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Immune checkpoint inhibitor (ICI) represented by anti-programmed death 1 (PD-1) antibodies has made great progress in the treatment of solid tumors. Recently, ICI has been gradually used in hematological malignancies, and many clinical trials have shown that it could bring better therapeutic efficacies and significantly improve the prognosis of patients with hematological malignancies. This article reviews the research progress of ICI in hematological malignancies combined with the clinical studies from the 62nd American Society of Hematology (ASH) Annual Meeting.
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Objective@#To clarify the characteristics of the A20 regulatory changes by analyzing mutations in the non-coding region of the A20 gene in patients with T-cell lymphoma leukemia (T-LCL) .@*Methods@#PCR and nucleotide sequence analysis were used to detect mutations in the non-coding region of the A20 gene, and DNA samples from PBMCs of 52 cases of T-LCL and 99 healthy controls.@*Results@#A missense mutation (c.-672T>G) was detected in the A20 gene promoter from one T-LCL patient, which has been registered as a SNP (rs139054966) in gene bank. Meanwhile, a new mutation was detected in the 3′ UTR mRNA (3916 (C>G) ) . These two mutations were absent in other T-LCL samples and controls.@*Conclusion@#The rs139054966 (c.-672T>G) and 3916 (C>G) mutations in the A20 gene were detected in T-LCL patients for the first time. There was also rs139054966 located on the binding region of the transcription factor P53, and its significance remained to be further clarified.
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In recent years,cellular immune therapy represented by antigen-chimeric receptor T cells (CAR-T) has made a great breakthrough in the treatment of hematological malignancies.T memory stem cells (TSCM) and central memory T cells (TCM) can be used as most powerful carrier for T cell immunotherapy,however,how to regulate their differentiation in vitro and in vivo as well as how to construct a strong treatment system while without potential side effect become quite interesting.This article summarized the studies from the 58th America Society of Hematology Annual Meeting regarding to values and associated research progress about TsCM and TCM in hematological malignancies.
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How to improve the efficacy of chimeric antigen receptor T-cell (CAR-T) is one of the key points for manufacture and application of CAR-T. In this review, the studies from the 57th American Society of Hematology (ASH) annual meeting regarding to the strategies for optimal CAR-T activity were summarized, including pathway inhibitors, enhancement antigen expression of target cells, optimization of conditioning chemotherapy, as well as the novel technology for CAR-T generation.
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Objective:To investigate mechanism of imatinib mesylate induced apoptosis of primary CD3+T cells.Methods:The CD3+T cells were stimulated by 0-100 nmol/L imatinib for 24 h,cell apoptosis was detected by flow cytometry;Caspase-3,Caspase-8, A20 and NF-κB expression levels were detected by Real-time quantitative PCR and Western blot.Results: IM significantly increased apoptosis of T cell;Caspase-3 and A20 gene expression levels were upregulated and NF-κB expression level was downregulated both in gene and protein levels.Conclusion:IM increased apoptosis of T cell by upregulating A20 expression.
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Objective:To explore the change of initial and memory T cells in peripheral blood and their clinical significance in peripheral T cell lymphoma patients( PTCL) before and after CHOP chemotherapy.Methods:The proportion of CD4+CD45RA+T cells and CD4+CD45RO+T cells,CD8+CD45RA+T cells and CD8+CD45RO+T cells in peripheral blood from 20 PTCL patients before and after chemotherapy was detected by flow cytometry, the relationship between curative effect and T cell subset was further analyzed.Results:Before treatment,the proportion of CD4+and CD4+CD45RO+T cells in PTCL patients was significantly lower than that from the control group,while the proportion of CD4+CD45RA+,CD8+,CD8+CD45RO+and CD8+CD45RA+T cells was significantly higher( P<0.05 );after treatment, proportion of CD4+, CD4+CD45RO+T was significantly increased, CD4+CD45RA+, CD8+, CD8+CD45RO+,CD8+CD45RA+T was slightly decreased( P<0.05).Before and after treatment,higher proportion of CD4+CD45RA+T cells was found in response group compared with no response group.Conclusion: CHOP chemotherapy might influence the thymic output function in PTCL patients,patients with higher thymic output function may have better response to chemotherapy.
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[ ABSTRACT] AIM:To investigate the expression and regulation of A20 in healthy individuals and the patients with systemic lupus erythematosus (SLE).METHODS:The expression levels of A20, NF-κB, MALT1, and MALT1V1 in peripheral blood mononuclear cells ( PBMC) of the patients with SLE ( including 2 cases with scleroderma, 1 case with rheumatoid arthritis, and 1 case with lymphoma) were analyzed by real-time PCR.RESULTS:A significantly lower A20 expression level was found in the PBMC from SLE group compared with the healthy controls, while the expression levels of MALT1 and NF-κB were also decreased.In addition, no significant correlation between A20 and NF-κB expression levels in healthy group was observed, but a positive correlation was found in SLE group ( P<0.05) .A significant positive corre-lation between MALT1 and NF-κB expression levels in healthy group ( P<0.05) was observed, and no significant correla-tion was found in SLE group.The expression level of MALT1V1 in SLE group was significantly lower than that in healthy control group, and there was a positive correlation between A20 and MALT1V1 in healthy volunteers (P<0.01), but that did not exist in SLE group.CONCLUSION: The characteristics of the expression pattern of MALT1-A20-NF-κB in the SLE patients were presented.Lower level of A20 expression was found in the SLE patients, in particular with other autoim-mune disease or lymphomas, indicating the lower immune tolerance in SLE.The positive correlation of A20 and NF-κB may relate to positive regulation of MALT1.
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T cell immune deficiency results in inefficient anti-tumor immune response in most patients with hematological malignancies,thereby tumor cells escaping the attack of host immune system,that is the immune escape of tumor cells.Recently,new insights regard to the CD8+ T cell exhaustion which is one of the most important mechanisms of tumor immune suppression.The CD8 + T cell exhaustion is mediated by abnormal expression of T-cell immunosuppressive receptors such as PD-1 and CTLA-4.Blocking these molecules may restore the partial or all functions of T cells.This article reviewed the advances on the role of the PD-1 and CTLA-4 in hematological malignancies,including their functions on mediating T cell-immune tolerance and the progression of targeted immunotherapy,to provide the new strategy for hematological malignancies.
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T cells redirected to specific antigen targets with engineered chimeric antigen receptors (CARs) are emerging as powerful therapies in hematologic malignancies.Various CAR designs,manufacturing processes,and study populations,among other variables,have been studied and reported in clinical trials.The accumulating data supporting CAR-T cells therapy for disease such as chronic lymphocytic leukemia (CLL)and acute lymphocytic leukemia (ALL) highlight what may well become the next sea change in the care of patients with all types of hematologic neoplasia.The scientific symposium on CAR-T cells therapy inspires the mounting enthusiasm regarding this new treatment strategy.Here,the results of the reported clinical trials and the outlook for CAR-T cells therapies were reviewed and discussed.Many questions remain in the field of CAR-T cells directed to hematologic malignancies,but the encouraging response rates pave a wide road for future investigation.
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AIM:To investigate the influence of continuous subculturing of human umbilical cord mesenchymal stem cells (hUC-MSCs) on the mRNA expression of all 23 family members of NOD-like receptors (NLRs), and to search for the way of improving the subculture quality of hUC-MSCs and increasing the quantity and safety in the experimental and clinical application .METHODS:Neonatal umbilical cord was collected to isolate and purify the hUC-MSCs with the colla-genase II digestion and adherence screening methods .These cells were continuously subcultured .The hUC-MSCs at pas-sage 3 and passage 28 were identified by flow cytometry and induced differentiation .The mRNA expression of NLRs in the passage 3 and passage 28 hUC-MSCs was detected by RT-qPCR.RESULTS: The cell phenotypes of both passage 3 and passage 28 hUC-MSCs were CD29 +/CD44 +/CD105 +/CD31 -/CD34 -/CD40 -/CD45 -/CD106 -/HLA-DR-, and both of the cells were induced into osteoblasts and adipocytes , which were conformed to the criteria of International Society for Cellular Therapy to define MSCs .All the NLR family members were expressed in passage 3 hUC-MSCs.NOD1, NLRC4, NLRC5, NLRP1, NLRP3, NLRP10, NAIP, NLRX1 and APAF1 at mRNA levels were highly expressed , and the rest were lowly expressed.When hUC-MSCs were subcultured to passage 28, NLRP10 mRNA was increased, NLRC5 mRNA and NLRX1 mRNA were hardly changed , and all of the rest members were decreased .The difference of NLRP1 mRNA expres-sion between passage 3 and passage 28 hUC-MSCs was observed with statistical significance (P<0.05).CONCLU-SION:The effects of subculturing on the expression of NLR family in hUC-MSCs are pleiotropic .It requires further investi-gation to confirm whether these effects are related to the proliferation , differentiation and immunomodulation of MSCs .
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T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematologic malignancy associated with poor prognosis.Increasing data regarding to alteration of gene expression signatures of oncogenes and tumor suppressors involved in the pathogenesis of T-ALL and the major mechanisms of T-cell transformation may contribute to define the biological markers for treatment response and prognosis,and has important clinical implications.In this review,advance knowledge concerning the characteristics of early T-cell precursor ALL,the alteration of TAL1 and NOTCH1 related genes and target inhibiton effects based on these alterations from 2012 the 54th ASH annual meeting ars summarized.
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Cellular immunodeficiency is an important factor related to relapse of hematological malignancy post stem cell transplantation. On the other hand, allogeneic stem cell transplantation can be considered the adoptive immunotherapy, which can overcome the host immunodeficiency and promote graftversus-tumor (GVT) effect for elimination of minimal residual disease and prevention of relapse. How to optimize the GVT induction is required to be defined more clearly. In this review, advance knowledge concerning the optimized and clinical setting of GVT induction from 2011 ASH annual meeting is summarized.
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This paper is aimed to investigate the transcription and expression of BCR-ABL-pIRES-SEA fusion gene vaccines in vivo in mice. The reconstructed plasmids (BCR-ABL-pIRES-SEA) which were developed previously in our laboratory were injected into the skeletal muscles of BALB/c mice at 14d intervals for three cycles. The transcription and expression of BCR-ABL and staphylococcal enterotoxin A (SEA) in injection site were detected using RT-PCR and immunohistological methods. The BCR-ABL/SEA mRNA and protein could be identified in the injection site of BCR-ABL-pIRES-SEA vaccinated mice. The reconstructed BCR-ABL-pIRES-SEA plasmids can effectively express gene production in the skeletal muscles of mice and have the common features of DNA vaccine.
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Animals , Male , Mice , Enterotoxins , Genetics , Allergy and Immunology , Metabolism , Fusion Proteins, bcr-abl , Genetics , Allergy and Immunology , Metabolism , Mice, Inbred BALB C , Muscle, Skeletal , Metabolism , Plasmids , Allergy and Immunology , RNA, Messenger , Genetics , Metabolism , Recombinant Fusion Proteins , Genetics , Allergy and Immunology , Metabolism , Vaccines, DNA , Allergy and ImmunologyABSTRACT
T-cell immune reconstitution after hematopoietic stem cell transplantation(HSCT)is important for prevention of virus infections and disease relapse. How to modify the conditioning regimen and the graft composition to promote immune recovery post HSCT was one of the key issue of transplant immunology from 2011 ASH annual meeting.In this review,advance knowledge concerning the T-cell immune reconstitution post HSCT is summarized.
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Objective To investigate the distribution of TCR Vβ genealogy and clonal expansion in peripheral blood after infusing mesenchymal stem cells (MSC) in patients with chronic GVHD. Methods The complementarity determining region 3 (CDR3) of 24 TCR Vβ subfamily genes in peripheral blood mononuclear cell from 1 case with cGVHD after allogeneic hematopoietic stem cell transplantation (Allo-HSCT),who were treated with infusing MSC,were amplified using RT-PCR. The blood samples were taken at the first and the fifth day after 1st infusion; and the first day,the 10 th day and the 20 th day after the second infusion of MSC,as well as the MSC infused as control . The products were labelled by fluorescein and then analyzed the CDR3 size with gene scan technique to determine the clonality of T cells. Results There were no expression of TCR Vβ subfamily with the MSC infused and after the 1st day of the first infusion of MSC. Then 3,10,14,10 Vβ subfamilies clones are appeared at the other time points,of which were polyclone and oligoclone predominately. In the same time,the manifestations of cCVHD have been abated. Conclusion MSC played a certain role in reviving the immune function of the patients after Allo-HSCT and mitigating the disease of chronic GVHD. Lineage analysis of TCR Vβ subfamily showed some predominant expression.
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AIM: To investigate the expression level of transcriptional factor Elf-1 in mononuclear cells, CD4~+ and CD8~+ T cells from umbilical cord blood (UCB). METHODS: Real-time PCR with SYBR green I technique was used for detecting the Elf-1 expression in mononuclear cells, sorted CD4~+ and CD8~+ T cells from 12 cases of umbilical cord blood. The relative mRNA expression level of Elf-1 was analyzed by a formula of 2~(-△Ct)×100%. The expression level of β_2-microglobulin gene (β_2M) was used as an endogenous reference. The peripheral blood from 10 cases of healthy adults was served as control. RESULTS: Elf-1 mRNA expressed in all blood samples collected from both UCB and healthy adults. The expression level showed apparent diversity in different individuals. The relative mRNA expression of Elf-1 in both mononuclear cells (18.55%±2.48%) and CD8~+ T cells (3.52%±0.45%) from UCB were significantly higher than those from healthy adults (9.16%±1.92%, 2.02%±0.27%, respectively, P<0.01, P<0.05). CONCLUSION: The results of Elf-1 expression level from umbilical cord blood indicate that the over-expression of Elf-1 gene in mononuclear cells and CD8~+ T cells might be one of the features of T cell immune state in umbilical cord blood.
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Elf-1 (E74-like factor 1) is a member of Ets transcription factor family,which participated in physiological and pathological process of cells proliferation,differentiation and tumorigenesis. In this review,we summarize that Elf-1 is related to T cell differentiation and development,tumor and autoimmune disease.
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Allogeneic hematopoietic stem cell transplantation(allo-HSCT) represents a potentially curative treatment modality in a range of hematologic malignancies and autoimmune disease. Immune reconstitution is a major factor to evaluate the outcome of transplantation.As markers for recent thymic output function,T cell receptor excision circles (TRECs) have been widely applied to evaluate thymie output function in normal individuals or in patients with hematopoietic stem cell transplantation, hematologic malignancies,HIV infection or autoinunune disease.
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Objective To investigate T-cell receptor(TCR)ζchain gene expression level in peripheral blood T cells from patients with multiple myeloma(MM),thereby to estimate the feature of T cells activation status.Methods Real-time PCR with SYBR Green I technique Was used for detecting TCR ζchain expression level in peripheral blood mononuelear cells(PBMC)of 24 cages with MM and 24 normal individuals.β2-microglobulin(β2M)gene expression was used as an endogenous reference.Relative changes in TCRζchain expression level were analyzed by the 2-△α×100%method between patients with MM and normal individuals.Results Compared with normal individuals,TCRζchain gene expression was obviously down regulated in PBMC from patients with MM(P=0.019).The expression level of TCR ζchain gene is not significantly age-associated in MM patients[(1.83±1.72)%,(3.46±2.75)%](P=0.525).Conclusion This is the first description in the expression feature of TCRζchain gene in MM patients.TCRζchain expression Was decreased in most of MM patients,which might be related to celhar immunodeficiency.
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Objective To investigate the expression and clonality of TCR V? subfamily T cell in 11 patients undergoing chronic hemodialysis before and after renal transplantation.Methods The CDR3 of TCR V? 24 subfamily genes were amplified in samples of peripheral blood mononuclear cells which were drawn before hemodialysis and at 20th day post-operatively. To observe the usage of TCR V? repertoire, the RT-PCR products were further labeled with fluorescent and analyzed by genescan technique for CDR3 size.Results (1) One patient was attacked by acute cellular rejection (ACR) and one suffered from delayed graft function (DGF) diagnosed by renal transplant biopsy. (2) 1-10 TCR V? subfamilies T cells could be identified before transplantation, and most of TCR V? subfamily T cells expressed as polyclonality. The most frequent expression of TCR V? genes was V?3. (3) Only 1-5 TCR V? subfamilies T cells could be detected post-operatively, most of them expressed as oligoclonality. The TCR V?3 subfamilies still were the most frequently expressed (in 9 cases). (4) There were no TCR V? subfamilies T cells before pulse of methylprednisolone, and were 5 subfamilies during pulse of methylprednisolone expressed as oligoclonality or biclonality, 2 subfamilies after ACR expressed as polyclonality. In DGF patient, there were 4 TCR V? subfamilies during DGF, and 5 following DGF.Conclusion (1) The significantly skew distribution of TCR V? subfamily T cells could be found in all patients with chronic renal failure and chronic hemodialysis. (2) Furthermore, the skewing distributions of TCR V? genes came to more significant at 20th day post-transplantation than before. (3) ACR might be closely associated with some special clones of TCR V? subfamily T cells, which subsided immediately after ACR. (4) The expression as polyclonality after ACR and DGF may indicate that the immune function partially was inclined to normalization even though immunosuppressed.