The TLR7/8 Ligand R848 Is Superior In Generation of Monocyte Derived Dendritic Cells From AML Patients for the Induction of Potent T and NK Cell Immune Responses

Abstract Abstract 2195 Introduction: Therapeutic vaccination with dendritic cells (DC) is currently considered as an investigational therapy in acute myeloid leukemia (AML) for eradication of minimal residual disease (MRD). Dendritic cells derived from autologous peripheral blood monocytes have been tested as cellular adjuvants for therapeutic vaccination of malignancies and proven feasibility and safety, but overall clinical response rates remain very low. The vast majority of DCs used for clinical trials were differentiated with a standard maturation cocktail composed of the cytokines TNF-a, IL-1b, IL-6 and PGE2 leading to DCs unable to secrete biologically active IL-12. This cytokine is fervently desired because of its leading role in promoting T helper 1 cell polarization and therefore fostering the appropriate adaptive immune responses needed to combat minimal residual disease. Cocktails containing synthetic Toll-like receptors (TLR) agonists emerged as an attractive alternative for the induction of DC maturation with T helper type 1 polarizing capacity. Our present investigation was designed to study the feasability of a clinical grade DC 3-day mDC generation protocol from nonleukemic monocytes of intensively pretreated AML patients with novel maturation cocktails containing different TLR-agonists in vitro and assessment of their potency to induce adaptive and innate immune responses. Material & Methods: Monocytes isolated from peripheral blood of AML patients in CR and healthy donors were differentiated into immature DC with GM-CSF and IL-4. After 48 hours DC were additionally cultured with TNF-a, IL1-b, INF-g, PGE2 and corresponding to the defined cocktail with the TLR7/8 agonists R848 (R) or CL075 (C) with or without the TLR3 agonist poly(I:C) (P) for 24 hours. mDCs were analyzed for expression of maturation surface markers, costimulatory profile, IL-12(p70)/IL-10 ratio, migratory capacity, NK cell activation and polarization of T cells. Results: No significant difference in absolute monocyte counts and percentage of DC recovery between healthy controls and AML patients in CR was found using different maturation cocktails (C, CP, R, and RP). Phenotype analysis of surface marker expression revealed no substantial differences between the different DC generation protocols used in healthy donors and AML patients in CR. The costimulatory profile assesed by the expression of two members of the B7 family, CD80 (B7.1) and CD274 (B7-H1 or PD-L1), was in healthy donors superior to AML patients, but these differences were not statistically significant. Variations were noted in the capacity of DCs derived from different donors to produce IL-12(p70) and IL-10, but importantly no significant differences between AML patients in CR and healthy controls could be observed. Interestingly, both healthy donor and AML derived DCs secrete a significantly higher proportion of IL-12(p70) with R848 containing cocktails compared to CL075. Treatment with the CP cocktails even leads to a inverse Il12/IL-10 ratio in AML patients. The high CCR7 expression was paralleled by a strong migratory capacity as well as positive chemotactic reponses to CCL19 chemokine signals. DCs matured with these novel cocktails induced potent alloresponses and strongly activated NK cells measured by upregulation of CD69 expression and IFN-g secretion. No differences beetween R848 and CL075 could be observed. Conclusion: Here we report for the first time a clinically applicable, time- and resource saving 3-day TLR-agonist containing maturation protocol for the generation of IL-12(p70) secreting DCs from AML patients in remission validated with healthy controls which allowed efficient generation, easy harvesting, stable maturation and substantial recoveries of mature DCs. Comparison of different TLR7/8 agonists showed superiority of R848 in IL-12(p70) production to CL075. We believe that these studies point the way to improved DCs that will induce better and long lasting immune responses in the vaccination against acute myelo Disclosures: No relevant conflicts of interest to declare.

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Expanded Natural Killer Cells For The Control Of Minimal Residual Disease In Ph+ Acute Lymphoblastic Leukemia Patients

Blood ◽

10.1182/blood.v122.21.2026.2026 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2026-2026

Author(s):

Giovanni Fernando Torelli ◽

Nadia Peragine ◽

Sara Raponi ◽

Paola Mariglia ◽

Simona Pauselli ◽

...

Keyword(s):

Nk Cells ◽

Nk Cell ◽

Residual Disease ◽

Ex Vivo ◽

Lymphoblastic Leukemia ◽

The Elderly ◽

Activating Receptors ◽

Healthy Donors ◽

Tk Inhibitors ◽

Minimal Residual

Abstract The management of Ph+ acute lymphoblastic leukemia (ALL) patients has profoundly changed during the last decade. Virtually all adult Ph+ ALL patients, including the elderly where the abnormality accounts for over 50% of cases, can obtain a complete remission (CR) with the use of TK inhibitors (and steroids) without systemic chemotherapy (Vignetti M et al. Blood 2007;109:3676; Foà R et al. Blood 2011;118:6521). Most patients remain, however, minimal residual disease (MRD)-positive. The possibility of targeting MRD via an immune-mediated control is particularly appealing in these patients. Previous studies have shown that natural killer (NK) cells with killing activity against autologous blasts may be expanded from ALL patients in CR (Torelli GF et al. Haematologica 2005;90:785). NK cell recognition of malignant targets is regulated by activating and inhibitory receptors. The major receptors with activating functions are NKG2D, DNAM-1 and the natural cytotoxicity receptors (NCRs) (NKp30, NKp44 and NKp46). MIC-A/B and ULBPs are ligands for NKG2D, PVR and Nec-2 for DNAM-1, while NCRs are orphan receptors. The pathways of NK-ALL recognition are unclear. Possible differences in NK cell killing susceptibility and in the expression of NK cell activating ligands among subgroups of ALL patients have been suggested. The aims of this study were: 1) to analyze the pathways of NK-ALL recognition, with particular attention to Ph+ samples; and 2) to verify whether differences in NK cell activating receptor ligand expression among molecularly-defined subgroups of patients correlate with the susceptibility to recognition and killing by NK cells activated and expanded under GMP conditions. PBMCs were collected from 23 healthy donors and 3 adult Ph+ ALL patients in CR. NK cells were enriched and cultured for 14 days in the presence of irradiated autologous feeder cells, autologous plasma, IL-2 and IL-15. The expression of the activating receptors NKG2D, DNAM-1 and NCRs was then analyzed. Samples from 46 newly diagnosed adult ALLs, median age 34 years (18-74), were also investigated: 39 patients had B-ALL - 15 BCR-ABL+, 7 MLL-AF4+, 2 E2A-PBX1+, 15 negative - and 7 had T-ALL. The expression of the NKG2D and DNAM-1 ligands on ALL blasts was analyzed. The cytotoxic activity of ex vivo expanded NK cells against primary ALL blasts was determined in a 51Cr release assay. For blocking experiments, NK cells were pre-treated with the anti-NKG2D or anti-DNAM-1 neutralizing mAbs. NK cells from healthy donors and from Ph+ ALL patients could be expanded respectively 33.2±15.2 and 39.1±19.3 fold. Expanded NK cells were represented by a homogenous population displaying a high expression of CD56 and CD16, in the absence of CD3. DNAM-1, NKG2D, NKp30 and NKp44 activating receptors presented a significantly increased expression after expansion from healthy donors (DNAM-1 p=.0007; NKG2D p=.0004; NKp30 p=.05; NKp44 p=.001). DNAM-1 and NKG2D showed a significantly increased expression after expansion also from Ph+ ALL patients (DNAM-1 p=.0012; NKG2D p=.045), while the expression of NCRs was not tested on these samples. The phenotypic analysis performed within molecularly-defined subgroups of ALL revealed that Ph+ cases presented an overall high surface expression of NKG2D and DNAM1 ligands. In particular, when compared to ALLs carrying no known molecular markers, Ph+ samples showed significantly higher levels of ULBP-1, ULBP-3 and MIC-B (p=.008, p=.026 and p=.033, respectively). In line with the phenotypic results, primary blasts from Ph+ ALL (n=5) appeared significantly more susceptible to NK-dependent lysis than B-ALL without molecular aberrations (n=6) (p=.007). When cytotoxic assays were performed in the presence of neutralizing mAbs, the NK cell killing potential was significantly inhibited by anti-DNAM-1 (p=.006), suggesting a pathway of recognition of ALL blast cells in the setting of the Nec-2/DNAM-1 interaction. The high expression of ligands for activating receptors in Ph+ ALL cases, together with the highest levels of susceptibility to NK cell-mediated lysis by this subgroup of ALL, point to a possible therapeutic use of autologous NK cells activated and expanded ex vivo. Management of Ph+ ALL patients - particularly the elderly - with TK inhibitors plus an immune-based strategy aimed at controlling/eradicating MRD without the use of systemic chemotherapy and/or transplant program is worthy of being investigated. Disclosures: No relevant conflicts of interest to declare.

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Serum Peptidome Based Biomarkers Searching for Monitoring Minimal Residual Disease in Adult Acute Monocytic Leukemia

Blood ◽

10.1182/blood.v128.22.5233.5233 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5233-5233

Author(s):

Ju Bai ◽

Yun Yang ◽

Jianli Wang ◽

Wanggang Zhang ◽

Lei Zhang ◽

...

Keyword(s):

Correlation Analysis ◽

Minimal Residual Disease ◽

Molecular Diagnosis ◽

Residual Disease ◽

Acute Monocytic Leukemia ◽

Healthy Controls ◽

Monocytic Leukemia ◽

Disease States ◽

Significant Difference ◽

Minimal Residual

Abstract Background: Acute monocytic leukemia (M5) is one common type in acute myeloid leukemia (AML). The present study found that a few M5 had special reproducible chromosomal abnormalities and molecular abnormalities. The heterogeneity and complexity of M5 lead to lack of specific tumor-associated markers for molecular diagnosis and targeted therapy. CLINPROT system, with unique advantages, is a firenew and distinctive proteomics technology and has been widely used in the researches of solid tumor and hemopathic malignancies. This study was to screen a panel of serum peptides associated with M5 different disease states for molecular diagnosis and monitoring minimal residual disease. Methods: 92 M5 were enrolled for the study from those who were newly diagnosed (ND) in the Second Affiliated Hospital of Xi'an Jiao Tong University from January 2009 to July 2014. The median age was 45 years old (range 18-73) and 57.6% were male. Diagnosis was made according to bone marrow cell morphology, cytochemical staining and cellular immune phenotype. 90 healthy cases (HC) (age range 19-70, median age 43 years old, male/female 51/39) were recruited from those who came to our hospital to undergo healthy physical examination and had no any abnormal symptoms and results. Sera of 92 M5 were gained pre- and post-treatment of chemotherapy. Weak cation exchange magnetic bead combined with matrix assisted laser desorption/ ionization time of flight mass spectrometry were used to compare and analyze serum peptidome of M5 with different disease states. Spearman method was used to do correlation analysis of two variables. Statistical significance was defined as p<0.05. Results: A total of 42 peptides in the molecular weight range of 700-10000 Da were detected using ClinProt system and statistically different between adult M5 and healthy controls. Among them, 9 peptides were elevated and 33 were decreased in M5. Genetic algorithm (GA) was used to obtain a diagnostic model consisting of 6 peptides that could discriminate M5 from controls with a high sensitivity (100%) and specificity (96.67%). Mass charge ratios (m/z) were 6041.91, 4662.15, 7823.02, 9210.97, 1108.91 and 3263.37 respectively. Blind test verified that this model correctly identified 60 cases out of total 62 M5 and 57 cases from 60 healthy controls. The relative intensities of peptides with m/z of 6041.91 and 4662.15 were increased in the ND group and non-complete remission (CR) group, when comparing with the CR group and HC group(p=0.002; p<0.001), but there was no significant difference between the two groups for any of the peptides (p=0.27, p=0.31). No significant difference was found between the CR group and HC group (p=0.22, p=0.41). The relative intensities of peptides with m/z of 7823.02, 9210.97, 1108.91 and 3263.37 were reduced in the ND group and non-CR group when comparing with the CR group and HC group (p<0.001, p=0.0023, p=0.004, p<0.001), and the two groups had no significant difference (p=0.26, p=0.09, p=0.32, p=0.61). No significant difference was observed between the HC group and CR group (p=0.52, p=0.35, p=0.17, p=0.73). Spearman correlation analysis showed that relative intensities of peptides with m/z of 4662.15, 7823.02 and 9210.97 were correlated with high white blood cells (r=0.88, p<0.001; r=-0.89, p<0.001; p=-0.87, p<0.001), FLT3 mutation (r=0.90, p<0.001; r=-0.87, p<0.001; r=-0.88, p<0.001) , extramedullary disease (r=0.80, p<0.001; r=-0.86, p<0.001; r=- 0.82, p<0.001). The relative intensities of the other three peptides had weak correlation with the unfavorable clinical features of M5 at diagnosis. Conclusion: This panel of peptides has encouraging efficiency in discriminating M5 from HCs and potential value in monitoring M5 minimal residual disease. Disclosures No relevant conflicts of interest to declare.

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Modulation of Tetraspanin 32 (TSPAN32) Expression in T Cell-Mediated Immune Responses and in Multiple Sclerosis

International Journal of Molecular Sciences ◽

10.3390/ijms20184323 ◽

2019 ◽

Vol 20 (18) ◽

pp. 4323 ◽

Cited By ~ 10

Author(s):

Salvo Danilo Lombardo ◽

Emanuela Mazzon ◽

Maria Sofia Basile ◽

Giorgia Campo ◽

Federica Corsico ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

T Cell ◽

Immune Responses ◽

Cancer Metastasis ◽

Treg Cells ◽

T Helper ◽

Autoimmune Encephalomyelitis ◽

Healthy Donors

Tetraspanins are a conserved family of proteins involved in a number of biological processes including, cell–cell interactions, fertility, cancer metastasis and immune responses. It has previously been shown that TSPAN32 knockout mice have normal hemopoiesis and B-cell responses, but hyperproliferative T cells. Here, we show that TSPAN32 is expressed at higher levels in the lymphoid lineage as compared to myeloid cells. In vitro activation of T helper cells via anti-CD3/CD28 is associated with a significant downregulation of TSPAN32. Interestingly, engagement of CD3 is sufficient to modulate TSPAN32 expression, and its effect is potentiated by costimulation with anti-CD28, but not anti-CTLA4, -ICOS nor -PD1. Accordingly, we measured the transcriptomic levels of TSPAN32 in polarized T cells under Th1 and Th2 conditions and TSPAN32 resulted significantly reduced as compared with unstimulated cells. On the other hand, in Treg cells, TSPAN32 underwent minor changes upon activation. The in vitro data were finally translated into the context of multiple sclerosis (MS). Encephalitogenic T cells from Myelin Oligodendrocyte Glycoprotein (MOG)-Induced Experimental Autoimmune Encephalomyelitis (EAE) mice showed significantly lower levels of TSPAN32 and increased levels of CD9, CD53, CD82 and CD151. Similarly, in vitro-activated circulating CD4 T cells from MS patients showed lower levels of TSPAN32 as compared with cells from healthy donors. Overall, these data suggest an immunoregulatory role for TSPAN32 in T helper immune response and may represent a target of future immunoregulatory therapies for T cell-mediated autoimmune diseases.

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MicroRNAs in the regulation of immune cell functions – implications for atherosclerotic vascular disease

Thrombosis and Haemostasis ◽

10.1160/th11-08-0603 ◽

2012 ◽

Vol 107 (04) ◽

pp. 626-633 ◽

Cited By ~ 28

Author(s):

Alma Zernecke

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Molecular Mechanisms ◽

Immune Cell ◽

Chronic Inflammatory Disease ◽

Vascular Pathology ◽

Lipid Uptake ◽

T Helper ◽

Atherosclerotic Vascular Disease ◽

Cell Functions

SummaryRegarded as a chronic inflammatory disease of the vessel wall, the development of atherosclerotic lesions is shaped by immune responses and their regulation. Macrophages and dendritic cells are positioned at the crossroad of innate and adaptive immune responses by sensing atherogenic danger signals and by taking up and presenting antigens. T helper cells and auto-antibodies produced by B cells, together with their cytokine responses in turn modulate atheroprogression. In addition, platelets contribute to atherosclerosis by multiple pathways. microRNAs (miRNAs) that post-transcriptionally regulate gene expression may thus critically control immune cell differentiation and functions during plaque evolution. This review summarises the role of miRNAs in regulating lipid uptake and expression of inflammatory mediators in monocytes/macrophages and dendritic cells, in lymphocyte functions with a focus on T helper cell responses, as well as in platelet biology, and the implications of altering these functions in vascular pathology and atherosclerosis. T systematically survey miRNA functions in controlling molecular mechanisms and immune responses in atherosclerosis holds potential for the development of novel miRNA-based strategies for therapies targeting inflammation and immunity in atherosclerosis.

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Friend virus limits adaptive cellular immune responses by imprinting a maturation-resistant and T helper type 2-biased immunophenotype in dendritic cells

PLoS ONE ◽

10.1371/journal.pone.0192541 ◽

2018 ◽

Vol 13 (2) ◽

pp. e0192541 ◽

Cited By ~ 2

Author(s):

Limei Shen ◽

Stefan Tenzer ◽

Moritz Hess ◽

Ute Distler ◽

Ingrid Tubbe ◽

...

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Friend Virus ◽

T Helper ◽

Cellular Immune Responses ◽

Cellular Immune ◽

Helper Type

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Identification Of a Partial Fragment Of SERPINA3 For Acute Leukemia Diagnosis and Minimal Residual Disease Assessment

Blood ◽

10.1182/blood.v122.21.2604.2604 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2604-2604

Author(s):

Wei Song ◽

Jiuwei Cui ◽

Wei Li ◽

Guanjun Wang ◽

Yan Li

Keyword(s):

Mass Spectrometry ◽

Overall Survival ◽

Acute Leukemia ◽

Residual Disease ◽

Healthy Controls ◽

Newly Diagnosed ◽

Serum Samples ◽

Svm Algorithm ◽

Partial Fragment ◽

Minimal Residual

Abstract Background Detection and eradication of minimal residual disease (MRD) is a key issue that assesses response and relapse of treatment of acute leukemia (AL). However, there is no serum biomarker available for diagnosis of AL and assessment of MRD. The serum peptides, especially low molecular weight peptides, contain important information for cancer diagnosis. In this study, we analyzed serum peptidomic profiling of AL patients to screen biomarkers for AL diagnosis and MRD assessment. Methods Serum samples from 105 patients with AL and 40 healthy controls were analyzed by bead fractionation/MALDI-TOF-MS.There are 30 newly diagnosed patients, 30 AL patients with hematological CR (AL-HCR), 30 AL patients with molecular complete remission (AL-MR) and 15 AL patients with relapse. The characteristics of the AL patients was shown in table 1. The peptides from the serum were purified and isolated by copper-chelated magnetic beads and analyzed by MALDI-TOF-MS. The peptide identification was performed using a nano-liquid chromatography-electrospray ionization-tandem mass spectrometry (nano-LC/ESI-mass spectrometry/mass spectrometry) system. Serum peptide patterns from all serum samples were analyzed and intensity of each peptides peak was calculated to screen differential peptides. Diagnostic models of differential peptides using SVM algorithm were established to discriminate AL patients from healthy controls and discriminate AL patients with different remission degree. The overall survival of the patients was estimated using Kaplan-Meier log rank survival analysis. Results SVM algorithm was utilized to generate models of serum peptidomic patterns to discriminate patients with AL from the control and different remission degree. A sensitivity of 96% and a specificity of 100% were obtained for distinguishing all AL patients from healthy controls. The model for distinguishing newly-diagnosed AL patients from AL patients with AL-HCR obtained a sensitivity of 88% and a specificity of 100%. And a sensitivity of 92% and a specificity of 100% were obtained for distinguishing AL-CR from AL-MR group. Statistical analysis revealed that a peptide with m/z 4468 may serve as a serum biomarker for MRD assessment, and that its intensity gradually decreased with increase of remission degree (figure 1). In healthy controls, the intensity of m/z 4468 was similar to that of the AL-MR group. And its intensity in the relapse group was significantly higher than that of the AL-MR group. There was no significant difference between newly-diagnosed AL group and relapse AL group. Moreover, the high intensity of m/z 4468 was significantly associated with poor overall survival (p = 0.03) ( figure 2). Finally, the peptide of m/z 4468 was identified as a partial fragment of SERPINA3. Conclusion The diagnostic model of serum peptidomic pattern could discriminate AL patients from healthy controls, and also distinguish AL patients with different remission degree with high sensitivity and specificity. The peptide of m/z 4468 identified as a partial fragment of SERPINA3 was significantly correlated with MRD level and its high intensity was associated with poor prognosis in patients with AL. In summary, a fast, sensitive and minimally invasive approach was developed in our study, and it may potentially facilitate the screening of MRD and provide useful information for AL prognosis predication. Disclosures: No relevant conflicts of interest to declare.

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Transfer of Ex Vivo Expanded NK and γδT Cells from Untouched Posttransplant PBMCs to Clear Minimal Residual Disease in Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v124.21.5294.5294 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5294-5294

Author(s):

Patrick Schlegel ◽

Chihab Klose ◽

Christina Kyzirakos ◽

Ursula J.E. Seidel ◽

Kai Witte ◽

...

Keyword(s):

Cell Culture ◽

Acute Myeloid Leukemia ◽

Nk Cells ◽

Cell Expansion ◽

Myeloid Leukemia ◽

Nk Cell ◽

Residual Disease ◽

Cell Transfer ◽

Minimal Residual ◽

Acute Myeloid

Abstract GMP-grade NK cell expansion for clinical purpose has been demonstrated feasible and safe. Here we share our pilot data on posttransplant immunotherapy with ex vivo expanded NK cells to treat minimal residual disease in a pediatric patient with posttransplant relapsed myeloid leukemia. Our patient, a 13 year old boy who underwent 2nd allogeneic stem cell transplantation (haploidentical stem cell transplantation from his mother) due to posttransplant relapsed acute myeloid leukemia. After the 2nd haploidentical stem cell transplantation (SCT) minimal residual disease (MRD) was detected by multiparameter flow cytometry and by two molecular markers CALM-AF10 fusion transcript and a NRAS-mutation. For posttransplant compassionate use immunotherapy by NK cell transfer, NK cells were expanded from untouched isolated PBMCs of the patient post 2nd haploidentical SCT. GMP-grade expansion of the NK cells was done under static conditions in our GMP-facility. Isolated PBMCs were pooled with 100Gy irradiated K562mb15 4-1BBL feeder cells (kindly provided by Dario Campana) in a proportion of 1:20 (NK to K562mb15 4-1BBL). PBMCs and K562mb15 4-1BBL were seeded in conventional cell culture flasks (175cm2) at a density of 1.1E6 cells/ml. Cell culture media contained RPMI1640 supplemented with 10% AB-human serum, 1% L-glutamine and 100IU Proleukine® IL2/ml. Cell culture was monitored daily for cell number, white blood cell differentiation, pH of the cell culture, glucose metabolism, lactate production and microbial sterility testing at the beginning and the end of the expansion period. The cell product was harvested on day 15-17. Fresh isolated PBMCs and the expanded NK cell product were characterized by flow cytometry. NK cells were expanded >1000 fold (3.1 and 3.4 log-fold) in 14-17 days. The product contained a total number of 9.8E9 and 19.9E9 cells, which was 328 and 665E6/kgBW. The expansion protocol supports NK and γδ T cell expansion whereas the number of αβ T cells stays stable. Cytotoxicity assay against various targets revealed excellent cellular cytotoxicity and antibody dependent cellular cytotoxicity. To prevent relapse in our patient with posttransplant MRD positivity, NK cells from the patient post 2nd haploidentical SCT were expanded for cellular immunotherapy. 2 weeks post 1st NK cell transfer (day +170) the patient achieved complete MRD response in the bone marrow. Unfortunately the patient showed detectable MRD one month later. Therefore another NK cell expansion and transfer was done. 2 weeks post 2nd NK cell transfer (day +232) the patient again achieved complete MRD response in the bone marrow and is in complete molecular remission ever since (day +340). The NK cell products were tolerated well. Transient coughing and temporary increase of temperature were registered. Both, in vitro and in vivo effect of the NK cell product were documented. Clinical use of expanded and activated NK cells and γδ T cells can induce molecular remission in posttransplant MRD positive acute myeloid leukemia. Disclosures No relevant conflicts of interest to declare.

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CD4+ CD25+ Regulatory T Cells Control T Helper Cell Type 1 Responses to Foreign Antigens Induced by Mature Dendritic Cells In Vivo

Journal of Experimental Medicine ◽

10.1084/jem.20030654 ◽

2003 ◽

Vol 198 (2) ◽

pp. 259-266 ◽

Cited By ~ 169

Author(s):

Guillaume Oldenhove ◽

Magali de Heusch ◽

Georgette Urbain-Vansanten ◽

Jacques Urbain ◽

Charlie Maliszewski ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Regulatory T Cells ◽

Immune Responses ◽

Peripheral Tolerance ◽

T Helper Cell ◽

Helper Cell ◽

T Helper

Recent evidence suggests that in addition to their well known stimulatory properties, dendritic cells (DCs) may play a major role in peripheral tolerance. It is still unclear whether a distinct subtype or activation status of DC exists that promotes the differentiation of suppressor rather than effector T cells from naive precursors. In this work, we tested whether the naturally occurring CD4+ CD25+ regulatory T cells (Treg) may control immune responses induced by DCs in vivo. We characterized the immune response induced by adoptive transfer of antigen-pulsed mature DCs into mice depleted or not of CD25+ cells. We found that the development of major histocompatibility complex class I and II–restricted interferon γ–producing cells was consistently enhanced in the absence of Treg. By contrast, T helper cell (Th)2 priming was down-regulated in the same conditions. This regulation was independent of interleukin 10 production by DCs. Of note, splenic DCs incubated in vitro with Toll-like receptor ligands (lipopolysaccharide or CpG) activated immune responses that remained sensitive to Treg function. Our data further show that mature DCs induced higher cytotoxic activity in CD25-depleted recipients as compared with untreated hosts. We conclude that Treg naturally exert a negative feedback mechanism on Th1-type responses induced by mature DCs in vivo.

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