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Antonio Curti

Publications and source records attributed to Antonio Curti.

18 recordsLinked to original sources
PubMed2007

Modulation of tryptophan catabolism by human leukemic cells results in the conversion of CD25- into CD25+ T regulatory cells.

Indoleamine 2,3-dioxygenase (IDO) is a novel immunosuppressive agent expressed in some subsets of normal and neoplastic cells, including acute myeloid leukemia (AML) cells. Here, we show that IDO expression correlates with increased circulating CD4+CD25+FOXP3+ T cells in patients with AML at diagnosis. In vitro, IDO+ AML cells increase the number of CD4+ CD25+ T cells expressing surface CTLA-4 and FOXP3 mRNA, and this effect is completely abrogated by the IDO inhibitor, 1-methyl tryptophan (1-MT). Purified CD4+CD25+ T cells obtained from coculture with IDO+ AML cells act as T regulatory (T(reg)) cells because they do not proliferate, do not produce interleukin (IL)-2, and inhibit naive T-cell proliferation. Coculture with IDO+AML cells results in the conversion of CD4+CD25- into CD4+CD25+ T cells, which is completely abrogated by 1-MT. Moreover, in mice, intrasplenic injection of IDO+ leukemia/ lymphoma A20 cells induces the expansion of bona fide T(reg) cells by conversion of CD4+CD25- T cells; this effect is counteracted by 1-MT treatment. These data indicate that AML cells induce T-cell tolerance by directly converting CD4+CD25- T cells into CD4+CD25+ T(reg) cells through an IDO-dependent mechanism.

Adult↗
PubMed2006

The P2X7 receptor: a key player in IL-1 processing and release.

Human IL-1 family proteins are key mediators of the host response to infections, injury, and immunologic challenges. The mechanism by which IL-1 activates proinflammatory responses in target cells, and the plasma membrane receptors involved, is fairly well known. This has led to the development of innovative drugs that block IL-1 downstream to its synthesis and secretion. On the contrary, the mechanism of IL-1 and other IL-1 family members (e.g., IL-18) maturation and release is incompletely understood. Accruing evidence points to a plasma membrane receptor for extracellular ATP, the P2X(7) receptor, as a key player in both processes. A deeper understanding of the mechanism by which the P2X(7) receptor triggers IL-1 maturation and exteriorization may suggest novel avenues for the treatment of inflammatory diseases and provide a deeper insight in the fundamental mechanism of protease activation and cellular export of proteins lacking a leader sequence.

Adenosine Triphosphate↗
PubMed2006

Hepatocyte growth factor favors monocyte differentiation into regulatory interleukin (IL)-10++IL-12low/neg accessory cells with dendritic-cell features.

Several hematopoietic growth factors, including interleukin-10 (IL-10) and transforming growth factor-beta1 (TGF-beta1), promote the differentiation of tolerogenic dendritic cells (DCs). Hepatocyte growth factor (HGF) is a pleiotropic cytokine whose effects on human DC differentiation and function have not been investigated. Monocytes cultured with HGF (HGFMo) differentiated into accessory cells with DC-like morphology, released low amounts of IL-12p70 and up-regulated IL-10 both at the mRNA and at the protein level. Upon activation with HGFMo, allogeneic CD4+CD25- T cells expressed the T regulatory (Treg)-associated transcription factor FoxP3, proliferated poorly, and released high levels of IL-10. Interestingly, blockade of surface immunoglobulin-like transcript 3 (ILT3) on HGFMo or neutralization of secreted IL-10 translated into partial restoration of T-cell proliferation. Secondary stimulation of HGFMo-primed CD4+ T cells with immunogenic DCs differentiated with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4 from monocytes of the same donor resulted in measurable T-cell proliferation. HGFMo-primed CD4+ T cells significantly inhibited the proliferation of naive CD4+CD25- T cells in a cell-contact-dependent manner. Finally, DNA microarray analysis revealed a unique gene-expression profile of HGF-activated monocytes. Collectively, our findings point to a novel role for HGF in the regulation of monocyte/DC functions that might be exploited therapeutically.

CD4-Positive T-Lymphocytes↗
PubMed2006

Dendritic cells of immune thrombocytopenic purpura (ITP) show increased capacity to present apoptotic platelets to T lymphocytes.

OBJECTIVE: Altered self-antigen processing/presentation of apoptotic cells by DCs and/or modifications of autoantigens may lead to the development of autoantibodies. Increasing evidence indicates that platelets may undergo apoptosis. Therefore, in the present study we investigated whether platelet apoptosis and/or dendritic cells (DCs) may play a role in the stimulation of the immuno-mediated anti-platelet response in chronic immune thrombocytopenic purpura (ITP). METHODS AND RESULTS: Twenty-nine patients with active ITP and 29 healthy adult volunteers were enrolled into the study. Freshly washed platelets and platelets aged in a plasma-free buffer for 72 hours at 37 degrees C were assessed by flow cytometry for phosphatidylserine exposure using annexin V-FITC, caspase activation, and platelet activation markers. CD14-derived DCs were characterized by immunophenotyping, cytokine production, and ability to present fresh and aged platelets to T lymphocytes. We demonstrated that platelets from ITP patients, either fresh or in vitro aged, show increased apoptosis (with low levels of activation) in comparison to their normal counterparts. We also found that immature DCs readily ingest apoptotic platelets. Furthermore, in ITP patients DCs, prepulsed with autologous/allogeneic fresh and aged platelets, are highly efficient in stimulating autologous T-cell proliferation as compared to DCs derived from healthy donors. This finding may be related to the upregulated expression of CD86 in DCs from ITP patients and not to higher phagocytic activity. CONCLUSION: These results suggest that DC dysfunction, together with increased propensity of platelets to undergo apoptosis, may play a role in the stimulation of the immune system in ITP.

Adult↗
PubMed2005

Targeting CD99 in association with doxorubicin: an effective combined treatment for Ewing's sarcoma.

CD99 is a 32kDa surface glycoprotein that is involved in the migration of leukocytes, cell-cell adhesion and apoptosis of T cells and Ewing's sarcoma (ES) cells, two cell types with a high level of CD99 expression. Engagement of the molecule induces a rapid death signal that appears to be related to the level of expression of this antigen. The rapid apoptosis induced by agonistic anti-CD99 monoclonal antibodies is of clinical interest in ES, a tumour for which no new drugs have been described as clearly effective in the last 10 years. In this study, we show that an anti-CD99 monoclonal antibody can be used to advantage in association with doxorubicin. Striking effectiveness was observed against local tumours and metastases. No remarkably toxic effects of anti-CD99 monoclonal antibody were found in bone marrow against blood precursors. These results provide the necessary rationale and support for a novel modality of therapeutic intervention, which may have application in the care of patients with ES.

12E7 Antigen↗
PubMed2005

Nucleofection is an efficient nonviral transfection technique for human bone marrow-derived mesenchymal stem cells.

Viral-based techniques are the most efficient systems to deliver DNA into stem cells because they show high gene transduction and transgene expression in many cellular models. However, the use of viral vectors has several disadvantages mainly involving safety risks. Conversely, nonviral methods are rather inefficient for most primary cells. The Nucleofector technology, a new nonviral electroporation-based gene transfer technique, has proved to be an efficient tool for transfecting hard-to-transfect cell lines and primary cells. However, little is known about the capacity of this technique to transfect adult stem cells. In this study, we applied the Nucleofector technology to engineer human bone marrow- derived mesenchymal stem cells (hMSCs). Using a green fluorescent protein reporter vector, we demonstrated a high transgene expression level using U-23 and C-17 pulsing programs: 73.7%+/-2.9% and 42.5%+/-3.4%, respectively. Cell recoveries and viabilities were 38.7%+/-2.9%, 44.5%+/-3.9% and 91.4%+/-1.3%, 94.31%+/-0.9% for U-23 and C-17, respectively. Overall, the transfection efficiencies were 27.4%+/-2.9% (U-23) and 16.6%+/-1.4% (C-17) compared with 3.6%+/-2.4% and 5.4%+/-3.4% of other nonviral transfection systems, such as FUGENE6 and DOTAP, respectively (p<.005 for all comparisons). Nucleofection did not affect the immunophenotype of hM-SCs, their normal differentiation potential, or ability to inhibit T-cell alloreactivity. Moreover, the interleukin-12 gene could be successfully transfected into hMSCs, and the immunomodulatory cytokine was produced in great amount for at least 3 weeks without impairment of its biological activity. In conclusion, nucleofection is an efficient nonviral transfection technique for hMSCs, which then may be used as cellular vehicles for the delivery of biological agents.

Antigens, CD↗
PubMed2005

Interleukin-12 production by leukemia-derived dendritic cells counteracts the inhibitory effect of leukemic microenvironment on T cells.

OBJECTIVE: Acute myeloid leukemia (AML) cells are poorly immunogenic and inhibit T-cell function. AML-derived dendritic cells (AML-DCs) have better antigen-presentation capacity than undifferentiated leukemic blasts, but may not be fully competent to stimulate T cells previously inhibited by leukemic cells. MATERIALS AND METHODS: AML-DCs were generated from AML cells and used to stimulate proliferation and cytokine production by T cells previously inhibited by AML cells. AML-DCs were also transfected with interleukin (IL)-12 gene by the nonviral method, nucleofection. RESULTS: Mature AML-DCs stimulated naive and, to a lesser extent, leukemic cell (LC)-cultured T cells more efficiently than their immature counterparts and their activity was mediated by IL-12. AML-DCs generated from CD14(-) AML samples (which represent 80% of total AML patients) were defective in IL-12 production and T-cell activation. Addition of exogenous IL-12 to LC-cultured T cells stimulated by CD14(-)-derived AML-DCs restored optimal interferon-gamma (IFN-gamma) production and Th1 skewing. IL-12 gene-nucleofected AML-DCs derived from CD14(-) cells produced significant amounts of IL-12, maintained leukemia-specific karyotype, DC-like phenotype, and function. When stimulated by IL-12-gene transduced CD14(-)-derived AML-DCs, LC-cultured T cells produced higher concentrations of IFN-gamma, thus maintaining a Th1 cytokine profile. CONCLUSION: IL-12 produced by AML-DCs plays a critical role in counteracting the inhibitory activity of LCs on T-cell function. IL-12 gene can be successfully expressed into AML-DCs defective in endogenous IL-12 production by using a novel nonviral method that does not modify their phenotypical, cytogenetic, and functional features. Genetically modified AML-DCs restore a near normal T-cell function.

Adult↗
PubMed2005

Phase II study of a single pegfilgrastim injection as an adjunct to chemotherapy to mobilize stem cells into the peripheral blood of pretreated lymphoma patients.

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the efficacy of pegfilgrastim, in combination with salvage chemotherapy, in mobilizing CD34(+) stem cells into the peripheral blood of pretreated lymphoma patients. DESIGN AND METHODS: This was an open-label phase II study including 25 pretreated patients (Hodgkin's disease=4; aggressive non-Hodgkin's lymphoma=21). The primary end-point of the study was the successful mobilization of a target cell dose of 2x10(6) CD34(+) cells/kg in lymphoma patients receiving ifosfamide, epirubicin and etoposide (IEV) chemotherapy and a fixed dose (6 mg) of pegfilgrastim given as single subcutaneous injection. RESULTS: Following chemotherapy, all patients had grade 4 neutropenia that lasted a median of 1.5 days (1-3). Pegfilgrastim treatment was well tolerated and only 2/25 patients required pain-control medication. CD34+ cells were mobilized in all patients. The median (range) peak value of peripheral blood CD34+ cells after IEV chemotherapy and pegfilgrastim was 141x10(6)/L (12.8-386) and occurred almost invariably on day +14 (13-16). Twenty-three of the 25 patients underwent a single standard volume leukapheresis to collect a median of 8.7x10(6) CD34(+) cells/kg (1.78-17.3). Twenty four/25 patients (96%) reached the target cell dose of 2x10(6) CD34(+) cells/kg. High concentrations of circulating CD34+ cells (> 50x10(6)/L) were observed for several days after the achievement of the peak value. All the study patients were transplanted with their pegfilgrastim-mobilized CD34(+) cells and showed a rapid and sustained engraftment after high-dose chemotherapy. INTERPRETATION AND CONCLUSIONS: Our results show that pegfilgrastim as an adjunct to chemotherapy is a predictable and highly effective mobilization regimen in pretreated lymphoma patients.

Adult↗
PubMed2004

Granulocyte colony-stimulating factor promotes the generation of regulatory DC through induction of IL-10 and IFN-alpha.

We have recently demonstrated that G-CSF promotes the generation of human T regulatory (T(REG)) type 1 cells. In this study, we investigated whether the immunomodulatory effects of G-CSF might be mediated by DC. CD14(+) monocytes were cultured with serum collected after clinical administration of G-CSF (post-G), which contained high amounts of IL-10 and IFN-alpha. Similar to incompletely matured DC, monocytes nurtured with post-G serum acquired a DC-like morphology, expressed high levels of costimulatory molecules and HLA-DR, and exhibited diminished IL-12p70 release and poor allostimulatory capacity. Importantly, post-G DC-like cells were insensitive to maturation stimuli. As shown by neutralization studies, IFN-alpha and, even more pronounced, IL-10 contained in post-G serum inhibited IL-12p70 release by post-G DC-like cells. Furthermore, phenotypic and functional features of post-G DC-like cells were replicated by culturing post-G monocytes with exogenous IL-10 and IFN-alpha. Post-G DC-like cells promoted Ag-specific hyporesponsiveness in naive allogeneic CD4(+) T cells and orchestrated a T(REG) response that was dependent on secreted TGF-beta 1 and IL-10. Finally, neutralization of IL-10 and IFN-alpha contained in post-G serum translated into abrogation of the regulatory features of post-G DC-like cells. This novel mechanism of immune regulation effected by G-CSF might be therapeutically exploited for tolerance induction in autoimmune disorders.

Adult↗
PubMed2004

Generation of dendritic cells from positively selected CD14+ monocytes for anti-tumor immunotherapy.

Peripheral blood CD14+ monocytes from multiple myeloma (MM) patients can be induced to differentiate into fully functional, mature, CD83+ dendritic cells (DCs) which are highly efficient in priming autologous T lymphocytes in response to the patient-specific tumor idiotype (Id). We have recently scaled up our manufacturing protocol for application in a phase I-II clinical trial of anti-Id vaccination with DCs in MM patients. Elegible patients received a series of by-monthly immunizations consisting of three subcutaneous and two intravenous injections of Id-keyhole limpet hemocyanin (KLH)-pulsed DCs (5 x -, 10 x -, 50 x 10(6) cells and 10 x -, 50 x 10(6) cells, respectively). To generate DCs, monocytes were labeled with clinical grade anti-CD14 conjugates and positively selected by immunomagnetic separation. Cells were then cultured, according to Good Manufacturing Practice guidelines, in FCS-free medium in cell culture bags, and differentiated to DCs with GM-CSF plus IL-4 followed by TNF-alpha or, more recently, by a cocktail of IL-1beta, IL-6, TNF-alpha and prostaglandin-E2. Before maturation, Mo-DCs were pulsed with the autologous Id as whole protein or Id (VDJ)-derived HLA class I restricted peptides. Ten MM patients, who had been treated with two courses of high-dose chemotherapy with peripheral blood stem cell support, entered into the clinical study. CD14+ monocytes were enriched from 16.1+/-5.7% to 95.5+/-3.2% (recovery 67.9+/-15%, viability > 97%). After cell culture, phenotypic analysis showed that 89.6+/-6.6% of the cells were mature DCs. We obtained 2.89+/-1 x 10(8) DCs/leukapheresis which represented 24.5+/-9% of the initial number of CD14+ cells. Notably, the cytokine cocktail induced a significantly higher percentage and yield (31+/-10.9 of initial CD14+ cells) of DCs than TNF-alpha alone, secretion of larger amounts of IL-12, potent stimulatory activity on allogeneic and autologous T cells. Storage in liquid nitrogen did not modify the phenotype or functional characteristics of pre-loaded DCs. The recovery of thawed, viable DCs, was 78+/-10%. Thus, positive selection of CD14+ monocytes allows the generation of a uniform population of mature pre-loaded DCs which can be cryopreserved with no effects on phenotype and function and are suitable for clinical trials. Based on these results, a DCs-based phase II trial of anti-Id vaccination with VDJ-derived HLA class I-restricted peptides and KLH is underway for lymphoma patients.

Cancer Vaccines↗
PubMed2003

Autologous transplantation of granulocyte colony-stimulating factor-primed bone marrow is effective in supporting myeloablative chemotherapy in patients with hematologic malignancies and poor peripheral blood stem cell mobilization.

We assessed the hematopoietic recovery and transplantation-related mortality (TRM) of patients who had failed peripheral blood stem cell mobilization and subsequently received high-dose chemotherapy supported by granulocyte colony-stimulating factor (G-CSF)-primed bone marrow (BM). Studied were 86 heavily pretreated consecutive patients with acute leukemia (n = 21), refractory/relapsed non-Hodgkin lymphoma (n = 41) and Hodgkin disease (n = 17), and multiple myeloma (n = 7). There were 78 patients who showed insufficient mobilization of CD34+ cells (< 10 cells/microL), whereas 8 patients collected less than 1 x 106 CD34+ cells/kg. BM was primed in vivo for 3 days with 15 to 16 microg/kg of subcutaneous G-CSF. Median numbers of nucleated cells, colony-forming unit cells (CFU-Cs), and CD34+ cells per kilogram harvested were 3.5 x 10(8), 3.72 x 10(4), and 0.82 x 10(6), respectively. Following myeloablative chemotherapy, median times to achieve a granulocyte count higher than 0.5 x 10(9)/L and an unsupported platelet count higher than 20 and 50 x 10(9)/L were 13 (range, 8-24), 15 (range, 12-75), and 22 (range, 12-180) days, respectively, for lymphoma/myeloma patients and 23 (range, 13-53), 52 (range, 40-120), and 90 (range, 46-207) days, respectively, for leukemia patients. Median times to hospital discharge after transplantation were 17 (range, 12-40) and 27 (range, 14-39) days for lymphoma/myeloma and acute leukemia patients, respectively. TRM was 4.6%, whereas 15 patients died of disease. G-CSF-primed BM induces effective multilineage hematopoietic recovery after high-dose chemotherapy and can be safely used in patients with poor stem cell mobilization.

Adolescent↗
PubMed2003

Generation of dendritic cells from CD14+ monocytes positively selected by immunomagnetic adsorption for multiple myeloma patients enrolled in a clinical trial of anti-idiotype vaccination.

Circulating monocytes from multiple myeloma patients enrolled in a clinical study of anti-idiotype vaccination were labelled with clinical-grade anti-CD14 microbeads and positively selected with the CliniMACS instrument. Cells were then grown, according to good manufacturing practice guidelines, in fetal-calf-serum-free medium in cell culture bags and differentiated to dendritic cells (DC) with granulocyte-macrophage colony stimulating factor plus interleukin 4 (IL-4), followed by either tumour necrosis factor-alpha (TNF-alpha) or a cocktail of IL-1beta, IL-6, TNF-alpha and prostaglandin-E2. The CD14+ cell yield was increased from 17.6 +/- 6.5% to 93.8 +/- 6.3% (recovery 64.4 +/- 15.4%, viability > 97%). After cell culture, phenotypic analysis showed that 86.7 +/- 6.8% of the cells were DC: 2.27 +/- 0.9 x 108 DC/leukapheresis were obtained, which represented 20.7 +/- 4.6% of the initial number of CD14+ cells. Notably, the cytokine cocktail induced a significantly higher percentage and yield (28.6 +/- 3% of initial CD14+ cells) of DC than TNF-alpha alone, with secretion of larger amounts of IL-12, potent stimulatory activity on allogeneic T cells and efficient presentation of tumour idiotype to autologous T cells. Storage in liquid nitrogen did not modify the phenotype or functional characteristics of preloaded DC. The recovery of thawed, viable DC was 78 +/- 10%. Finally, interferon-alpha-2b was at least as efficient as IL-4 in inducing the differentiation of mature, functional DC from monocytes.

Antibodies, Anti-Idiotypic↗
PubMed2003

Functional and kinetic characterization of granulocyte colony-stimulating factor-primed CD34- human stem cells.

We assessed the functional properties and the kinetic status in vitro, and the engraftment potential in vivo of human haematopoietic stem cells according to the expression of CD34 antigen. Lin-CD34- and Lin-CD34+ cells were isolated from granulocyte colony-stimulating factor-primed peripheral blood (PB) cells of healthy donors. The CD34- cell fraction did not contain either clonogenic cells in semisolid culture or long-term culture initiating cells (LTC-IC). However, stroma-dependent liquid cultures and cytokines induced CD34 expression on a minority of stem cells, acquisition of clonogenic capacity and generation of LTC-IC. Significantly higher percentages of quiescent G0 cells and lower percentages of cycling G1 cells were found in Lin-CD34- cells when compared with Lin-CD34+ cells. Kinetic quiescence of Lin-CD34- cells was associated with a significantly higher expression of the negative regulators of the cell cycle, p27Kip1 and p21(cip1/waf1). Cytokine-mediated induction of CD34, in vitro, resulted in cycling of stem cells and downregulation of p27. There was a higher rate of human long-term engraftment in immunocompromised non-obese diabetic (NOD)/recombination activating gene 1null and NOD/severe combined immunodeficient-beta2microglobulin(null) mice injected with CD34+ cells. Thus, our study indicated that CD34 expression on human PB stem cells was associated with haematopoietic activity, cell-cycle recruitment and downregulation of p27Kip1 in vitro and higher engraftment capacity in vivo.

Animals↗
PubMed2002

Autologous and MHC class I-negative allogeneic tumor cells secreting IL-12 together cure disseminated A20 lymphoma.

Cytokine gene-modified tumor cells have increased immunogenicity and retain the antigenic repertoire of a particular neoplasia. However, practical concerns have led to an increased interest in allogeneic gene-transduced bystander cells as a broader source of cytokines for autologous tumor cell-based vaccines. Here, we show that allogeneic B78H1 major histocompatibility complex (MHC) class I-negative and -positive (H-2K(b)- and D(b)-transfected) cells induced cytotoxic T lymphocytes (CTLs) and protection in BALB/c mice at comparable levels in response to a challenge with C26 (H-2(d)) colon carcinoma cells sharing the tumor-associated antigen envelope glycoprotein 70 (env-gp70) with both cell lines. Class I-negative B78H1 cells transduced to express interleukin-12 (IL-12) and mixed with autologous A20 tumor cells led to eradication of preestablished A20 lymphoma in 50% or 100% of treated mice after 3 or 4 vaccinations, respectively, whereas A20 cells alone or mixed with nontransduced B78H1 cured none or 50% of mice after 3 or 4 vaccinations, respectively. Immunization with the IL-12-producing bystander cell line increased tumor-specific proliferation and type 1 cytokine production by CD4(+) T cells. By contrast, CD4 T-cell function appeared impaired after immunization with A20 cells alone or mixed with B78H1 cells. Indeed, only CD4(+) T cells from IL-12-treated mice could be restimulated with anti-OX40 monoclonal antibody (mAb) in place of a fourth cellular boost. Moreover, the IL-12-based tumor vaccine induced expansion of tumor-specific interferon-gamma (IFN-gamma)-producing CD8(+) T cells. These results are clinically relevant for the development of feasible IL-12 cancer vaccines based on engineered class I-negative bystander cells.

Animals↗
PubMed2002

Dendritic cells are functionally defective in multiple myeloma: the role of interleukin-6.

We studied concentration, phenotype, and function of peripheral blood (PB) dendritic cells (DCs) from patients with multiple myeloma (MM). The absolute number of circulating precursors of myeloid and plasmacytoid DCs was significantly lower in MM patients than in healthy subjects. After maturation, PBDCs from MM patients showed significantly lower expression of HLA-DR, CD40, and CD80 antigens and impaired induction of allogeneic T-cell proliferation compared with controls. Remarkably, they were not capable of presenting the patient-specific tumor idiotype to autologous T cells. Conversely, DCs generated in vitro from CD14(+) monocytes from the same patients, and PBDCs freshly isolated from healthy donors efficiently stimulated allogeneic and autologous T cells. To clarify the mechanism of PBDC deficiency in MM, we investigated the effects of the main plasma cell growth factor, interleukin-6 (IL-6), on the development of DCs from CD34(+) cells. IL-6 inhibited the colony growth of CD34(+) DC progenitors and switched the commitment of CD34(+) cells from DCs to CD14(+) CD1a(-) CD86(-)CD80(-) CD40(+/-)HLA-DR +/- monocytic cells exerting potent phagocytic activity but no antigen-presentation capacity. This effect was reversed by anti-IL-6 antibodies. Growing CD34(+) cells in the presence of autologous serum (without IL-6) also suppressed the development of functional DCs. This study demonstrates that PBDCs from MM patients are functionally defective, partially because of IL-6-mediated inhibition of development. This brings into question the advisability of using PBDCs as antigen carriers for immunotherapy trials in MM. The results also suggest a novel mechanism whereby myeloma cells escape immune recognition.

Antigen Presentation↗
PubMed2002

Interleukin-11 induces proliferation of human T-cells and its activity is associated with downregulation of p27(kip1).

BACKGROUND AND OBJECTIVES: We have recently shown that interleukin (IL-)11 induces polarization of human T-cells by inhibiting macrophage production of IL-12 and by exerting a direct effect on CD4+ T-cells. In this study, we investigated the effects of IL-11 on the kinetic activation and apoptosis of T-cell subsets stimulated with anti-CD3/CD28 antibodies, anti-CD3 and IL-2 or dendritic cells. DESIGN AND METHODS: Apoptosis and cell cycle analysis of T-cells were assessed by double staining with propidium iodide and intracellular Ki-67 and by acridine orange staining. The expression of the negative regulator of the cell cycle p27Kip1 (p27) was also determined by flow cytometry. RESULTS: Our results show that 18 hours of incubation with IL-11 resulted in a significantly higher number of cycling CD4+ cells, CD4+CD45RA+ naive T-cells and CD4+CD45RO+ memory T-cells, but not of CD8+ cells. The kinetic activity of IL-11 was observed up to 72 hours, when the peak value of S-phase cells occurred. IL-11 also significantly enhanced CD4+ and CD4+CD45RA+ cell proliferation when T-cells were co-incubated with allogeneic dendritic cells. Conversely, IL-11 did not protect any of the T-cell subsets from apoptosis. At the functional level, a type-2 cytokine pattern of cultured T-lymphocytes was observed after 5 days of incubation with IL-11. Proliferation and functional activation of T-cells were preceeded by downregulation of p27, which occurred as early as 12 hours after incubation with IL-11. INTERPRETATION AND CONCLUSIONS: IL-11 induces Th-2 polarization and cell-cycle entry of human CD4+, CD4+CD45RA+ and CD4+CD45RO+cells and their activation is associated with the downregulation of p27.

Apoptosis↗