Publications by authors named "Baptiste Lamarthée"

18 Publications

  • Page 1 of 1

A combination of cyclophosphamide, interleukin-2 allow CD4+ T cells converted to Tregs to control scurfy syndrome.

Blood 2021 Feb 5. Epub 2021 Feb 5.

INSERM U1163, Paris, France.

Immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome is caused by mutations in FOXP3, which lead to the loss of function of regulatory T cells (Treg) and the development of autoimmune manifestations early in life. The selective induction of a Treg program in autologous CD4+ T cells by FOXP3 gene transfer is a promising approach for curing IPEX. We have established a novel in vivo assay of Treg functionality, based on adoptive transfer of these cells into scurfy mice (an animal model of IPEX) and a combination of cyclophosphamide conditioning and interleukin-2 treatment. This model highlighted the possibility of rescuing scurfy disease after the latter's onset. By using this in vivo model and an optimized lentiviral vector expressing human Foxp3 and as a reporter a truncated form of the 5 low-affinity nerve growth factor receptor (DLNGFR), we demonstrated that the adoptive transfer of FOXP3-transduced scurfy CD4+ T cells enabled the long-term rescue of scurfy autoimmune disease. The efficiency was similar to that seen with wild-type Treg. After in vivo expansion, the converted CD4FOXP3 cells recapitulated the transcriptomic core signature for Treg. These findings demonstrate that FOXP3 expression converts CD4+ T cells into functional Treg capable of controlling severe autoimmune disease.
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http://dx.doi.org/10.1182/blood.2020009187DOI Listing
February 2021

MicroRNAs: small molecules, big effects.

Curr Opin Organ Transplant 2021 Feb;26(1):10-16

Université de Paris, Necker-Enfants Malades Institute, French National Institute of Health and Medical Research U1151.

Purpose Of Review: In kidney transplantation, microRNAs (miRNAs) have been extensively studied over the past decade, and panels of differentially expressed miRNAs have been identified from various body fluids/tissues, including blood, plasma, urine, or allograft biopsies, and in various conditions, such as acute T-cell-mediated and antibody-mediated rejections, chronic allograft rejection, interstitial fibrosis and tubular atrophy, acute tubular necrosis or BKV nephropathy.

Recent Findings: This review outlines our current knowledge regarding the complexity of miRNA regulation in fine-tuning expression of two-thirds of the human genome and the potential of miRNAs as biomarkers, based on an increasing number of case--control studies with, however, no evidence of short-term clinical development. Instead, a progressive change in study objectives is reported, with the most recent literature using miRNA-targeted genes as entry points for studying disease pathways.

Summary: Our nascent understanding of their presumed roles in alloimmunity suggests that miRNAs are key regulators in many allograft injuries. Future directions should investigate how the integration of miRNAs with other layers of molecular data, such as genomic, transcriptomic, or proteomic data, could help to characterize the cellular interactions involved in allograft rejection and whether miRNA-based therapy could be of relevance for transplant medicine.
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http://dx.doi.org/10.1097/MOT.0000000000000835DOI Listing
February 2021

Arsenic trioxide induces regulatory functions of plasmacytoid dendritic cells through interferon- inhibition.

Acta Pharm Sin B 2020 Jun 31;10(6):1061-1072. Epub 2020 Jan 31.

Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris F-75012, France.

Arsenic trioxide (AsO) is recently found to have therapeutic potential in systemic sclerosis (SSc), a life-threatening multi-system fibrosing autoimmune disease with type I interferon (IFN-I) signature. Chronically activated plasmacytoid dendritic cells (pDCs) are responsible for IFN-I secretion and are closely related with fibrosis establishment in SSc. In this study, we showed that high concentrations of AsO induced apoptosis of pDCs mitochondrial pathway with increased BAX/BCL-2 ratio, while independent of reactive oxygen species generation. Notably, at clinical relevant concentrations, AsO preferentially inhibited IFN- secretion as compared to other cytokines such as TNF-, probably due to potent down-regulation of the total protein and mRNA expression, as well as phosphorylation of the interferon regulatory factor 7 (IRF7). In addition, AsO induced a suppressive phenotype, and in combination with cytokine inhibition, it down-regulated pDCs' capacity to induce CD4 T cell proliferation, Th1/Th22 polarization, and B cell differentiation towards plasmablasts. Moreover, chronically activated pDCs from SSc patients were not resistant to the selective IFN- inhibition, and regulatory phenotype induced by AsO. Collectively, our data suggest that AsO could target pDCs and exert its treatment efficacy in SSc, and more autoimmune disorders with IFN-I signature.
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http://dx.doi.org/10.1016/j.apsb.2020.01.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332672PMC
June 2020

Donor-targeted serotherapy as a rescue therapy for steroid-resistant acute GVHD after HLA-mismatched kidney transplantation.

Am J Transplant 2020 08 10;20(8):2243-2253. Epub 2020 Mar 10.

Paris University, Paris, France.

Acute graft-versus-host disease (GVHD) is a rare but frequently lethal complication after solid organ transplantation. GVHD occurs in unduly immunocompromised hosts but requires the escalation of immunosuppression, which does not discriminate between host and donor cells. In contrast, donor-targeted therapy would ideally mitigate graft-versus-host reactivity while sparing recipient immune functions. We report two children with end-stage renal disease and severe primary immune deficiency (Schimke syndrome) who developed severe steroid-resistant acute GVHD along with full and sustained donor T cell chimerism after isolated kidney transplantation. Facing a therapeutic dead end, we used a novel strategy based on the adoptive transfer of anti-HLA donor-specific antibodies (DSAs) through the transfusion of highly selected plasma. After approval by the appropriate regulatory authority, an urgent nationwide search was launched among more than 3800 registered blood donors with known anti-HLA sensitization. Adoptively transferred DSAs bound to and selectively depleted circulating donor T cells. The administration of DSA-rich plasma was well tolerated and notably did not induce antibody-mediated rejection of the renal allografts. Acute GVHD symptoms promptly resolved in one child. This report provides a proof of concept for a highly targeted novel therapeutic approach for solid organ transplantation-associated GVHD.
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http://dx.doi.org/10.1111/ajt.15827DOI Listing
August 2020

In situ multiplex immunofluorescence analysis of the inflammatory burden in kidney allograft rejection: A new tool to characterize the alloimmune response.

Am J Transplant 2020 04 11;20(4):942-953. Epub 2019 Dec 11.

Department of Pathology, Necker Hospital, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France.

The exact composition of leukocyte infiltration during kidney allograft rejection is difficult to comprehend and visualize on the same biopsy slide. Using an innovative technology of multiplex immunofluorescence (mIF), we were able to detect simultaneously NK cells, macrophages, and T cells and to determine their intra- or extravascular localization using an endothelial marker. Twenty antibody-mediated rejection (ABMR), 20 T cell-mediated rejection (TCMR), and five normal biopsies were labeled, with automatic leukocyte quantification and localization. This method was compared to a classic NKp46 immunohistochemistry (IHC) with manual quantification and to mRNA quantification. mIF automatic quantification was strongly correlated to IHC (r = .91, P < .001) and to mRNA expression levels (r > .46, P < .021). T cells and macrophages were the 2 predominant populations involved in rejection (48.0 ± 4.4% and 49.3 ± 4.4%, respectively, in ABMR; 51.8 ± 6.0% and 45.3 ± 5.8% in TCMR). NK cells constituted a rare population in both ABMR (2.7 ± 0.7%) and TCMR (2.9 ± 0.6%). The intravascular compartment was mainly composed of T cells, including during ABMR, in peritubular and glomerular capillaries. However, NK cell and macrophage densities were significantly higher during ABMR in glomerular and peritubular capillaries. To conclude, this study demonstrates the feasibility and utility of mIF imaging to study and better understand the kidney allograft rejection process.
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http://dx.doi.org/10.1111/ajt.15699DOI Listing
April 2020

MicroRNA-146a-deficient mice develop immune complex glomerulonephritis.

Sci Rep 2019 10 30;9(1):15597. Epub 2019 Oct 30.

INSERM, U1151, Paris, France.

MicroRNAs (miRNAs) play an important role in the kidneys under physiological and pathological conditions, but their role in immune glomerulonephritis is unclear. miR-146a has been identified as a key player in innate immunity and inflammatory responses, and in the kidney, this miRNA is involved in the response of injured tubular cells. We studied the renal and immune phenotypes of miR-146a and miR-146a mice at 12 months of age, and the results showed that miR-146a mice developed autoimmunity during aging, as demonstrated by circulating antibodies targeting double-stranded DNA and an immune complex-mediated glomerulonephritis associated with a mild renal immune infiltrate. In addition, miR-146a mice showed reduced expression of the transmembrane protein Kim1/Tim1, a key regulator of regulatory B cell (Breg) homeostasis, in the kidney and the immune cells. The numbers of memory B cells and plasmablasts were increased in miR-146a mice compared with the numbers in wild-type mice, whereas Bregs were decreased in number and displayed an altered capacity to produce IL-10. Finally, we showed that miR-146a mice develop an autoimmune syndrome with increasing age, and this syndrome includes immune complex glomerulonephritis, which might be due to altered B cell responses associated with Kim1/Tim1 deficiency. This study unravels a link between miR-146a and Kim1 and identifies miR-146a as a significant player in immune-mediated glomerulonephritis pathogenesis.
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http://dx.doi.org/10.1038/s41598-019-51985-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821765PMC
October 2019

Genomic Mismatch at LIMS1 Locus and Kidney Allograft Rejection.

N Engl J Med 2019 08;381(9):e16

Hôpital Necker-Enfants Malades, Paris, France

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http://dx.doi.org/10.1056/NEJMc1908072DOI Listing
August 2019

Sensitization to endothelial cell antigens: Unraveling the cause or effect paradox.

Hum Immunol 2019 Aug 1;80(8):614-620. Epub 2019 May 1.

Imagine Institute, French National Institute of Health and Medical Research (Inserm) U1163, Department of Biotherapy, Necker Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Necker-Enfants Malades Institute, Inserm U1151, Paris Descartes, Sorbonne Paris Cité University, RTRS Centaure, LabEx Transplantex, Department of Nephrology and Kidney Transplantation, Necker Hospital, AP-HP, Paris, France.

Anti-endothelial cell antibodies (AECAs) have been correlated with increased acute and chronic rejection across all organ types and early graft dysfunction in kidney and heart transplantation. Nevertheless, the lack of appropriate tools and clear criteria for defining injurious versus non-injurious AECAs prohibits their routine inclusion in clinical risk assessments and diagnostic algorithms for antibody mediated injury. Clinical characterization of AECAs is complicated due to the wide range of polymorphic and non-polymorphic antigens expressed across different vascular tissues and the diverse array of specificities observed between individuals. This complexity is also reflected in the broad spectrum of reported injury phenotypes. AECAs detected at time of allograft dysfunction may represent biomarkers of past vascular injury or active contributors to a current rejection process. New tools within the fields of proteomics, genomics, bioinformatics, and imaging are currently being validated and hold great promise for unraveling the AECA paradox.
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http://dx.doi.org/10.1016/j.humimm.2019.04.014DOI Listing
August 2019

Non anti-HLA antibodies and acute rejection: A critical viewpoint

Nephrol Ther 2019 04;15 Suppl 1:S53-S59

Service de néphrologie et transplantation rénale adulte, hôpital Necker-Enfants-Malades, 149, rue de Sèvres, 75015 Paris, France; Université Paris Descartes Sorbonne Paris Cité, 12, rue de l'École-de-Médecine, 75006 Paris, France; Inserm, U1151, 149, rue de Sèvres, 75015 Paris, France.

In solid organ transplantation, the deleterious effect of antibodies directed against donor HLA antigens, whether preformed or de novo, is well established. Anti-HLA antibodies have been associated not only with the risk of antibody-mediated rejection but also with late graft dysfunction and are now considered to be the leading cause of allograft loss after renal transplantation. In addition to HLA antibodies, the possible involvement of non-HLA antibodies targeting donor endothelial cells has long been the subject of intense research. The purpose of this review is to discuss current knowledge and remaining issues related to the involvement of non-HLA antibodies in solid organ transplantation. More specifically, the clinical data underlying the hypothesis of the role of non-HLA antibodies will be discussed, as well as the different techniques for antibody detection, their clinical relevance and their antigenic targets.
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http://dx.doi.org/10.1016/j.nephro.2019.03.003DOI Listing
April 2019

Early Acute Microvascular Kidney Transplant Rejection in the Absence of Anti-HLA Antibodies Is Associated with Preformed IgG Antibodies against Diverse Glomerular Endothelial Cell Antigens.

J Am Soc Nephrol 2019 04 8;30(4):692-709. Epub 2019 Mar 8.

Paris Descartes, Sorbonne Paris Cité University, Paris, France;

Background: Although anti-HLA antibodies (Abs) cause most antibody-mediated rejections of renal allografts, non-anti-HLA Abs have also been postulated to contribute. A better understanding of such Abs in rejection is needed.

Methods: We conducted a nationwide study to identify kidney transplant recipients without anti-HLA donor-specific Abs who experienced acute graft dysfunction within 3 months after transplantation and showed evidence of microvascular injury, called acute microvascular rejection (AMVR). We developed a crossmatch assay to assess serum reactivity to human microvascular endothelial cells, and used a combination of transcriptomic and proteomic approaches to identify non-HLA Abs.

Results: We identified a highly selected cohort of 38 patients with early acute AMVR. Biopsy specimens revealed intense microvascular inflammation and the presence of vasculitis (in 60.5%), interstitial hemorrhages (31.6%), or thrombotic microangiopathy (15.8%). Serum samples collected at the time of transplant showed that previously proposed anti-endothelial cell Abs-angiotensin type 1 receptor (AT1R), endothelin-1 type A and natural polyreactive Abs-did not increase significantly among patients with AMVR compared with a control group of stable kidney transplant recipients. However, 26% of the tested AMVR samples were positive for AT1R Abs when a threshold of 10 IU/ml was used. The crossmatch assay identified a common IgG response that was specifically directed against constitutively expressed antigens of microvascular glomerular cells in patients with AMVR. Transcriptomic and proteomic analyses identified new targets of non-HLA Abs, with little redundancy among individuals.

Conclusions: Our findings indicate that preformed IgG Abs targeting non-HLA antigens expressed on glomerular endothelial cells are associated with early AMVR, and that cell-based assays are needed to improve risk assessments before transplant.
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http://dx.doi.org/10.1681/ASN.2018080868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442343PMC
April 2019

Quantitative and functional alterations of 6-sulfo LacNac dendritic cells in multiple myeloma.

Oncoimmunology 2018;7(7):e1444411. Epub 2018 Mar 19.

Sorbonne Universités, UPMC Université Paris 06, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France.

Multiple myeloma (MM) results from expansion of abnormal plasma cells in the bone marrow (BM). Previous studies have shown that monocytes play a crucial role in MM pathophysiology. A 6-sulfo LacNAc-expressing population of dendritic cells (Slan-DCs) that overlaps with intermediate and non-classical monocytes in terms of phenotype has been described. Slan-DCs represent a circulating and tissue proinflammatory myeloid population which has been shown to play a role in different cancer contexts, and which exhibits a remarkable plasticity. Herein, we studied Slan-DCs from the BM and blood of MM patients. We performed quantitative and functional analyses of these cells from 54 patients with newly diagnosed, symptomatic MM, 21 patients with MGUS and 24 responding MM patients. We found that circulating Slan-DCs were significantly decreased in MM patients as compared to those of healthy donors or patients with MGUS, while CD14+CD16+ intermediate monocytes accumulate in the BM. Moreover, after activation with TLR7/8 ligand R848, IL-12-producing Slan-DCs from the BM or peripheral blood from MM patients were decreased as compared with healthy donors. We show that MM cell lines or MM cells isolated from patients at diagnosis were able to inhibit the production of IL-12 by Slan-DCs, as well as to shift the phenotype of Slan-DCs towards an intermediate monocyte-like phenotype. Finally, Slan-DCs that have been cultured with MM cells reduced their capacity to induce T cell proliferation and Th1 polarization. We conclude that Slan-DCs represent previously unrecognized players in MM development and may represent a therapeutic target.
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http://dx.doi.org/10.1080/2162402X.2018.1444411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5993501PMC
March 2018

LXR agonist treatment of blastic plasmacytoid dendritic cell neoplasm restores cholesterol efflux and triggers apoptosis.

Blood 2016 12 4;128(23):2694-2707. Epub 2016 Oct 4.

Unité 1098, INSERM, Besançon, France.

Blastic plasmacytoid dendritic cell (PDC) neoplasm (BPDCN) is an aggressive hematological malignancy with a poor prognosis that derives from PDCs. No consensus for optimal treatment modalities is available today and the full characterization of this leukemia is still emerging. We identified here a BPDCN-specific transcriptomic profile when compared with those of acute myeloid leukemia and T-acute lymphoblastic leukemia, as well as the transcriptomic signature of primary PDCs. This BPDCN gene signature identified a dysregulation of genes involved in cholesterol homeostasis, some of them being liver X receptor (LXR) target genes. LXR agonist treatment of primary BPDCN cells and BPDCN cell lines restored LXR target gene expression and increased cholesterol efflux via the upregulation of adenosine triphosphate-binding cassette (ABC) transporters, ABCA1 and ABCG1. LXR agonist treatment was responsible for limiting BPDCN cell proliferation and inducing intrinsic apoptotic cell death. LXR activation in BPDCN cells was shown to interfere with 3 signaling pathways associated with leukemic cell survival, namely: NF-κB activation, as well as Akt and STAT5 phosphorylation in response to the BPDCN growth/survival factor interleukin-3. These effects were increased by the stimulation of cholesterol efflux through a lipid acceptor, the apolipoprotein A1. In vivo experiments using a mouse model of BPDCN cell xenograft revealed a decrease of leukemic cell infiltration and BPDCN-induced cytopenia associated with increased survival after LXR agonist treatment. This demonstrates that cholesterol homeostasis is modified in BPDCN and can be normalized by treatment with LXR agonists which can be proposed as a new therapeutic approach.
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http://dx.doi.org/10.1182/blood-2016-06-724807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5271175PMC
December 2016

Interleukin-22 in Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation.

Front Immunol 2016 19;7:148. Epub 2016 Apr 19.

Centre de Recherche Saint Antoine, INSERM UMR 938, Paris, France; Université Pierre et Marie Curie, Paris, France.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potential curative treatment for hematologic malignancies and non-malignant diseases. Because of the lower toxicity of reduced intensity conditioning, the number of transplants is in constant increase. However, allo-HSCT is still limited by complications, such as graft-versus-host disease (GVHD), which is associated with important morbidity and mortality. Acute GVHD is an exacerbated inflammatory response that leads to the destruction of healthy host tissues by donor immune cells. Recently, the contribution of innate immunity in GVHD triggering has been investigated by several groups and resulted in the identification of new cellular and molecular effectors involved in GVHD pathogenesis. Interleukin-22 (IL-22) is produced by both immune and adaptive cells and has both protective and inflammatory properties. Its role in GVHD processes has been investigated, and the data suggest that its effect depends on the timing, the target tissue, and the origin of the producing cells (donor/host). In this review, we discuss the role of IL-22 in allo-HSCT and GVHD.
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http://dx.doi.org/10.3389/fimmu.2016.00148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836046PMC
May 2016

Impact of donor hematopoietic cells mobilized with G-CSF and plerixafor on murine acute graft-versus-host-disease.

Cytotherapy 2015 Jul 23;17(7):948-55. Epub 2015 Mar 23.

Institut de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR)1098, Besançon, France; Université de Franche-Comté, Besançon, F-25000, France; Etablissement Français du Sang Bourgogne Franche-Comté, Besançon Cedex, France. Electronic address:

Background Aims: This study aimed to characterize the immune effectors contained in the grafts from donor mice mobilized by granulocyte colony-stimulating factor (G-CSF) and plerixafor and to evaluate their impact on the development of acute graft-versus-host-disease (aGVHD).

Methods: Mobilization was done with G-CSF alone or G-CSF plus plerixafor (G+P).

Results: In grafts collected after G+P mobilization, we observed a significantly higher proportion of c-kit(+)Sca-1(+) hematopoietic stem cells compared with G-CSF. A significant increase in the percentage of plasmacytoid dendritic cells was detected in the G+P graft compared with G-CSF graft. We also studied the ability of stem cell grafts mobilized with G+P to induce GVHD in a mouse model. We observed higher mortality (P < 0.001) associated with increased aGVHD clinical score (P < 0.0001) as well as higher pathology score in the intestine of mice receiving G+P as compared with G-CSF grafts (P < 0.001). Moreover, the exacerbated aGVHD severity was associated with upregulation of CCR6 expression on both CD4(+) and CD8(+) T cells from the G+P grafts, as well as on T cells from mice transplanted with G+P grafts.

Conclusions: In conclusion, we showed that grafts mobilized with G+P exhibited functional features different from those mobilized with G-CSF alone, which increase the severity of aGVHD in the recipients.
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http://dx.doi.org/10.1016/j.jcyt.2015.02.009DOI Listing
July 2015

Human monocyte-derived suppressor cells control graft-versus-host disease by inducing regulatory forkhead box protein 3-positive CD8+ T lymphocytes.

J Allergy Clin Immunol 2015 Jun 25;135(6):1614-24.e4. Epub 2015 Jan 25.

INSERM UMR1098, University of Bourgogne Franche-Comté, EFS Bourgogne Franche-Comté, LabEX LipSTIC, ANR-11-LABX-0021, Besançon, France; Department of Internal Medicine, University Hospital, Dijon, France.

Background: Adoptive transfer of immunosuppressive cells has emerged as a promising strategy for the treatment of immune-mediated disorders. However, only a limited number of such cells can be isolated from in vivo specimens. Therefore efficient ex vivo differentiation and expansion procedures are critically needed to produce a clinically relevant amount of these suppressive cells.

Objective: We sought to develop a novel, clinically relevant, and feasible approach to generate ex vivo a subpopulation of human suppressor cells of monocytic origin, referred to as human monocyte-derived suppressive cells (HuMoSCs), which can be used as an efficient therapeutic tool to treat inflammatory disorders.

Methods: HuMoSCs were generated from human monocytes cultured for 7 days with GM-CSF and IL-6. The immune-regulatory properties of HuMoSCs were investigated in vitro and in vivo. The therapeutic efficacy of HuMoSCs was evaluated by using a graft-versus-host disease (GvHD) model of humanized mice (NOD/SCID/IL-2Rγc(-/-) [NSG] mice).

Results: CD33+ HuMoSCs are highly potent at inhibiting the proliferation and activation of autologous and allogeneic effector T lymphocytes in vitro and in vivo. The suppressive activity of these cells depends on signal transducer and activator of transcription 3 activation. Of therapeutic relevance, HuMoSCs induce long-lasting memory forkhead box protein 3-positive CD8+ regulatory T lymphocytes and significantly reduce GvHD induced with human PBMCs in NSG mice.

Conclusion: Ex vivo-generated HuMoSCs inhibit effector T lymphocytes, promote the expansion of immunosuppressive forkhead box protein 3-positive CD8+ regulatory T cells, and can be used as an efficient therapeutic tool to prevent GvHD.
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http://dx.doi.org/10.1016/j.jaci.2014.12.1868DOI Listing
June 2015

In vivo and in vitro sensitivity of blastic plasmacytoid dendritic cell neoplasm to SL-401, an interleukin-3 receptor targeted biologic agent.

Haematologica 2015 Feb 7;100(2):223-30. Epub 2014 Nov 7.

INSERM UMR1098, F25020 Besançon Cedex, France Université de Bourgogne Franche-Comté, SFR FED4234, F25000 Besançon Cedex, France EFS Bourgogne Franche-Comté, F25020 Besançon Cedex, France LabEX LipSTIC, ANR-11-LABX-0021, F25020 Besançon Cedex, France

Blastic plasmacytoid dendritic cell neoplasm is an aggressive malignancy derived from plasmacytoid dendritic cells. There is currently no accepted standard of care for treating this neoplasm, and therapeutic strategies have never been prospectively evaluated. Since blastic plasmacytoid dendritic cell neoplasm cells express high levels of interleukin-3 receptor α chain (IL3-Rα or CD123), antitumor effects of the interleukin-3 receptor-targeted drug SL-401 against blastic plasmacytoid dendritic cell neoplasm were evaluated in vitro and in vivo. The cytotoxicity of SL-401 was assessed in patient-derived blastic plasmacytoid dendritic cell neoplasm cell lines (CAL-1 and GEN2.2) and in primary blastic plasmacytoid dendritic cell neoplasm cells isolated from 12 patients using flow cytometry and an in vitro cytotoxicity assay. The cytotoxic effects of SL-401 were compared to those of several relevant cytotoxic agents. SL-401 exhibited a robust cytotoxicity against blastic plasmacytoid dendritic cell neoplasm cells in a dose-dependent manner. Additionally, the cytotoxic effects of SL-401 were observed at substantially lower concentrations than those achieved in clinical trials to date. Survival of mice inoculated with a blastic plasmacytoid dendritic cell neoplasm cell line and treated with a single cycle of SL-401 was significantly longer than that of untreated controls (median survival, 58 versus 17 days, P<0.001). These findings indicate that blastic plasmacytoid dendritic cell neoplasm cells are highly sensitive to SL-401, and support further evaluation of SL-401 in patients suffering from blastic plasmacytoid dendritic cell neoplasm.
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http://dx.doi.org/10.3324/haematol.2014.111740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4803130PMC
February 2015

Histone deacetylase inhibitor valproic acid affects plasmacytoid dendritic cells phenotype and function.

Immunobiology 2014 Aug 29;219(8):637-43. Epub 2014 Mar 29.

INSERM UMR1098, Besançon F25020, France; Université de Franche-Comté, Besançon F25000, France; EFS Bourgogne Franche-Comté, F25020 Besançon Cedex, France; Centre d'Investigation Clinique en Biothérapie CIC 1431, Plateforme de Biomonitoring, FHU INCREASE, Besançon F25020, France.

Objective: Plasmacytoid dendritic cells (PDC) represent a rare subset of dendritic cells specialized in the production of type I IFN in response to microbial pathogens. Recent data suggested that histone deacetylase (HDAC) inhibitors possess potent immunomodulatory properties both in vitro and in vivo. In this study, we assayed the ability of the HDAC inhibitor, valproic acid (VPA), to influence the phenotype and functional properties of human PDC isolated from peripheral blood.

Methods And Results: We showed that VPA inhibited the production of IFN-α and the proinflammatory cytokines TNF-α and IL-6 by CpG-activated PDC. VPA also affected the phenotype of PDC by reducing the expression of costimulatory molecules induced by CpG activation. Moreover, VPA reduced the capacity of CpG-stimulated PDC to promote CD4(+) T cell proliferation and IFN-γ production, while enhancing the proportion of IL-10 positive T cells.

Conclusion: These results suggest that HDAC inhibition by VPA alters essential human PDC functions, highlighting the need for monitoring immune functions in cancer patients receiving HDAC inhibitors, but also making these drugs attractive therapies in inflammatory, and autoimmune diseases implicating PDC.
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http://dx.doi.org/10.1016/j.imbio.2014.03.013DOI Listing
August 2014

[Interleukin-22: its role in graft-versus-host-disease unraveled].

Med Sci (Paris) 2013 Jun-Jul;29(6-7):577-9. Epub 2013 Jul 12.

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http://dx.doi.org/10.1051/medsci/2013296008DOI Listing
September 2013