ICB)therapeutics are highly effective in cancer immunotherapy,but gastrointestinal toxicity limited the application.Intestinal microbiota plays a crucial role in ICB-associated colitis.2’-Fucosyllactose(2’FL)is most abundance prebiotic in human milk that can reshape gut microbiota and exert immune regulatory effect.The study aimed to determine the effects of 2’FL on ICB-associated colitis and to uncover the mediating mechanism.ICB-associated colitis was induced by the ipilimumab and dextran sulfate sodium.Oral administration of 2’FL(0.6 g/(kg∙day))ameliorated ICB-induced colitis by enhancing regulatory T cells(Treg)and the M2/M1 ratio of macrophages in colon.2’FL treatment also increased the expression of tight junction proteins(zonula occludens-1(ZO-1)and mucin 2(MUC2))and antioxidant stress indicators(superoxide dismutase(SOD)and catalase(CAT)).In addition,administration of 2’FL increased the abundance of Bifidobacterium and Lactobacillus,and elevated the levels of microbial metabolites,such as indole-3-lactic acid(ILA),which activated the aryl hydrocarbon receptor ligands(AHR)pathway.The protective effect of 2’FL was abolished upon depletion of gut microbiota,and ILA treatment partially simulated the protective effect of 2’FL.Notably,2’FL did not exhibit inhibition of antitumor immunity.These findings suggest that 2’FL could serve as a potential protective strategy for ICB-associated colitis by modulating the intestinal microbiota and bacterial metabolites.

Tumor-derived DEFB1 induces immune tolerance by inhibiting maturation of dendritic cell and impairing CD8+T cell function in esophageal squamous cell carcinoma

Objective:CD8+T cells are the key effector cells in the anti-tumor immune response.The mechanism underlying the infiltration of CD8+T cells in esophageal squamous cell carcinoma(ESCC)has not been clearly elucidated.Methods:Fresh ESCC tissues were collected and grouped according to the infiltration density of CD8+T cells.After the transcriptome sequencing on these samples and the combined analyses with The Cancer Genome Atlas(TCGA)ESCC data,a secreted protein DEFB1 was selected to explore its potential role in the infiltration of CD8+T cells.Bioinformatics analyses,histological verification and in vitro experiments were then performed.Results:DEFB1 was highly expressed in ESCC,and the high expression of DEFB1 was an independent risk factor for overall survival.Since the up-regulation or down-regulation of DEFB1 did not affect the proliferation,migration and apoptosis of ESCC cells,we speculated that the oncogenic effect of DEFB1 was achieved by regulating microenvironmental characteristics.Bioinformatics analyses suggested that DEFB1 might play a major role in the inflammatory response and anti-tumor immune response,and correlate to the infiltration of immature dendritic cell(imDC)in ESCC.Histological analyses further confirmed that there were less CD8+T cells infiltrated,less CD83+mature DC(mDC)infiltrated and more CD1a+imDC infiltrated in those ESCC samples with high expression of DEFB1.After the treatment with recombinant DEFB1 protein,the maturation of DC was hindered significantly,followed by the impairment of the killing effects of T cells in both 2D and 3D culture in vitro.Conclusions:Tumor-derived DEFB1 can inhibit the maturation of DC and weaken the function of CD8+T cells,accounting for the immune tolerance in ESCC.The role of DEFB1 in ESCC deserves further exploration.

Roles of antigen receptors and CA215 in the innate immunity of cancer cells

Antigen receptors, including immunoglobulins and T-cell receptors, are known to be widely expressed by cancer cells through unconfirmed mechanisms and for unknown purposes. Recently, a monoclonal antibody, designated as RP215, was generated against the ovarian cancer cell line, OC-3-VGH, and was shown to react with CA215, which consisted mainly of these cancer cell-expressed antigen receptors. Experimental evidence has clearly indicated that cancerous immunoglobulins play significant roles in the growth and proliferation of cancer cells in vitro and in vivo. RP215 and anti-antigen receptor antibodies were equally effective in inducing apoptosis and complement-dependent cytotoxicity reactions to cultured cancer cells. Through gene regulation studies, both RP215 and antibodies against antigen-receptors were shown to affect more than a dozen of genes involved in cell proliferation (such as NFκB-1, IgG, P21, cyclin D1, ribosomal P1, and c-fos). Furthermore, selected toll-like receptor genes (TLR- 2, -3, -4, and -9) were also found to be highly regulated by both RP215 and anti-antigen receptor antibodies. For example, RP215 and anti-antigen receptor antibodies were found to both up-regulate TLR-2 and/or TLR-3 and down- regulate TLR-4 and TLR-9 intwo types of cancer cells. Based on these studies, it is reasonable to postulate that cancerous immunoglobulins play important roles in the modulation of the innate immune system to allow the growth and survival of cancer cells within the human body. Consequently, RP215 inits humanized forms may be utilized to target cancer cells for potential therapeutic purposes.

Predictors of prognosis in Alzheimer’s disease: The role of cognitive dysfunction, immune abnormalities, and advanced neuroimaging

Alzheimer’s disease(AD)is a grave illness that results in cognitive and social issues.A recent study examined the association between neuroimaging results,cognitive dysfunction,atypical cellular immune function,and poor prognostic factors in AD patients who demonstrated poor prognosis.Poor prognosis was associated with abnormal cellular immune function,extrapyramidal symptoms,altered consciousness,abnormal electroencephalogram,modified Rankin scale,increased neutrophil lymphocyte ratio,and severe pneumonia.The impaired cellular immune function characterized by a reduction in the blood T lym-phocytes’proportion predicted poor prognosis as an independent risk factor in AD.Early initiation and maintenance of AD medications is associated with better outcomes.

Downregulation of CD4+CD25+ regulatory T cells may underlie enhanced Th1 immunity caused by immunization with activated autologous T cells

Regulatory T cells （Treg） play important roles in immune system homeostasis, and may also be involved in tumor immunotolerance by suppressing Th1 immune response which is involved in anti-tumor immunity. We have previously reported that immunization with attenuated activated autologous T cells leads to enhanced anti-tumor immunity and upregulated Thl responses in vivo. However, the underlying molecular mechanisms are not well understood. Here we show that Treg function was significantly downregulated in mice that received immunization of attenuated activated autologous T cells. We found that Foxp3 expression decreased in CD4＋CD25＋ T cells from the immunized mice. Moreover, CD4＋CD25＋Foxp3＋ Treg obtained from immunized mice exhibited diminished immunosuppression ability compared to those from naive mice. Further analysis showed that the serum of immunized mice contains a high level ofanti-CD25 antibody （about 30 ng/ml, p〈0.01 vs controls）. Consistent with a role ofanti-CD25 response in the downregulation of Treg, adoptive transfer of serum from immunized mice to naive mice led to a significant decrease in Treg population and function in recipient mice. The triggering of anti-CD25 response in immunized mice can be explained by the fact that CD25 was induced to a high level in the ConA activated autologous T cells used for immunization. Our results demonstrate for the first time that immunization with attenuated activated autologous T cells evokes anti-CD25 antibody production, which leads to impeded CD4＋CD25＋Foxp3＋ Treg expansion and function in vivo. We suggest that dampened Treg function likely contributes to enhanced Thl response in immunized mice and is at least part of the mechanism underlying the boosted anti-tumor immunity.

The quantal theory of immunity

Exactly how the immune system discriminates between all environmental antigens to which it reacts vs. all selfantigens to which it does not, is a principal unanswered question in immunology. As set forth in this review, because of the advances in our understanding of the immune system that have occurred in the last 50 years, for the first time it is possible to formulate a new theory, termed the ＂Quantal Theory of Immunity＂, which reduces the problem from the immune system as a whole, to the individual cells comprising the system, and finally to a molecular explanation as to how the system behaves as it does.

Histopathological analysis of infiltrating T cell subsets in acute T cell-mediated rejection in the kidney transplant

AIM To compare the differential immune T cell subset com-position in patients with acute T cell-mediated rejection in the kidney transplant with subset composition in the absence of rejection, and to explore the association of their respective immune profiles with kidney transplant outcomes.METHODS A pilot cross-sectional histopathological analysis of the immune infiltrate was performed using immunohistochemistry in a cohort of 14 patients with acute T cellmediated rejection in the kidney transplant and 7 kidney transplant patients with no rejection subjected to biopsy to investigate acute kidney transplant dysfunction. All patients were recruited consecutively from 2012 to 2014 at the Singapore General Hospital. Association of the immune infiltrates with kidney transplant outcomes at up to 54 mo of follow up was also explored prospectively.RESULTS In a comparison to the absence of rejection, acute T cell-mediated rejection in the kidney transplant was characterised by numerical dominance of cytotoxic T lymphocytes over Foxp3^+ regulatory T cells, but did not reach statistical significance owing to the small sample size in our pilot study. There was no obvious difference in absolute numbers of infiltrating cytotoxic T lymphocytes, Foxp3^+ regulatory T cells and Th17 cells between the two patient groups when quantified separately. Our exploratory analysis on associations of T cell subset quantifications with kidney transplant outcomes revealed that the degree of Th17 cell infiltration was significantly associated with shorter time to doubling of creatinine and shorter time to transplant loss.CONCLUSION Although this was a small pilot study, results support our suspicion that in kidney transplant patients the immune balance in acute T cell-mediated rejection is tilted towards the pro-rejection forces and prompt larger and more sophisticated studies.