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1.
Skewed T-cell differentiation in patients with indolent non-Hodgkin lymphoma reversed by ex vivo T-cell culture with gammac cytokines 总被引:1,自引:0,他引:1
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Anichini A Mortarini R Romagnoli L Baldassari P Cabras A Carlo-Stella C Gianni AM Di Nicola M 《Blood》2006,107(2):602-609
The unfavorable clinical evolution in indolent non-Hodgkin lymphomas suggests defective control of neoplastic growth by the immune system. To address this issue, we evaluated phenotype, function, and maturation profile of CD4(+) and CD8(+) T cells from peripheral-blood, lymph nodes, or bone marrow of patients with B-cell non-Hodgkin lymphoma (NHL) at diagnosis. T cells from these patients frequently showed an activated but apoptosis-prone phenotype with low frequency of tumor-reactive T cells showing a TH2/Tc2 functional profile in the response to autologous tumor. In peripheral blood or in lymph nodes and bone marrow, and, in comparison to healthy donors, patients' T cells showed a skewed differentiation toward Tnaive and Tcentral memory stages, with low expression of granzyme B and perforin. T-cell culture with autologous tumor in the presence of IL-2, IL-15, and autologous bone marrow-derived cells led to massive T-cell expansion and to differentiation of cytotoxic factor(+) CD8(+) T cells releasing IFN-gamma and killing autologous B-cell tumor in an HLA-class I-restricted fashion. These results suggest impaired T-cell differentiation to effector stage in patients with B-cell NHL, but indicate that T-cell responsiveness to gammac cytokines is retained, thus allowing to promote generation of antitumor T cells for immune intervention. 相似文献
2.
Impaired T-cell regulation of B-cell growth in Helicobacter pylori--related gastric low-grade MALT lymphoma. 总被引:6,自引:0,他引:6
M M D'Elios A Amedei M Manghetti F Costa C T Baldari A S Quazi J L Telford S Romagnani G Del Prete 《Gastroenterology》1999,117(5):1105-1112
BACKGROUND & AIMS: Neoplastic B cells of the Helicobacter pylori-related low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma are responsive to T helper cells and sensitive to withdrawal of H. pylori-induced T-cell help. METHODS: The clonal progeny of T cells from the gastric mucosa of 5 patients with MALT lymphoma was compared with that of T-cell clones obtained from 5 H. pylori-infected patients with chronic gastritis. RESULTS: T-cell clones were assessed for specificity to H. pylori, cytokine profile, help for B-cell proliferation, and perforin- or Fas-mediated cytotoxic regulation of B-cell growth. Twenty-eight of 165 CD4(+) gastric clones from MALT lymphoma and 33 of 178 CD4(+) clones from chronic gastritis recognized H. pylori antigens. Cytokine production was similar in the 2 series of clones. All MALT lymphoma-derived clones dose-dependently increased their B-cell help, whereas clones from chronic gastritis lost helper activity at T-to-B-cell ratios greater than 1 because of concomitant cytolytic killing of B cells. T-cell clones from MALT lymphoma had both reduced perforin-mediated cytotoxicity and poor ability to induce Fas-mediated apoptosis. These defects were limited to gastric T cells. CONCLUSIONS: H. pylori-induced T cell-dependent B-cell activation and deficient cytotoxic control of B-cell growth may link H. pylori infection, local T-cell response, and genesis of low-grade gastric MALT lymphoma. 相似文献
3.
CD70+ non-Hodgkin lymphoma B cells induce Foxp3 expression and regulatory function in intratumoral CD4+CD25 T cells
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Foxp3 expression was initially thought to be restricted to the CD4(+)CD25(+) regulatory T-cell population. However, recent studies suggest that forkhead box P3 (Foxp3) is expressed in CD4(+)CD25(-) T cells in aged mice. In the present study in B-cell non-Hodgkin lymphoma (NHL), we found that a subset of intratumoral but not peripheral blood CD4(+)CD25(-) T cells, comprising about 15% of intratumoral CD4(+) T cells, express Foxp3 and are capable of suppressing the proliferation of autologous infiltrating CD8(+) T cells. In vitro activation with OKT3/anti-CD28 antibody (Ab) or dendritic cells (DCs) induced Foxp3 expression in a subset of these CD4(+)CD25(-)Foxp3(-) T cells. We found that the presence of lymphoma B cells during activation augmented activation-induced Foxp3 expression in CD4(+)CD25(-) T cells. We also found that CD70(+) lymphoma B cells significantly contributed to the activation-induced Foxp3 expression in intratumoral CD4(+)CD25(-) T cells. Furthermore, the blockade of CD27-CD70 interaction by anti-CD70 Ab abrogated lymphoma B-cell-mediated induction of Foxp3 expression in intratumoral CD4(+)CD25(-) T cells. Taken together, these studies reveal a novel role for NHL B cells in the development of intratumoral regulatory T cells. 相似文献
4.
Pooja Ramesh Henry Y. L. Hui Leon M. Brownrigg Kathy A. Fuller Wendy N. Erber 《International journal of laboratory hematology》2023,45(4):425-435
Chimeric antigen receptor (CAR) T-cell therapy is a novel adoptive T-cell immunotherapy for haematological malignancies. First introduced into clinical practice in 2017, CAR T-cell therapy is now finding its place in the management of lymphoid malignancies, primarily of B-cell lineage, including lymphoblastic leukaemia, non-Hodgkin lymphoma and plasma cell myeloma, with remarkable therapeutic outcomes. CAR T-cells are a customised therapeutic product for each patient. Manufacture commences with collection of autologous T-cells, which are then genetically engineered ex vivo to express transmembrane CARs. These chimeric proteins consist of an antibody-like extracellular antigen-binding domain, to recognise specific antigens on the surface of tumour cells (e.g. CD19), linked to the intracellular co-stimulatory signalling domains of a T-cell receptor (e.g. CD137). The latter is required for in vivo CAR T-cell proliferation, survival, and durable efficacy. Following reinfusion, CAR T-cells harness the cytotoxic capacity of a patient's immune system. They overcome major mechanisms of tumour immuno-evasion and have potential to generate robust cytotoxic anti-tumour responses. This review discusses the background to CAR T-cell therapies, including their molecular design, mechanisms of action, methods of production, clinical applications and established and emerging technologies for CAR T-cell evaluation. It highlights the need for standardisation, quality control and monitoring of CAR T-cell therapies, to ensure their safety and efficacy in clinical management. 相似文献
5.
Hatakeyama N Tamura Y Sahara H Suzuki N Suzuki K Hori T Mizue N Torigoe T Tsutsumi H Sato N 《Experimental hematology》2006,34(2):197-207
OBJECTIVE: Several studies have demonstrated that dendritic cells (DCs) pulsed with tumor lysate or apoptotic tumor cells can elicit effective T-cell responses. This technique does not require the identification of the tumor antigen or HLA haplotype of the patient. We applied this approach to induce HLA class I- and class II-restricted T-cell responses directed against autologous acute lymphocytic leukemia (B-ALL) cell line NH-1. METHODS: Autologous T cells were stimulated by apoptotic tumor cell-loaded DCs generated from a patient with ALL. The stimulated and expanded T cells were isolated into CD8(+) T-cell line and CD4(+) T-cell line, and each of them was examined as to their functions. RESULTS: Both CD8(+) and CD4(+) T-cell lines demonstrated cytotoxicity against NH-1 in an major histocompatibility complex-dependent manner. Finally, we established two independent CD4(+) T-cell clones restricted to HLA-DR. The CD4(+) T-cell line responded strongly to autologous Epstein-Barr virus-transformed lymphoblastoid cell lines (EBV-LCL) but not to autologous normal cells. Furthermore, the T-cell clones also responded to allogeneic EBV-LCLs and B-ALL cell lines in the context of the HLA-DRB1( *)04051 molecule. Interestingly, 293T and COS-7 cells, which had been transfected with the HLA-DRB1( *)04051, were also recognized by T-cell clones. CONCLUSION: These findings indicate that B-ALL has shared and strong immunogenic epitopes expressed on HLA class II molecules, the expression of which is limited to immortalized cells. These data suggest that vaccinations using DCs loaded with apoptotic tumor cells might be a potent strategy in the treatment of B-ALL. 相似文献
6.
Chaperot L Manches O Mi JQ Moine A Jacob MC Gressin R Molens JP Sotto JJ Leroux D Bensa JC Plumas J 《British journal of haematology》2002,119(2):425-431
We have previously reported that specific anti-tumour cytotoxic T cells (CTL) can be differentiated from tumour-infiltrating lymphocytes (TIL) in non-Hodgkin's lymphoma. We found that the combination of interleukin (IL)-1, IL-2 and IL-12 was very efficient for expansion of CD8+ T-cell receptor (TCR)alphabeta+ T cells and for development of their ability to specifically lyse tumour cells. In this study, we investigated whether anti-tumour T cells could be generated from the peripheral blood of patients using the culture protocol developed for TIL. Autologous T cells and tumour B cells from five patients were included in this study. It was found that polyclonal anti-tumour cytotoxic effector cells were generated when cultured in the presence of IL-1beta, IL-2 and IL-12. Interestingly, tumour cells were lysed by perforin/granzyme-mediated cytolysis and not by CD95-mediated apoptosis. By performing inhibition experiments, it was observed that both CD8+ and CD4+ T cells were responsible for the cytotoxic effect and that they were able to recognize malignant B cells by either a major histocompatibility complex (MHC)-restricted or MHC-non-restricted mechanism. Intriguingly, in addition to interferon-gamma and tumour necrosis factor-alpha, IL-10 was secreted continuously during culture. The source of patient T cells used for the generation of anti-tumour CTL should be based on the results obtained with peripheral blood lymphocytes and TIL. 相似文献
7.
Christopoulos P Pfeifer D Bartholomé K Follo M Timmer J Fisch P Veelken H 《Blood》2011,117(14):3836-3846
Epidemiologic data show that the immune system may control or promote the emergence and growth of neoplastic lymphomatous clones. Conversely, systemic lymphomas, especially myeloma and chronic lymphocytic leukemia (CLL), are associated with clinical immunodeficiency. This prospective controlled study demonstrates substantially reduced circulating T helper cells, predominantly naive CD4(+) cells, in patients with nonleukemic follicular lymphoma and extranodal marginal zone lymphoma, but not in monoclonal gammopathy and early CLL. These changes were correlated with a preactivated phenotype, hyperreactivity in vitro, pre-senescence, and a T helper 2 shift of peripheral T helper cells. No prominent alterations existed in the regulatory T-cell compartment. Gene expression profiling of in vitro-stimulated CD4(+) cells revealed an independent second alteration of T helper cell physiology, which was most pronounced in early CLL but also detectable in follicular lymphoma/extranodal marginal zone lymphoma. This pattern consisted of down-regulation of T-cell receptor signaling cascades and globally reduced cytokine secretion. Both types of T-cell dysfunction may contribute to significant immunodeficiency in nonleukemic indolent B-cell lymphomas as demonstrated by unresponsiveness to hepatitis B vaccination. The precise definition of systemic T-cell dysfunction serves as the basis to study its prognostic impact, its relationship to the established influence of the lymphoma microenvironment, and its therapeutic manipulation. 相似文献
8.
Weng J Rawal S Chu F Park HJ Sharma R Delgado DA Fayad L Fanale M Romaguera J Luong A Kwak LW Neelapu SS 《Blood》2012,120(8):1613-1623
Immunotherapy with therapeutic idiotype vaccines offers promise for treatment of B-cell malignancies. However, identification of novel immunogenic lymphoma-associated antigens that are universally expressed is necessary to overcome the barriers of patient-specific idiotype vaccines. Here, we determined whether T-cell leukemia/lymphoma 1 (TCL1) oncoprotein encoded by the TCL1 gene could be a target for immunotherapy of B-cell malignancies. We show that TCL1 mRNA and protein are selectively expressed in normal B cells but markedly hyperexpressed in multiple human B-cell lymphomas, including follicular lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma, and splenic marginal zone B-cell lymphoma. We demonstrated that TCL1-specific CD8(+) T cells can be generated from HLA-A*0201 (HLA-A2)(+) normal donors and identified TCL1(71-78) (LLPIMWQL) as the minimal epitope recognized by these T cells. More importantly, TCL1(71-78) peptide-specific T cells were present in the peripheral blood and tumor-infiltrating lymphocytes of lymphoma patients, could be expanded in vitro, and lysed autologous tumor cells but not normal B cells in an HLA-A2-restricted manner. Our results suggest that TCL1 is naturally processed and presented on the surface of lymphoma cells for recognition by cytotoxic T cells and can serve as a novel target for development of immunotherapeutic strategies against common B-cell lymphomas. 相似文献
9.
Identical T-cell expansions in the colon mucosa and the synovium of a patient with enterogenic spondyloarthropathy 总被引:4,自引:0,他引:4
May E Märker-Hermann E Wittig BM Zeitz M Meyer zum Büschenfelde KH Duchmann R 《Gastroenterology》2000,119(6):1745-1755
Intestinal T lymphocytes activated by antigen are suspected to play a key role in enterogenic spondyloarthropathies (SpA). Therefore, we aimed to identify and functionally characterize T-cell clones that are coexpanded in the intestinal mucosa and the synovium. Colon, peripheral blood, and synovium of a patient with enterogenic SpA were screened for clonal T-cell expansions by TCRB-CDR3 length analysis and sequencing. T-cell clones expanded in vivo were isolated from archived synovial cells by targeted T-cell cloning and characterized for phenotype, cytokine production, and antigen specificity. The synovial TCRBV18(+) T-cell repertoire of the patient was dominated by 2 CD8(+) T-cell clones using related CDR3. Both clones were expanded throughout the colon and were present in the peripheral blood. Upon in vitro stimulation with PDB/ionomycin, they showed predominantly interferon gamma and interleukin (IL)-4 but also tumor necrosis factor alpha and IL-10 production and did not specifically lyse autologous T-cell blasts, B-cell lines, or other autologous or allogeneic target or CD1d-transfected cells. These findings strongly suggest that T lymphocytes activated by antigen in the intestinal mucosa contribute to joint inflammation in enterogenic SpA by recognition of antigens specific for the inflamed synovium. 相似文献
10.
Enhanced antilymphoma efficacy of CD19-redirected influenza MP1-specific CTLs by cotransfer of T cells modified to present influenza MP1 总被引:1,自引:1,他引:1
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Cooper LJ Al-Kadhimi Z Serrano LM Pfeiffer T Olivares S Castro A Chang WC Gonzalez S Smith D Forman SJ Jensen MC 《Blood》2005,105(4):1622-1631
To enhance the in vivo antitumor activity of adoptively transferred, CD19-specific chimeric antigen receptor (CAR)-redirected cytotoxic T lymphocytes (CTLs), we studied the effect of restimulating CAR(+) CTLs through their endogenous virus-specific T-cell antigen receptor (TcR) by the cotransfer of engineered T-cell antigen-presenting cells (T-APCs). Using influenza A matrix protein 1 (MP1) as a model antigen, we show that ex vivo-expanded CD4(+) and CD8(+) T-APCs expressing a hygromycin phosphotransferase-MP1 fusion protein (HyMP1) process and present MP1 to autologous human leukocyte antigen (HLA)-restricted, MP1-specific CD4(+) and CD8(+) CTL precursors. The MP1-specific CTLs are amenable to subsequent genetic modification to express a CD19-specific CAR, designated CD19R, and acquire HLA-unrestricted reactivity toward CD19(+) leukemia and lymphoma tumor targets while maintaining HLA-restricted MP1 specificity. The restimulation of MP1xCD19 dual-specific CTLs in vivo by the adoptive transfer of irradiated HyMP1(+) T-APCs resulted in the enhanced antilymphoma potency of bispecific effector cells, as measured by elimination of the biophotonic signal of established firefly luciferase-expressing Burkitt lymphoma xenografts in nonobese diabetic/severe combined immunodeficiency (NOD/scid) animals compared with control groups restimulated by Hy(+)MP1(neg) T-APCs. Engineered T-APCs are a novel and versatile antigen-delivery system for generating antigen-specific T cells in vitro and enhancing the in vivo effector functioning of CAR-redirected antitumor effector cells. 相似文献
11.
Intratumoral CD4+CD25+ regulatory T-cell-mediated suppression of infiltrating CD4+ T cells in B-cell non-Hodgkin lymphoma 总被引:16,自引:0,他引:16
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Most non-Hodgkin lymphomas (NHLs) are of B-cell origin, but the tumor tissue can be variably infiltrated with T cells. In the present study, we have identified a subset of CD4(+)CD25(+) T cells with high levels of CTLA-4 and Foxp3 (intratumoral T(reg) cells) that are overrepresented in biopsy specimens of B-cell NHL (median of 17% in lymphoma biopsies, 12% in inflammatory tonsil, and 6% in tumor-free lymph nodes; P = .001). We found that these CD4(+)CD25(+) T cells suppressed the proliferation and cytokine (IFN-gamma and IL-4) production of infiltrating CD4(+)CD25(-) T cells in response to PHA stimulation. PD-1 was found to be constitutively and exclusively expressed on a subset of infiltrating CD4(+)CD25(-) T cells, and B7-H1 could be induced on intratumoral CD4(+)CD25(+) T cells in B-cell NHL. Anti-B7-H1 antibody or PD-1 fusion protein partly restored the proliferation of infiltrating CD4(+)CD25(-) T cells when cocultured with intratumoral T(reg) cells. Finally, we found that CCL22 secreted by lymphoma B cells is involved in the chemotaxis and migration of intratumoral T(reg) cells that express CCR4, but not CCR8. Taken together, our results suggest that T(reg) cells are highly represented in the area of B-cell NHL and that malignant B cells are involved in the recruitment of these cells into the area of lymphoma. 相似文献
12.
Greeve J Philipsen A Krause K Klapper W Heidorn K Castle BE Janda J Marcu KB Parwaresch R 《Blood》2003,101(9):3574-3580
Activation-induced cytidine deaminase (AID) induces somatic hypermutation (SHM), class switch recombination (CSR), and immunoglobulin gene conversion in B-lymphocytes. Here we report for the first time the expression of AID in healthy human B-lymphocytes and in B-cell non-Hodgkin lymphomas (B-NHL). AID mRNA expression in humans is restricted to the CD19(+)CD38(+)IgD(-) germinal center cells, namely the CD19(+)CD38(+)CD44(-) centroblasts. After in vitro stimulation of naive human B cells by CD40-L and IL-4, AID mRNA is strongly induced for only 48 hours. In a survey of human B-NHL AID was found to be constitutively expressed in follicular lymphoma and in diffuse large B-cell lymphoma but to be absent in B-precursor lymphoblastic leukemia, in mantle cell lymphoma, and in plasma cell myeloma. In B-cell chronic lymphatic leukemia, in immunocytoma, and in extranodal marginal zone B-cell lymphoma of MALT, AID mRNA was expressed only in some samples. In follicular lymphoma and diffuse large B-cell lymphoma, the expression of AID mRNA was coincident with the presence of SHM in the variable region exons of the immunoglobulin heavy-chain gene. In human B-NHL, the AID mRNA is spliced into 4 different variants but does not contain point mutations. Thus AID, which is highly regulated during healthy B-cell development, is constitutively expressed in human germinal center B-NHL and in subsets of nongerminal center B-NHL. This constitutive expression of AID may promote illegitimate DNA recombinations and somatic mutations in B-NHL. 相似文献
13.
Antigen-specific CD8(+) cytotoxic T cells often demonstrate extreme conservation of T-cell receptor (TCR) usage between different individuals, but similar characteristics have not been documented for CD4(+) T cells. CD4(+) T cells predominantly have a helper immune role, but a cytotoxic CD4(+) T-cell subset has been characterized, and we have studied the cytotoxic CD4(+) T-cell response to a peptide from human cytomegalovirus glycoprotein B presented through HLA-DRB*0701. We show that this peptide elicits a cytotoxic CD4(+) T-cell response that averages 3.6% of the total CD4(+) T-cell repertoire of cytomegalovirus-seropositive donors. Moreover, CD4(+) cytotoxic T-cell clones isolated from different individuals exhibit extensive conservation of TCR usage, which indicates strong T-cell clonal selection for peptide recognition. Remarkably, this TCR sequence was recently reported in more than 50% of cases of CD4(+) T-cell large granular lymphocytosis. Immunodominance of cytotoxic CD4(+) T cells thus parallels that of CD8(+) subsets and suggests that cytotoxic effector function is critical to the development of T-cell clonal selection, possibly from immune competition secondary to lysis of antigen-presenting cells. In addition, these TCR sequences are highly homologous to those observed in HLA-DR7(+) patients with CD4(+) T-cell large granular lymphocytosis and implicate cytomegalovirus as a likely antigenic stimulus for this disorder. 相似文献
14.
15.
TCR gamma delta bearing lymphocyte clones with lymphokine-activated killer activity against autologous leukemic cells 总被引:1,自引:0,他引:1
Activated T lymphocytes with the T-cell receptor (TCR) gamma delta (CD3+ and TCR delta 1+) exhibit strong cytotoxic activity against the standard natural killer (NK) and lymphokine-activated killer (LAK) sensitive target cells. In order to test the cytotoxic activity of gamma delta T lymphocytes against autologous leukemic cells, 84 clones of gamma delta T lymphocytes were obtained from the peripheral blood of three acute lymphoblastic leukemia (ALL) patients. Forty-four of these T-cell clones were active against an LAK-sensitive cell line and the other 40 were active against K562, an NK target cell line. In each of the three patients, cytotoxic clones against autologous leukemic cells were obtained. Among the 84 clones, ten were able to kill autologous tumor cells, including eight that lyse the LAK-sensitive target and two with NK activity. The clones were highly cytotoxic, stable, and easily expanded in large quantity. 相似文献
16.
de Rijke B Fredrix H Zoetbrood A Scherpen F Witteveen H de Witte T van de Wiel-Van Kemenade E Dolstra H 《Blood》2003,102(8):2885-2891
Tumor relapses in patients with precursor B-cell acute lymphoblastic leukemia (BALL) occur frequently after primary treatment. Therefore, development of additional treatment modalities to eliminate residual tumor cells is needed. Active immunotherapy using dendritic cells (DCs) loaded with tumor-associated antigens is a promising approach to induce specific T-cell immunity in patients with cancer. In previous studies, we described HB-1 as a B-cell lineage-specific antigen that is recognized by donor-derived cytotoxic T lymphocytes (CTLs) on allogeneic B-ALL tumor cells. Here, we investigated the potential use of the HB-1 antigen as an autologous T-cell vaccine target. To determine whether HB-1-specific CTL precursors are present within the T-cell repertoire, we induced expansion of CD8+ T cells using mature monocyte-derived DCs pulsed with the previously identified HB-1.B44 antigenic peptide. In 6 of 8 donors, CD8+ CTL lines have been generated that exert cytotoxicity against target cells exogenously pulsed with peptide or endogenously expressing the HB-1 antigen. From one of these HB-1-specific T-cell lines, we isolated a CD8+ CTL that produces interferon-gamma on stimulation with B-ALL tumor cells. Interestingly, the HB-1 antigen also induced CD4+ T-helper responses on activation with protein-loaded mature monocyte-derived DCs. We identified 2 novel epitopes recognized in the context of HLA-DR4 and HLA-DR11 with the use of HB-1-specific CD4+ T-cell clones generated from different donors. These present data, that HB-1 induces both helper and cytotoxic T-cell responses, indicate that the HB-1 antigen is a candidate target to induce T-cell-mediated antitumor immunity in patients. 相似文献
17.
Di Nicola M Zappasodi R Carlo-Stella C Mortarini R Pupa SM Magni M Devizzi L Matteucci P Baldassari P Ravagnani F Cabras A Anichini A Gianni AM 《Blood》2009,113(1):18-27
Eighteen relapsed patients with measurable indolent non-Hodgkin lymphoma (NHL) were vaccinated with dendritic cells (DCs) loaded with killed autologous tumor cells. Six patients had objective clinical responses including 3 continuous complete responses (CRs) and 3 partial responses (PRs), with a median follow up of 50.5 months. Eight patients had stable disease, whereas 4 had progressive disease. Clinical responses were significantly associated with a reduction in CD4(+)CD25(+)FOXP3(+) regulatory T cells, an increase in CD3(-)CD56(dim)CD16(+) natural killer (NK) cells, and maturation of lymphocytes to the effector memory stage in either postvaccination peripheral blood or tumor specimen samples. In partial responding patients, vaccination significantly boosted the IFN-gamma-producing T-cell response to autologous tumor challenge. In one HLA-A*0201(+) patient who achieved CR, IL-4 release by circulating T cells in response to tumor-specific IgH-encoded peptides was also documented. Immunohistochemical analysis of tumor biopsies using biotin-conjugated autologous serum samples revealed a tumor-restricted humoral response only in the postvaccination serum from responding patients. Collectively these results demonstrate that vaccination with tumor-loaded DCs may induce both T- and B-cell responses and produces clinical benefits in indolent NHL patients with measurable disease. This study is registered with the Istituto Superiore di Sanità: http://www.iss.it with protocol number 7578-PRE 21-801. 相似文献
18.
Charles ED Green RM Marukian S Talal AH Lake-Bakaar GV Jacobson IM Rice CM Dustin LB 《Blood》2008,111(3):1344-1356
Hepatitis C virus (HCV) is associated with B-cell lymphoproliferative disorders such as mixed cryoglobulinemia (MC) and B-cell non-Hodgkin lymphoma (B-NHL). The pathogenesis of these disorders remains unclear, and it has been proposed that HCV drives the pro-liferation of B cells. Here we demonstrate that certain HCV(+)MC(+) subjects have clonal expansions of immunoglobulin M (IgM)(+)kappa(+)IgD(low/-)CD21(low)CD27(+) B cells. Using RT-PCR to amplify Ig from these singly sorted cells, we show that these predominantly rheumatoid factor-encoding V(H)1-69/J(H)4 and V(kappa)3-20 gene segment-restricted cells have low to moderate levels of somatic hypermutations. Ig sequence analysis suggests that antigen selection drives the generation of mutated clones. These findings lend further support to the notion that specific antigenic stimulation leads to B-cell proliferation in HCV MC and that chronic B-cell stimulation may set the stage for malignant transformation and the development of B-NHL. The finding that these hypermutated, marginal zone-like IgM(+)CD27(+) B cells are clonally expanded in certain subjects with MC offers insight into mechanisms of HCV-associated MC and B-cell malignancy. This study was registered at www.clinicaltrials.gov as NCT00219999. 相似文献
19.
Autoreactive CD4(+) T cells to beta2-glycoprotein I (beta2GPI) that promote antiphospholipid antibody production were recently identified in patients with antiphospholipid syndrome (APS). To further examine antigen recognition profiles and T-cell helper activity in beta2GPI-reactive T cells, 14 CD4(+) T-cell clones specific to beta2GPI were generated from 3 patients with APS by repeated stimulation of peripheral blood T cells with recombinant beta2GPI. At least 4 distinct T-cell epitopes were identified, but the majority of the beta2GPI-specific T-cell clones responded to a peptide encompassing amino acid residues 276 to 290 of beta2GPI (KVSFFCKNKEKKCSY; single-letter amino acid codes) that contains the major phospholipid-binding site in the context of the DRB4*0103 allele. Ten of 12 beta2GPI-specific T-cell clones were able to stimulate autologous peripheral blood B cells to promote anti-beta2GPI antibody production in the presence of recombinant beta2GPI. T-cell helper activity was exclusively found in T-cell clones capable of producing interleukin 6 (IL-6). In vitro anti-beta2GPI antibody production induced by T-cell clones was inhibited by anti-IL-6 or anti-CD40 ligand monoclonal antibody. In addition, exogenous IL-6 augmented anti-beta2GPI antibody production in cultures of the T-cell clone lacking IL-6 expression. These results indicate that beta2GPI-specific CD4(+) T cells in patients with APS preferentially recognize the antigenic peptide containing the major phospholipid-binding site and have the capacity to stimulate B cells to produce anti-beta2GPI antibodies through IL-6 expression and CD40-CD40 ligand engagement. These findings are potentially useful for clarifying the pathogenesis of APS and for developing therapeutic strategies that suppress pathogenic antiphospholipid antibody production in these patients. 相似文献
20.
Allogeneic hematopoietic cell transplantation can be curative in patients with leukemia and lymphoma. However, progressive growth of malignant cells, relapse after transplantation, and graft-versus-host disease (GVHD) remain important problems. The goal of the current murine study was to select a freshly isolated donor T-cell subset for infusion that separates antilymphoma activity from GVHD, and to determine whether the selected subset could effectively prevent or treat progressive growth of a naturally occurring B-cell lymphoma (BCL(1)) without GVHD after recipients were given T cell-depleted bone marrow transplantations from major histocompatibility complex-mismatched donors. Lethal GVHD was observed when total T cells, naive CD4(+) T cells, or naive CD8(+) T cells were used. Memory CD4(+)CD44(hi) and CD8(+)CD44(hi) T cells containing both central and effector memory cells did not induce lethal GVHD, but only memory CD8(+) T cells had potent antilymphoma activity and promoted complete chimerism. Infusion of CD8(+) memory T cells after transplantation was able to eradicate the BCL(1) lymphoma even after progressive growth without inducing severe GVHD. In conclusion, the memory CD8(+) T-cell subset separated graft antilymphoma activity from GVHD more effectively than naive T cells, memory CD4(+) T cells, or memory total T cells. 相似文献