Publications by authors named "Valerie Molinier-Frenkel"

38 Publications

Control of T-Cell Activation and Signaling by Amino-Acid Catabolizing Enzymes.

Front Cell Dev Biol 2020 17;8:613416. Epub 2020 Dec 17.

Univ Paris Est Creteil, INSERM, IMRB, Creteil, France.

Amino acids are essential for protein synthesis, epigenetic modification through the methylation of histones, and the maintenance of a controlled balance of oxidoreduction via the production of glutathione and are precursors of certain neurotransmitters. T lymphocytes are particularly sensitive to fluctuations in amino acid levels. During evolution, the production of amino-acid catabolizing enzymes by mainly antigen-presenting cells has become a physiological mechanism to control T-cell activation and polarization. The action of these enzymes interferes with TCR and co-stimulation signaling, allowing tuning of the T-cell response. These capacities can be altered in certain pathological conditions, with relevant consequences for the development of disease.
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http://dx.doi.org/10.3389/fcell.2020.613416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773816PMC
December 2020

IL4I1 Accelerates the Expansion of Effector CD8 T Cells at the Expense of Memory Precursors by Increasing the Threshold of T-Cell Activation.

Front Immunol 2020 4;11:600012. Epub 2020 Dec 4.

Virus-Immunity-Cancer Department, Institut Mondor de Recherche Biomédicale (IMRB), INSERM U955, Université Paris-Est Créteil, Créteil, France.

IL4I1 is an immunoregulatory enzyme that inhibits CD8 T-cell proliferation and in the tumoral context. Here, we dissected the effect of IL4I1 on CD8 T-cell priming by studying the differentiation of a transgenic CD8 T-cell clone and the endogenous repertoire in a mouse model of acute lymphocytic choriomeningitis virus (LCMV) infection. Unexpectedly, we show that IL4I1 accelerates the expansion of functional effector CD8 T cells during the first several days after infection and increases the average affinity of the elicited repertoire, supporting more efficient LCMV clearance in WT mice than IL4I1-deficient mice. Conversely, IL4I1 restrains the differentiation of CD8 T-cells into long-lived memory precursors and favors the memory response to the most immunodominant peptides. IL4I1 expression does not affect the phenotype or antigen-presenting functions of dendritic cells (DCs), but directly reduces the stability of T-DC immune synapses , thus dampening T-cell activation. Overall, our results support a model in which IL4I1 increases the threshold of T-cell activation, indirectly promoting the priming of high-affinity clones while limiting memory T-cell differentiation.
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http://dx.doi.org/10.3389/fimmu.2020.600012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746639PMC
December 2020

Circulating plasmablasts and high level of BAFF are hallmarks of minimal change nephrotic syndrome in adults.

Nephrol Dial Transplant 2020 Nov 26. Epub 2020 Nov 26.

Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Henri Mondor, Service de Néphrologie et Transplantation, Centre de Référence Maladie Rare « Syndrome Néphrotique Idiopathique », Fédération Hospitalo-Universitaire « Innovative Therapy for Immune Disorders », Créteil, France.

Background: The recent success achieved with the use of B cell-depleting agents in some patients with minimal change nephrotic syndrome (MCNS) suggests an unexpected role for B lymphocytes in the pathogenesis of this immune-mediated glomerular disease. Nevertheless, no extensive B-cell phenotyping analysis has ever been performed in untreated adult patients soon after MCNS diagnosis.

Methods: We investigated the distribution of the different B-cell subpopulations in 22 untreated adult patients with biopsy-proven MCNS [MCNS relapse (MCNS-Rel)]. We compared these data with those for 24 healthy controls, 13 MCNS patients in remission (with no specific treatment) and 19 patients with idiopathic membranous nephropathy (IMN).

Results: Patients with MCNS-Rel or IMN had higher proteinuria and lower serum albumin and gammaglobulin levels (P < 0.0001 for all comparisons) than MCNS patients in remission. Plasmablasts were the only B-cell subsets present at significantly higher levels in MCNS-Rel patients than in the patients of the other three groups (P < 0.05 for all comparisons). The lower albumin levels and higher proteinuria levels were positively correlated with the percentage of circulating plasmablasts (Spearman test's ρ = -0.54, P = 0.01 and ρ = 0.65, P = 0.002, respectively). Similarly, the increase of immunoglobulin M (IgM) and the decrease of IgG levels were significantly associated with the percentage of plasmablasts in MCNS-Rel patients (Spearman's ρ = 0.36, P = 0.01 and Spearman's ρ = -0.60, P = 0.01, respectively). Increased production of interleukin (IL)-21, IL-6 and B-cell activating factor (BAFF) in the serum of MCNS-Rel patients was found significantly correlated with the percentage of plasmablasts (ρ = 0.72, P = 0.0002, ρ = 0.49, P = 0.04 and ρ = 0.62, P = 0.009, respectively).

Conclusions: An increase in the proportion of circulating plasmablasts seems to be a hallmark of untreated MCNS in adult patients. Further studies are required to more precisely determine the phenotype and functions of these cells.
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http://dx.doi.org/10.1093/ndt/gfaa279DOI Listing
November 2020

High effector-memory CD8 T-cell levels correlate with high PML risk in natalizumab-treated patients.

Mult Scler Relat Disord 2020 Nov 27;46:102470. Epub 2020 Aug 27.

Abir Wahab, Alain Créange AP-HP, Henri Mondor University Hospital, Department of Neurology, Université Paris Est Créteil, EA 4391, F-94010 Creteil, France. Electronic address:

Background: Progressive multifocal leukoencephalopathy (PML) is a severe complication of natalizumab (NTZ) treatment in multiple sclerosis (MS) patients. Based on the analysis of cryopreserved cells, several reports have showed that CD62L+ CD4+ T-cells percentage drops before PML onset.

Objective: To analyze CD62L and CD45RA expression on fresh-blood CD4+ and CD8+ T-cells from NTZ-treated patients, according to their estimated PML risk.

Methods: We prospectively enrolled 74 MS patients, including 62 NTZ-treated, and stratified them into low, intermediate and high PML risk groups. Circulating naïve and memory T-cell subsets were analyzed by flow cytometry.

Results: We found no correlation between the percentage of CD62L+ CD4+ T-cells and PML risk. In contrast, the repartition of CD8+ T-cells subpopulations was altered in the high risk group: both the percentage and absolute count of CD8+ CD62L- CD45RA- effector memory T- cells (T) was significantly higher compared to patients at lower risk despite similar CD3+ and CD8+ T-cell counts. One high-risk patient with elevated CD8+ T and CD62L+ CD4+ T-cell levels developed PML six months after sampling.

Conclusion: Our results suggest that CD8+ T cells should be evaluated in larger studies as a potential surrogate marker of PML risk in NTZ-treated patients.
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http://dx.doi.org/10.1016/j.msard.2020.102470DOI Listing
November 2020

Extracardiac soft tissue uptake, evidenced on early Tc-HMDP SPECT/CT, helps typing cardiac amyloidosis and demonstrates high prognostic value.

Eur J Nucl Med Mol Imaging 2020 09 10;47(10):2396-2406. Epub 2020 Mar 10.

French Referral Center for Cardiac Amyloidosis, Mondor Network, F-94010, Créteil, France.

Purpose: Increased cardiac uptake (CU) on early-phase Tc-HMDP scintigraphy has demonstrated diagnostic and prognostic values in amyloid transthyretin (ATTR) cardiac amyloidosis (CA). Extracardiac uptake (ECU) has been poorly studied. We assessed the clinical value of ECU, in combination with CU, on Tc-HMDP scintigraphy using a novel Methodological Amyloidosis Diagnostic Index (MADI).

Methods: We reviewed all patients referred for suspicion of CA, who underwent Tc-HMDP scintigraphy over an 8-year period. ECU, CU, and MADI were determined: MADI0 = neither ECU or CU, MADI1 = ECU alone, MADI2 = CU alone, and MADI3 = ECU + CU.

Results: Of 308 eligible patients, 247 had CA, including 75 ATTRv, 107 ATTRwt, and 65 light-chain (AL), while 61 had another cardiopathy (controls). ECU was observed in 29% of CA and 3% of controls. Most frequent sites of ECU were pleuropulmonary (16% of CA, 3% of controls) followed by the digestive tract and subcutaneous tissues. The liver and spleen ECU was only observed in AL-CA (n = 8). CU was only observed in CA patients (n = 187), of whom 182 had ATTR-CA vs. 5 AL-CA, P < 0.001. MADI0 was only observed in controls (97%) and in AL-CA (60%). MADI1 was mainly observed in AL-CA (positive predictive value, PPV = 91%) while MADI2/3 were more frequent in ATTR-CA (PPV = 97%), P < 0.0001. MADI > 0 vs. MADI0 in AL and MADI3 vs. MADI2 in ATTR were associated with a worse prognosis (P = 0.03 and P = 0.002, respectively).

Conclusions: ECU combined with CU demonstrates high diagnostic and prognostic values in CA patients. MADI seems an easy and reliable score in clinical practice.
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http://dx.doi.org/10.1007/s00259-020-04753-7DOI Listing
September 2020

Identification of inhibitors of the immunosuppressive enzyme IL4I1.

Bioorg Chem 2020 01 23;94:103463. Epub 2019 Nov 23.

INSERM, U955, Equipe 09, Créteil, France; Université Paris Est, Faculté de Médecine, Créteil, France. Electronic address:

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http://dx.doi.org/10.1016/j.bioorg.2019.103463DOI Listing
January 2020

The IL4I1 Enzyme: A New Player in the Immunosuppressive Tumor Microenvironment.

Cells 2019 07 20;8(7). Epub 2019 Jul 20.

INSERM, U955, Team 09, 94010 Créteil, France.

The high metabolic needs of T lymphocytes in response to activation make them particularly vulnerable to modifications of their biochemical milieu. Immunosuppressive enzymes produced in the tumor microenvironment modify nutrient availability by catabolizing essential or semi-essential amino acids and producing toxic catabolites, thus participating in the local sabotage of the antitumor immune response. L-amino-acid oxidases are FAD-bound enzymes found throughout evolution, from bacteria to mammals, and are often endowed with anti-infectious properties. IL4I1 is a secreted L-phenylalanine oxidase mainly produced by inflammatory antigen-presenting cells-in particular, macrophages present in T helper type 1 granulomas and in various types of tumors. In the last decade, it has been shown that IL4I1 is involved in the fine control of B- and T-cell adaptive immune responses. Preclinical models have revealed its role in cancer immune evasion. Recent clinical data highlight IL4I1 as a new potential prognostic marker in human melanoma. As a secreted enzyme, IL4I1 may represent an easily targetable molecule for cancer immunotherapy.
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http://dx.doi.org/10.3390/cells8070757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678094PMC
July 2019

Renal Infarction and Its Consequences for Renal Function in Patients With Cardiac Amyloidosis.

Mayo Clin Proc 2019 06 15;94(6):961-975. Epub 2019 May 15.

Assistance Publique des Hôpitaux de ParisService de Néphrologie et Transplantation, Créteil, 94000, France; Centre de Référence Maladie Rare Syndrome Néphrotique Idiopathique de l'Enfant et de l'Adulte, Créteil, 94000, France; Réseau Amylose Mondor, Groupe de Recherche Clinique sur les Amyloses Amyloid Research Institute, Centre de référence des amyloses cardiaques, Université Paris Est Créteil, France; Groupe Hospitalier Henri-Mondor/Albert Chenevier, Université Paris Est Créteil, France; and Equipe 21, Institut National de la Santé et de la Recherche Médicale (INSERM) U955, Institut Mondor de Recherche Biomédicale (IMRB), Université Paris Est Créteil, France. Electronic address:

Objective: To describe the prevalence of and risk factors for renal infarction (RI) in patients with cardiac amyloidosis.

Patients And Methods: We evaluated 87 patients with cardiac amyloidosis who underwent renal technetium-99m-labeled dimercaptosuccinic acid scintigraphy in the Amyloidosis Referral Center of Henri-Mondor Hospital from October 1, 2015, through February 28, 2018.

Results: Three groups of patients were identified according to the underlying amyloidosis disorder: AL amyloidosis in 24 patients, mutated-transthyretin amyloidosis in 24 patients, and wild-type transthyretin amyloidosis in 39 patients. Patients with wild-type transthyretin amyloidosis were older (P<.001), more likely to be men (P=.02), to have arrhythmic heart diseases (P<.001), and to be receiving anticoagulation treatment (P<.001). Patients with AL amyloidosis had significantly higher N-terminal pro-B-type natriuretic peptide levels (P=.02) and were more likely to have nephrotic syndrome (P<.001). Renal infarction was detected in 18 patients (20.7%), at similar frequencies in the various groups. Baseline urinary protein to creatinine ratio was the only parameter for which a significant difference (P=.03) was found between patients with and without RI diagnoses. The likelihood of RI diagnosis was 47.1% (8 of 17) in the presence of AKI and 14.5% (10 of 69) in its absence (P=.003). Overall, heart transplant-censored patient survival did not differ significantly between patients with and without RI (P=.64), but death- and heart transplant-censored renal survival was significantly lower in patients with RI (P<.001).

Conclusion: Our study suggests that prevalence of RI in patients with cardiac amyloidosis is higher than previously thought, regardless of the underlying amyloidosis disorder. Acute kidney injury in a patient with cardiac amyloidosis should alert clinicians to the possibility of RI.
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http://dx.doi.org/10.1016/j.mayocp.2019.02.012DOI Listing
June 2019

Emerging Role of IL-4-Induced Gene 1 as a Prognostic Biomarker Affecting the Local T-Cell Response in Human Cutaneous Melanoma.

J Invest Dermatol 2018 12 23;138(12):2625-2634. Epub 2018 Jul 23.

INSERM, U1016, Institut Cochin, Paris, France; CNRS, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France. Electronic address:

Several studies have emphasized the importance of immune composition of the melanoma microenvironment for clinical outcome. The contribution of IL4I1, a phenylalanine oxidase with immunoregulatory functions, has not been yet explored. Here we studied a primary cutaneous melanoma series from stage I-III patients to investigate the association between in situ IL4I1 expression and clinical parameters or tumor-infiltrating T-cell subsets. IL4I1 was detected in 87% of tumors and was mainly expressed by tumor-associated macrophages and very rare FoxP3 regulatory T cells. The proportion of IL4I1 cells was higher in patients with an ulcerated melanoma or with a positive sentinel lymph node and tended to correlate with a rapid relapse and shorter overall survival. This proportion also correlated positively with the presence of regulatory T cells and negatively with the presence of cytotoxic CD8 T cells. The location of IL4I1 cells may also be relevant to predict prognosis, because their presence near tumor cells was associated with sentinel lymph node invasion and higher melanoma stage. Collectively, our data show that IL4I1 cells shape the T-cell compartment and are associated with a higher risk of poor outcome in melanoma, supporting a key role for IL4I1 in immune evasion.
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http://dx.doi.org/10.1016/j.jid.2018.06.178DOI Listing
December 2018

IL-4-Induced Gene 1: A Negative Immune Checkpoint Controlling B Cell Differentiation and Activation.

J Immunol 2018 02 29;200(3):1027-1038. Epub 2017 Dec 29.

INSERM, U1016, Institut Cochin, 75014 Paris, France;

Emerging data highlight the crucial role of enzymes involved in amino acid metabolism in immune cell biology. IL-4-induced gene-1 (IL4I1), a secreted l-phenylalanine oxidase expressed by APCs, has been detected in B cells, yet its immunoregulatory role has only been explored on T cells. In this study, we show that IL4I1 regulates multiple steps in B cell physiology. Indeed, IL4I1 knockout mice exhibit an accelerated B cell egress from the bone marrow, resulting in the accumulation of peripheral follicular B cells. They also present a higher serum level of natural Igs and self-reactive Abs. We also demonstrate that IL4I1 produced by B cells themselves controls the germinal center reaction, plasma cell differentiation, and specific Ab production in response to T dependent Ags, SRBC, and NP-KLH. In vitro, IL4I1-deficient B cells proliferate more efficiently than their wild-type counterparts in response to BCR cross-linking. Moreover, the absence of IL4I1 increases activation of the Syk-Akt-S6kinase signaling pathway and calcium mobilization, and inhibits SHP-1 activity upon BCR engagement, thus supporting that IL4I1 negatively controls BCR-dependent activation. Overall, our study reveals a new perspective on IL4I1 as a key regulator of B cell biology.
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http://dx.doi.org/10.4049/jimmunol.1601609DOI Listing
February 2018

An Overview of l-Amino Acid Oxidase Functions from Bacteria to Mammals: Focus on the Immunoregulatory Phenylalanine Oxidase IL4I1.

Molecules 2017 Dec 5;22(12). Epub 2017 Dec 5.

The Mondor Institute of Biomedical Research (IMRB), INSERM U955, Team 09, F-94010 Créteil CEDEX, France.

l-amino acid oxidases are flavin adenine dinucleotide-dependent enzymes present in all major kingdom of life, from bacteria to mammals. They participate in defense mechanisms by limiting the growth of most bacteria and parasites. A few mammalian LAAOs have been described, of which the enzyme "interleukin-4 induced gene 1" (IL4I1) is the best characterized. IL4I1 mainly oxidizes l-phenylalanine. It is a secreted enzyme physiologically produced by antigen presenting cells of the myeloid and B cell lineages and T helper type (Th) 17 cells. Important roles of IL4I1 in the fine control of the adaptive immune response in mice and humans have emerged during the last few years. Indeed, IL4I1 inhibits T cell proliferation and cytokine production and facilitates naïve CD4⁺ T-cell differentiation into regulatory T cells in vitro by limiting the capacity of T lymphocytes to respond to clonal receptor stimulation. It may also play a role in controlling the germinal center reaction for antibody production and limiting Th1 and Th17 responses. IL4I1 is expressed in tumor-associated macrophages of most human cancers and in some tumor cell types. Such expression, associated with its capacity to facilitate tumor growth by inhibiting the anti-tumor T-cell response, makes IL4I1 a new potential druggable target in the field of immunomodulation in cancer.
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http://dx.doi.org/10.3390/molecules22122151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6149928PMC
December 2017

Quantitative Analysis of Proteome Modulations in Alveolar Epithelial Type II Cells in Response to Pulmonary Infection.

Mol Cell Proteomics 2017 Dec 26;16(12):2184-2198. Epub 2017 Sep 26.

From the ‡University Duisburg-Essen, University Hospital, Institute for Experimental Immunology and Imaging, 45147 Essen; Germany;

The ubiquitous mold threatens immunosuppressed patients as inducer of lethal invasive aspergillosis. conidia are airborne and reach the alveoli, where they encounter alveolar epithelial cells (AEC). Previous studies reported the importance of the surfactant-producing AEC II during infection experiments using cell lines. We established a negative isolation protocol yielding untouched primary murine AEC II with a purity >90%, allowing analyses of the cells, which encountered the mold By label-free proteome analysis of AEC II isolated from mice 24h after or mock infection we quantified 2256 proteins and found 154 proteins to be significantly differentially abundant between both groups (ANOVA value ≤ 0.01, ratio of means ≥1.5 or ≤0.67, quantified with ≥2 peptides). Most of these proteins were higher abundant in the infected condition and reflected a comprehensive activation of AEC II on interaction with This was especially represented by proteins related to oxidative phosphorylation, hence energy production. However, the most strongly induced protein was the l-amino acid oxidase (LAAO) Interleukin 4 induced 1 (IL4I1) with a 42.9 fold higher abundance (ANOVA value 2.91). IL4I1 has previously been found in B cells, macrophages, dendritic cells and rare neurons. Increased IL4I1 abundance in AEC II was confirmed by qPCR, Western blot and immunohistology. Furthermore, infected lungs showed high levels of IL4I1 metabolic products. Importantly, higher IL4I1 abundance was also confirmed in lung tissue from human aspergilloma. Because LAAO are key enzymes for bactericidal product generation, AEC II might actively participate in pathogen defense. We provide insights into proteome changes of primary AEC II thereby opening new avenues to analyze the molecular changes of this central lung cell on infectious threats. Data are available ProteomeXchange with identifier PXD005834.
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http://dx.doi.org/10.1074/mcp.RA117.000072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5724180PMC
December 2017

IL4-induced gene 1 is secreted at the immune synapse and modulates TCR activation independently of its enzymatic activity.

Eur J Immunol 2018 01 11;48(1):106-119. Epub 2017 Oct 11.

INSERM, U955, Equipe 09, Créteil, France.

Amino-acid catabolizing enzymes produced by mononuclear phagocytes play a central role in regulating the immune response. The mammalian phenylalanine-catabolizing enzyme IL4-induced gene 1 (IL4I1) inhibits effector T lymphocyte proliferation and facilitates regulatory T-cell development. IL4I1 expression by macrophages of various human tumors may affect patient prognosis as it facilitates tumor escape from the T-cell response in murine models. Its enzymatic activity appears to participate in its effects, but some actions of IL4I1 remain unclear. Here, we show that the presence of IL4I1 during T-cell activation decreases early signaling events downstream of TCR stimulation, resulting in global T-cell inhibition which is more pronounced when there is CD28 costimulation. Surprisingly, the enzymatic activity of IL4I1 is not involved. Focal secretion of IL4I1 into the immune synaptic cleft and its binding to CD3 lymphocytes could be important in IL4I1 immunosuppressive mechanism of action.
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http://dx.doi.org/10.1002/eji.201646769DOI Listing
January 2018

Immunosuppressive enzymes in the tumor microenvironment.

FEBS Lett 2017 10 30;591(19):3135-3157. Epub 2017 Aug 30.

INSERM, U955, Equipe 09, Créteil, France.

Antigen encounter by T lymphocytes induces important metabolic changes. Antitumor T lymphocytes enter in a metabolic competition with tumors, which divert feedback mechanisms of the immune response. Immunosuppressive enzymes, modifying the nutrient availability and leading to the production of toxic catabolites, represent one of these mechanisms, contributing to the metabolic halo in which T lymphocytes evolve during immune responses. Two classes of immunosuppressive enzymes, expressed by the tumor cells or by cells of the microenvironment, have been described: those catabolizing essential or semiessential amino acids, tryptophan, arginine, and phenylalanine and the ectoenzymes, which degrade the ATP to produce adenosine. These enzymes are described, as well as some of the ongoing clinical trials aiming to block them in cancer treatment.
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http://dx.doi.org/10.1002/1873-3468.12784DOI Listing
October 2017

IL4-induced gene 1 promotes tumor growth by shaping the immune microenvironment in melanoma.

Oncoimmunology 2017;6(3):e1278331. Epub 2017 Jan 13.

Inserm, U1016, Institut Cochin, Paris, France; Cnrs, UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

Amino acid catabolizing enzymes emerged as a crucial mechanism used by tumors to dampen immune responses. The L-phenylalanine oxidase IL-4 induced gene 1 (IL4I1) is expressed by tumor-associated myeloid cells of most solid tumors, including melanoma. We previously provided the only evidence that IL4I1 accelerates tumor growth by limiting the CD8 T cell mediated immune response, in a mouse model of melanoma cell transplantation. Here, we explored the role of IL4I1 in Ret mice, a spontaneous model of melanoma. We found that IL4I1 was expressed by CD11b myeloid cells and that its activity correlated with disease aggressiveness. IL4I1 did not enhance tumor cell proliferation or angiogenesis, but orchestrated the remodeling of the immune compartment within the primary tumor. Indeed, the inactivation of IL4I1 limited the recruitment of polymorphonuclear myeloid-derived suppressor cells and enhanced the infiltration by Th1 and cytotoxic T cells, thus delaying tumor development and metastatic dissemination. Accordingly, human primary melanomas that were poorly infiltrated by IL4I1 cells exhibited a higher density of CD8 T cells. Collectively, our findings strengthen the rationale for therapeutic targeting of IL4I1 as one of the key immune regulators.
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http://dx.doi.org/10.1080/2162402X.2016.1278331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384381PMC
January 2017

Sequential cyclophosphamide-bortezomib-dexamethasone unmasks the harmful cardiac effect of dexamethasone in primary light-chain cardiac amyloidosis.

Eur J Cancer 2017 05 20;76:183-187. Epub 2017 Mar 20.

Paris XII University, UPEC, Créteil, France; GRC Amyloid Research Institute, IMRB-INSERM U955, and Mondor Amyloidosis Network, Créteil, France; Department of Cardiology, AP-HP, Henri-Mondor Hospital, Créteil, France; DHU ATVB, Créteil, France; Inserm Clinical Investigation Center 1430, Créteil, F-94000, France. Electronic address:

Chemotherapy combining cyclophosphamide, bortezomib and dexamethasone is widely used in light-chain amyloidosis. The benefit is limited in patients with cardiac amyloidosis mainly because of adverse cardiac events. Retrospective analysis of our cohort showed that 39 patients died with 42% during the first month. A new escalation-sequential regimen was set to improve the outcomes. Nine newly-diagnosed patients were prospectively treated with close monitoring of serum N-terminal pro-brain natriuretic peptide, troponin-T and free light chains. The results show that corticoids may destabilise the heart through fluid retention. Thus, a sequential protocol may be a promising approach to treat these patients.
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http://dx.doi.org/10.1016/j.ejca.2017.02.004DOI Listing
May 2017

[Cardiac amyloidosis: How to recognize them and manage them?]

Presse Med 2016 Oct 1;45(10):845-855. Epub 2016 Aug 1.

CHU Henri-Mondor, service de cardiologie, 94010 Créteil cedex, France; CHU Henri-Mondor, réseau Amylose Mondor, 94010 Créteil cedex, France; Université Paris-Est-Créteil, faculté de médecine, 94010 Créteil cedex, France; CHU Henri-Mondor, GRC-ARI, DHU-ATVB, Inserm U955, IMRB, 94010 Créteil cedex, France.

Cardiac amyloidosis must be suspected in all cases of hypertrophic cardiomyopathy with preserved left ventricular ejection fraction to allow specific management. Final diagnosis needs pathological evidence, but bone scintigraphy may be an alternative for TTR amyloidosis. Invasive samplings are limited by new tools. Amyloidosis typing is required to start specific therapies if possible. Main specific treatments that are available are chemotherapy for AL; transthyretin stabilizer or gene therapy, studied for TTR-related cardiac amyloidosis.
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http://dx.doi.org/10.1016/j.lpm.2016.07.001DOI Listing
October 2016

(99m)Tc-HMDP scintigraphy rectifies wrong diagnosis of AL amyloidosis.

J Nucl Cardiol 2015 Aug 22;22(4):853-7. Epub 2015 May 22.

UPEC, 94000, Créteil, France,

A 71-year-old African man without history of cardiac disease was referred to our center for dyspnea. Transthoracic echocardiogram and cardiac MRI were suggestive of cardiac amyloidosis (CA). The diagnosis of the light-chain cardiac amyloidosis (AL-CA) was made after a first endomyocardial biopsy. Accordingly chemotherapy was started. Systematic 99mTc-HMDP scintigraphy showed moderate cardiac uptake (visual score of 2), unusual for AL-CA, and permitted to rectify the diagnosis. Hereditary transthyretin cardiac amyloidosis was confirmed by a second endomyocardial biopsy with a positive Congo-red and anti-transthyretin antibody stainings, mass spectrometry and genetic analysis (Val122Ile mutation).
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http://dx.doi.org/10.1007/s12350-015-0176-6DOI Listing
August 2015

The immunosuppressive enzyme IL4I1 promotes FoxP3(+) regulatory T lymphocyte differentiation.

Eur J Immunol 2015 Jun 17;45(6):1772-82. Epub 2015 Apr 17.

INSERM, U955, Equipe 09 and Equipe 04, Créteil, France.

IL4I1 (interleukin-4-induced gene 1) is a phenylalanine oxidase produced mainly by APCs of myeloid origin, and converts phenylalanine (Phe) to phenylpyruvate, hydrogen peroxide, and ammonia. We have previously shown that IL4I1 is highly expressed by tumor-associated macrophages from various human cancers and facilitates immune evasion from the cytotoxic response in a murine tumor model. Indeed, IL4I1 inhibits T-cell proliferation via hydrogen peroxide toxicity on effector/memory T cells. Here, we explored the effect of IL4I1 on naïve CD4(+) T-cell differentiation. We show that IL4I1 stimulates the generation of Foxp3(+) regulatory T (Treg) cells in vitro from human and mouse T cells. This effect was observed with IL4I1 from different sources, including the naturally produced enzyme. Conversely, IL4I1 limits Th1 and Th2 polarization while modifying the Th17 phenotype, in particular, by inducing its own production. Analysis of Treg-cell induction under conditions of Phe deprivation and hydrogen peroxide addition suggests that Phe consumption by the enzyme participates in Treg-cell enrichment. In line with this hypothesis, IL4I1 inhibits mTORC1 signaling shortly after T-cell activation. Thus, the IL4I1 enzyme may act on T cells both by direct inhibition of effector cell proliferation and by indirect immunoregulation mediated by Treg-cell induction.
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http://dx.doi.org/10.1002/eji.201445000DOI Listing
June 2015

Antibacterial properties of the mammalian L-amino acid oxidase IL4I1.

PLoS One 2013 23;8(1):e54589. Epub 2013 Jan 23.

INSERM, U955, IMRB, Equipe 09, Créteil, France.

L-amino acid oxidases (LAAO) are flavoproteins that catalyze the oxidative deamination of L-amino acids to a keto-acid along with the production of H₂O₂ and ammonia. Interleukin 4 induced gene 1 (IL4I1) is a secreted LAAO expressed by macrophages and dendritic cells stimulated by microbial derived products or interferons, which is endowed with immunoregulatory properties. It is the first LAAO described in mammalian innate immune cells. In this work, we show that this enzyme blocks the in vitro and in vivo growth of Gram negative and Gram positive bacteria. This antibiotic effect is primarily mediated by H₂O₂ production but is amplified by basification of the medium due to the accumulation of ammonia. The depletion of phenylalanine (the primary amino acid catabolized by IL4I1) may also participate in the in vivo inhibition of staphylococci growth. Thus, IL4I1 plays a distinct role compared to other antibacterial enzymes produced by mononuclear phagocytes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0054589PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3552961PMC
June 2013

Follicular peripheral T-cell lymphoma expands the spectrum of classical Hodgkin lymphoma mimics.

Am J Surg Pathol 2012 Nov;36(11):1636-46

Département de Pathologie, APHP, Groupe Henri Mondor, Créteil, France.

Epstein-Barr virus (EBV)-infected B cells with Reed-Sternberg-like cell (RS) features may occur in peripheral T-cell lymphomas (PTCLs), especially in angioimmunoblastic T-cell lymphoma. Here, we report 5 patients presenting with lymphadenopathy whose first biopsies demonstrated nodular lymphoid proliferations containing scattered CD30+, CD15+, EBV+ Hodgkin and Reed-Sternberg-like cells, which led to an initial diagnosis of lymphocyte-rich classical Hodgkin lymphoma. However, the uncommon clinical features and/or the occurrence of relapse as PTCL prompted review of the biopsies with expanded immunohistologic and molecular studies and revision of the diagnoses to follicular variant of PTCL (F-PTCL). All cases had atypical small to medium-sized CD3+ T cells that expressed CD10 (4/5) and the follicular helper T-cell (TFH) antigens BCL6, PD1, CXCL13, and ICOS. All demonstrated clonal T cells with a similar pattern in multiple samples from 4 patients. In 2 cases, flow cytometry demonstrated circulating lymphocytes with an abnormal sCD3+, CD4+, ICOS+ immunophenotype. Two patients had a skin rash at presentation, and 1 had B symptoms. Two of the 4 patients treated with polychemotherapy are alive at 3 and 6 years after first diagnosis. These cases highlight how some F-PTCLs may closely mimic lymphocyte-rich classical Hodgkin lymphoma requiring careful assessment of the T cells before rendering the latter diagnosis. The functional properties of TFH cells might lead to the presence of EBV-positive B blasts with RS-like features in TFH-derived PTCL such as angioimmunoblastic T-cell lymphoma and F-PTCL.
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http://dx.doi.org/10.1097/PAS.0b013e318268d9ffDOI Listing
November 2012

Epidermotropic secondary cutaneous involvement by relapsed angioimmunoblastic T-cell lymphoma mimicking mycosis fungoides: a case report.

J Cutan Pathol 2012 Dec 10;39(12):1119-24. Epub 2012 Oct 10.

Department of Pathology, Hospital General San Juan de Dios, Guatemala City, Guatemala.

Angioimmunoblastic T-cell lymphoma (AITL) is frequently associated with skin lesions, but epidermotropic cutaneous involvement has never been described. A 37-year-old man presented with erythematous and pruriginous plaques, clinically suggestive of mycosis fungoides, distributed all over the body, 3 weeks after the last line of a polychemotherapy, given for an AITL diagnosed 1 year earlier on a lymph node biopsy. Skin biopsy showed an epidermotropic CD4(+) T-cell lymphoma, so that a diagnosis of mycosis fungoides was first proposed. Further investigations showed that atypical lymphocytes strongly expressed CD10 and markers of follicular helper T cells (T(FH) ) including PD1, BCL-6 and CXCL13. The diagnosis of an unusual epidermotropic cutaneous localization of the AITL was finally made, supported by the presence of the same T-cell clone in the initial lymph node biopsy and the skin. We therefore recommend performing markers of T(FH) cells in patients with unusual epidermotropic cutaneous T-cell lymphomas, particularly if they have any clinical features suggestive of AITL.
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http://dx.doi.org/10.1111/cup.12022DOI Listing
December 2012

Antiproliferative activity of trans-avicennol from Zanthoxylum chiloperone var. angustifolium against human cancer stem cells.

J Nat Prod 2012 Feb 3;75(2):257-61. Epub 2012 Feb 3.

Laboratoire de Pharmacognosie Associé au CNRS UMR 8076 BioCIS, LabEx LERMIT, Faculté de Pharmacie, Université Paris-Sud, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France.

Zanthoxylum chiloperone var. angustifolium root bark was studied with the aim of finding novel molecules able to overcome cancer stem cell chemoresistance. Purification of a methanol-soluble extract resulted in the isolation of a known pyranocoumarin, trans-avicennol (1). Compound 1 demonstrated antiproliferative activity on glioma-initiating cells, whereas it was inactive on human neural stem cells. trans-Avicennol (1) activated the MAPK/ERK pathway and was also evaluated for its ability to inhibit the enzyme indoleamine-2,3-dioxygenase.
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http://dx.doi.org/10.1021/np2004165DOI Listing
February 2012

IL4I1: an inhibitor of the CD8⁺ antitumor T-cell response in vivo.

Eur J Immunol 2011 Jun 13;41(6):1629-38. Epub 2011 May 13.

INSERM, U955, Créteil, France.

The L-phenylalanine oxidase IL4I1 inhibits T-cell proliferation in vitro through H(2) O(2) production, and is highly expressed in tumor-associated macrophages. IL4I1 is also detected by immunohistochemistry in neoplastic cells from several B-cell lymphomas and some non-lymphoid tumors. To evaluate IL4I1's effect on tumor growth, we developed a mouse melanoma model constitutively coexpressing IL4I1 and the GP33 epitope. After GP33 vaccination, tumors developed more frequently in mice injected with IL4I1-expressing cells in comparison with mice receiving control cells. Tumor escape was preceded by a rapid diminution of IFN-γ-producing cytotoxic antitumor CD8(+) T cells. Moreover, tumor incidence was already increased when only 20% of the injected cells expressed IL4I1. The minimal IL4I1 activities leading to tumor escape were close to those detected in human melanoma and mesothelioma. Thus, we demonstrate the immunosuppressive functions of IL4I1 in vivo and suggest that IL4I1 facilitates human tumor growth by inhibiting the CD8(+) antitumor T-cell response.
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http://dx.doi.org/10.1002/eji.201041119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3472400PMC
June 2011

Dichotomy between factors inducing the immunosuppressive enzyme IL-4-induced gene 1 (IL4I1) in B lymphocytes and mononuclear phagocytes.

Eur J Immunol 2010 Sep;40(9):2557-68

INSERM, Unité 955, IMRB, eq 09, Créteil, France.

MPhi and DC are key elements in the control of tissue homeostasis and response to insult. In this work, we demonstrate that MPhi and DC are the major producers of the phenylalanine catabolizing enzyme IL-4-induced gene 1 (IL4I1) under inflammatory conditions. IL4I1 was first described in B cells, which indeed can produce IL4I1 in vitro, although at much lower levels. In vivo, IL4I1 is highly expressed by MPhi and DC of Th1 granulomas (sarcoidosis, tuberculosis) but poorly detected in Th2 granulomas (schistosomiasis). In vitro, expression of the enzyme is induced in mononuclear phagocytes by various pro-inflammatory stimuli through the activation of the transcription factors NF-kappaB and/or STAT1. B cells also express IL4I1 in response to NF-kappaB-activating stimuli such as CD40L; however, in contrast to myeloid cells, B cells are insensitive to IFN-gamma but respond to stimulation of the IL-4/STAT6 axis. As we show that the expression of IL4I1 by a monocytic cell line inhibits T-cell proliferation and production of IFN-gamma and inflammatory cytokines, we propose that IL4I1 participates in the downregulation of Th1 inflammation in vivo.
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http://dx.doi.org/10.1002/eji.201040428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3001484PMC
September 2010

Treatment of t(11;18)-positive gastric mucosa-associated lymphoid tissue lymphoma with rituximab and chlorambucil: clinical, histological, and molecular follow-up.

Leuk Lymphoma 2010 Feb;51(2):284-90

Service d'Hépatologie et de Gastroentérologie, APHP, Groupe hospitalier Henri Mondor - Albert Chenevier, Créteil, France.

Translocation t(11;18) is a factor predictive of poor response to treatment of gastric marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT). We treated 13 patients with t(11;18)-positive gastric MALT lymphoma with the combination of rituximab and chlorambucil (nine patients as first treatment and four as second line therapy). The response to treatment was assessed on endoscopy, histology and molecular parameters including clonality and t(11;18) (median follow-up: 2 years). Macroscopic lesions disappeared in all cases. Histological remission was observed in 100% of the patients at the end of follow-up. At week 25, B cell monoclonality and t(11;18)-positive tumor cells were still detected in 77% and 73%, respectively. However, at long term follow-up, the tumor B cell clone was present in only 30% whereas the t(11;18) was still detected in 70%. The combination of rituximab - chlorambucil is highly effective in t(11;18)-positive gastric MALT lymphoma. Molecular disease persists despite histological remission. t(11;18) is more sensitive than B cell clonality for the monitoring of residual molecular disease.
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http://dx.doi.org/10.3109/10428190903431820DOI Listing
February 2010

DNA vaccination induces WT1-specific T-cell responses with potential clinical relevance.

Blood 2008 Oct 23;112(7):2956-64. Epub 2008 May 23.

Inserm U-841, Institut Mondor de Recherche Biomédicale (IMRB), Département d'Immunologie, Dermatologie et Oncologie, Créteil, France.

The Wilms tumor antigen, WT1, is associated with several human cancers, including leukemia. We evaluated WT1 as an immunotherapeutic target using our proven DNA fusion vaccine design, p.DOM-peptide, encoding a minimal tumor-derived major histocompatibility complex (MHC) class I-binding epitope downstream of a foreign sequence of tetanus toxin. Three p.DOM-peptide vaccines, each encoding a different WT1-derived, HLA-A2-restricted epitope, induced cytotoxic T lymphocytes (CTLs) in humanized transgenic mice expressing chimeric HLA-A2, without affecting hematopoietic stem cells. Mouse CTLs killed human leukemia cells in vitro, indicating peptide processing/presentation. Low numbers of T cells specific for these epitopes have been described in cancer patients. Expanded human T cells specific for each epitope were lytic in vitro. Focusing on human WT1(37-45)-specific cells, the most avid of the murine responses, we demonstrated lysis of primary leukemias, underscoring their clinical relevance. Finally, we showed that these human CTL kill target cells transfected with the relevant p.DOM-peptide DNA vaccine, confirming that WT1-derived epitopes are presented to T cells similarly by tumors and following DNA vaccination. Together, these data link mouse and human studies to suggest that rationally designed DNA vaccines encoding WT1-derived epitopes, particularly WT1(37-45), have the potential to induce/expand functional tumor-specific cytotoxic responses in cancer patients.
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http://dx.doi.org/10.1182/blood-2008-02-137695DOI Listing
October 2008

Study of the reactive dendritic cells in small B-cell lymphoproliferations of the skin.

Virchows Arch 2007 Apr 15;450(4):441-7. Epub 2007 Feb 15.

Département de Pathologie, Hôpital Henri Mondor, VI AP-HP, Université Paris XII, Créteil, France.

Distinguishing between low-grade primary cutaneous B-cell lymphoma (LG-pCBCL) and cutaneous lymphoid hyperplasia (CLH) based on histological features is often difficult. CLH lesions contain numerous reactive cells of the histiocyte lineage [Langerhans cells (LC), dermal dendritic cells (DDC), and macrophages], which are also often present in CBCL. The aim of this study was to determine whether immunohistochemical detection of those cells could help differentiate between CLH and LG-pCBCL. We determined the percentages of those histiocytic cells in the dermal infiltrates of 45 cases of cutaneous lymphoproliferations comprising 16 CLH and 29 LG-pCBCL (19 follicle-center cell lymphomas and 10 marginal zone lymphomas) by immunohistochemical labeling with antibodies to CD1a, FXIIIa, and CD68 to respectively detect LC, DDC, and macrophages. To avoid observer-dependent bias, an automated morphometric analysis method was used to recognize immunoreactive cells and calculate their percentages within the infiltrate. FXIIIa(+) cells were significatively more frequent in CLH than in LG-pCBCL, whereas CD1a(+) and CD68(+) cell frequencies were comparable in the two groups. The results of our study suggest that DDC might play an important role in the genesis of cutaneous lymphomas.
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http://dx.doi.org/10.1007/s00428-007-0372-0DOI Listing
April 2007