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ABSTRACT: Rejection is still the major cause of allograft loss following organ transplantation and a more complete comprehension of the alloimmune response is required in order to develop new therapeutic approaches. Allogenicity is primarily generated by the expression of major histocompatibility complex (MHC) molecules in the donor organ. Graft microvascular endothelial cells express both HLA class I and class II molecules. They are the first target of the allogeneic response because of their vascular localization and are also able to present antigen to recipient T cells. The endothelium can therefore be considered as both a stimulator of and a target for alloimmune responses and both aspects require further study. We have established a model of constitutive expression of HLA-DR by human microvascular endothelial cells following transduction with a lentiviral vector. This model was employed in a study demonstrating that endothelial cells can induce allogeneic expansion of regulatory and pro-inflammatory CD4(+) T lymphocyte subsets. Because microvascular endothelial cells rapidly lose their expression of HLA-DR ex vivo, this experimental system of lentiviral-mediated expression of HLA-DR allows the study of alloantigen presentation without requiring addition of inflammatory cytokines and thus provides a model for the study of the intra-graft allogeneic CD4(+) T cell response at the single-cell level.
Methods in molecular biology (Clifton, N.J.) 01/2013; 960:461-472.
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Nora Hamdani,
Claire Daban-Huard,
Mohamed Lajnef,
Jean-Romain Richard,
Marine Delavest,
Ophélia Godin,
Emmanuel Le Guen,
François-Eric Vederine,
Jean-Pierre Lépine,
Stéphane Jamain,
Josselin Houenou,
Philippe Le Corvoisier,
Masayuki Aoki,
Helene Moins-Teisserenc, Dominique Charron,
Rajagopal Krishnamoorthy,
Robert Yolken,
Faith Dickerson,
Ryad Tamouza,
Marion Leboyer
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ABSTRACT: BACKGROUND: Prenatal exposure to viruses or parasites with tropism for the central nervous system is one of the risk factors for psychotic disorders. However, the relationship between past exposure to Toxoplasma gondii (T. gondii) and incidence of bipolar disorders (BD) is poorly documented across populations. METHODS: We explored the potential association between T. gondii exposure and BD in France, a country of high prevalence of Toxoplasmosis, comparing the prevalence of serological markers (IgG/IgM class antibodies) for T. gondii infection in 110 BD patients and 106 healthy controls all living in France. In a subgroup of 42 patients and 42 controls we also evaluated the levels of interleukin 6 (IL-6) transcripts, an adjunct marker of inflammation. RESULTS: We found that the sero-positive group for IgG antibodies to T. gondii had a 2.7 fold odds of having BD as compared to the sero-negative group (OR=2.17 CI 95%=1.09-4.36, p=0.028). Despite the fact that BD patients had significantly higher levels of IL-6 than the non-patient controls, no notable association between T. gondii status and IL-6 transcript levels was found. We did not find any clinical or demographic correlates of Toxoplasma exposure in the study population. LIMITATIONS: Our results are to be interpreted with caution because of our small sample size. RESULTS: We confirm the association between seropositive status to T. gondii and bipolar disorders reported in other populations and extend it to French patients. Our data strengthen the importance of early detection of T. gondii infected patients in order to propose specific and adequate treatments.
Journal of affective disorders 12/2012; · 3.76 Impact Factor
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Annalisa Ruggeri,
Vanderson Rocha,
Emeline Masson,
Myriam Labopin,
Renato Cunha,
Lena Absi,
Ali Boudifa,
Brigitte Coeffic,
Anne Devys,
Muriel De Matteis, [......],
Isabelle Jollet,
Dominique Masson,
Béatrice Pédron,
Pascale Perrier,
Christophe Picard,
Annie Ramouneau-Pigot,
Fernanda Volt, Dominique Charron,
Eliane Gluckman,
Pascale Loiseau
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ABSTRACT: Background. Graft failure is a major complication after unrelated cord blood transplantation. Presence of HLA-antibodies before cord blood transplantation may impact graft failure. Design and Methods. To analyze the effect of anti-HLA-antibodies on unrelated cord blood transplantation outcomes, we analyzed 294 unrelated cord blood transplant recipients after reduced intensity conditioning regimen. The majority of the patients (82%) were transplanted for malignancies, 60% with double-unrelated cord blood transplant, 63% were HLA mismatched. Retrospectively, pre-unrelated cord blood transplant serum was tested for HLA-Ab using LuminexTM platform. Results were interpreted as mean fluorescence intensity (MFI) against donor-specific mismatch. Results. Among 62 recipients (23%) who had anti-HLA- antibodies before unrelated cord blood transplant, 14 patients had donor specific anti-HLA-antibodies (DSA) (7 were donor-specific- anti-HLA-antibodies for single-unrelated cord blood transplant and 7 for double- unrelated cord blood transplant). Donor-specific- anti-HLA-antibodies threshold ranged from 1620-17629 of mean fluorescence intensity (MFI). Cumulative incidence of day-60 neutrophil engraftment was 76%. It was 44% for recipients with donor-specific- anti-HLA-antibodies and 81% in those without donor-specific- anti-HLA-antibodies (p=0.006). The cumulative incidence of 1-year transplant related mortality was 46% in patients with donor-specific- anti-HLA-antibodies and 32% in those without antibodies (p=0.06). The presence of donor-specific-anti-HLA-antibodies was associated with a trend for decreased survival rate (42% vs. 29%, p=0.07). Conclusions. Donor-specific-anti-HLA-antibody in recipients of unrelated cord blood transplant is associated with graft failure and decreased survival. Patient's screening for donor-specific-anti-HLA-antibodies before unrelated cord blood transplantation is recommended before choosing a HLA mismatched cord blood unit. Whenever possible it is important to avoid selecting a unit when the patient has donor-specific-anti-HLA-antibodies against.
Haematologica 12/2012; · 6.42 Impact Factor
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ABSTRACT: Rationale:Transplantation of allogeneic cardiac stem/progenitor cells (CPC) in experimental myocardial infarction promoted cardiac regeneration and improved heart function. While this has enhanced prospects of using allogeneic CPC for cardiac repair, the mechanisms regulating the behavior of these allogeneic cells, which are central to clinical applications, remain poorly understood. Objective: T cells orchestrate the allogeneic adaptive immune response. Therefore, to provide insight into the mechanisms regulating the immunologic behavior of human CPC (hCPC), we investigated the allogeneic T-cell response elicited by cryopreserved c-kit-selected hCPC. Methods and Results: By using an experimental model of allogeneic stimulation, we demonstrate that, whether under inflammatory conditions or not, hCPC do not trigger conventional allogeneic Th1 or Th2 type responses but instead induce proliferation and selective expansion of suppressive CD25(high)CD127(low)HLA-DR(+)FoxP3(high) effector regulatory T cells (Treg). The Treg proliferation and amplification was dependent on the interaction with the B7 family member programmed death-ligand 1 (PD-L1) which is substantially expressed on hCPC and increased under inflammatory conditions. Thus, hCPC in allogeneic settings acquire the capacity to down-regulate an ongoing immune response, which was dependent on PD-L1. Conclusions: Collectively these data reveal that hCPC in allogeneic settings have a "tolerogenic" immune behavior, promoting a contact-PD-L1-dependent regulatory response and a PD-L1-dependent allogeneic-driven immunomodulation. Our study attributes an important role for PD-L1 in the immune behavior of allogeneic hCPC and raises the possibility of using PD-L1 expression as a marker to identify and select low-risk high-benefit allogeneic cardiac repair cells.
Circulation Research 12/2012; · 9.49 Impact Factor
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Monojit Debnath,
Marc Busson,
Stéphane Jamain,
Bruno Etain,
Nora Hamdani,
José Oliveira,
Wahid Boukouaci,
Kahina Amokrane,
Hélène Moins-Teisserenc,
Mohamed Lajnef,
Djaouida Bengoufa,
Alain Malafosse,
Frank Bellivier,
Chantal Henry,
Jean-Pierre Kahn,
Rajagopal Krishnamoorthy, Dominique Charron,
Marion Leboyer,
Ryad Tamouza
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ABSTRACT: Implication of immune processes in bipolar disorder (BD) has recently gained increasing attention. Tolerogenic molecules, among which HLA-G plays a prominent role, mediate the modulation of such processes. The HLA-G locus is characterized by a high number of polymorphisms including a functionally relevant 14 base pair (bp) insertion/deletion (Ins/Del) allele affecting the HLA-G expression. Here, we analyzed the distribution of this polymorphism in 561 BD patients and 161 healthy and found that the HLA-G 14bp Ins/Ins genotype was significantly more prevalent in healthy controls than in patients (corrected p; pc = 0.032) and that the prevalence of such protective genotype is lower among patients born during the winter season as compared to those born in other periods (pc = 0.006). Possible mechanisms between low HLA G expression and resistance to infections as well as potential relationships between infections in early life and susceptibility to BD are discussed.
Human immunology 12/2012; · 2.55 Impact Factor
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Carmen Lefaucheur,
Alexandre Loupy,
Dewi Vernerey,
Jean-Paul Duong-Van-Huyen,
Caroline Suberbielle,
Dany Anglicheau,
Jérôme Vérine,
Thibaut Beuscart,
Dominique Nochy,
Patrick Bruneval, Dominique Charron,
Michel Delahousse,
Jean-Philippe Empana,
Gary S Hill,
Denis Glotz,
Christophe Legendre,
Xavier Jouven
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ABSTRACT: BACKGROUND: Rejection of allografts has always been the major obstacle to transplantation success. We aimed to improve characterisation of different kidney-allograft rejection phenotypes, identify how each one is associated with anti-HLA antibodies, and investigate their distinct prognoses. METHODS: Patients who underwent ABO-compatible kidney transplantations in Necker Hospital and Saint-Louis Hospital (Paris, France) between Jan 1, 1998, and Dec 31, 2008, were included in our population-based study. We assessed patients who provided biopsy samples for acute allograft rejection, which was defined as the association of deterioration in function and histopathological lesions. The main outcome was kidney allograft loss-ie, return to dialysis. To investigate distinct rejection patterns, we retrospectively assessed rejection episodes with review of graft histology, C4d in allograft biopsies, and donor-specific anti-HLA antibodies. FINDINGS: 2079 patients were included in the main analyses, of whom 302 (15%) had acute biopsy-proven rejection. We identified four distinct patterns of kidney allograft rejection: T cell-mediated vascular rejection (26 patients [9%]), antibody-mediated vascular rejection (64 [21%]), T cell-mediated rejection without vasculitis (139 [46%]), and antibody-mediated rejection without vasculitis (73 [24%]). Risk of graft loss was 9·07 times (95 CI 3·62-19·7) higher in antibody-mediated vascular rejection than in T cell-mediated rejection without vasculitis (p<0·0001), compared with an increase of 2·93 times (1·1-7·9; P=0·0237) in antibody-mediated rejection without vasculitis and no significant rise in T cell-mediated vascular rejection (hazard ratio [HR] 1·5, 95% CI 0·33-7·6; p=0·60). INTERPRETATION: We have identified a type of kidney rejection not presently included in classifications: antibody-mediated vascular rejection. Recognition of this distinct phenotype could lead to the development of new treatment strategies that could salvage many kidney allografts. FUNDING: None.
The Lancet 11/2012; · 38.28 Impact Factor
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Régis Peffault de Latour,
Rodrigo T Calado,
Marc Busson,
Jeffrey Abrams,
Nadir Adoui,
Marie Robin,
Jérôme Larghero,
Nathalie Dhedin,
Alienor Xhaard,
Emmanuel Clave, Dominique Charron,
Antoine Toubert,
Pascale Loiseau,
Gérard Socié,
Neal S Young
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ABSTRACT: Telomere attrition induces cell senescence and apoptosis. We hypothesized that age-adjusted pretransplantation telomere length might predict treatment-related mortality (TRM) after hematopoietic stem cell transplantation (HSCT). Between 2000 and 2005, 178 consecutive patients underwent HSCT from HLA-identical sibling donors after myeloablative conditioning regimens, mainly for hematologic malignancies (n = 153). Blood lymphocytes' telomere length was measured by real-time quantitative PCR before HSCT. Age-adjusted pretransplantation telomere lengths were analyzed for correlation with clinical outcomes. After age adjustment, patients' telomere-length distribution was similar among all 4 quartiles except for disease stage. There was no correlation between telomere length and engraftment, GVHD, or relapse. The overall survival was 62% at 5 years (95% confidence interval [CI], 54-70). After a median follow-up of 51 months (range, 1-121 months), 43 patients died because of TRM. The TRM rate inversely correlated with telomere length. TRM in patients in the first (lowest telomere length) quartile was significantly higher than in patients with longer telomeres (P = .017). In multivariate analysis, recipients' age (hazard ratio, 1.1; 95% CI, .0-1.1; P = .0001) and age-adjusted telomere length (hazard ratio, 0.4; 95% CI; 0.2-0.8; P = .01) were independently associated with TRM. In conclusion, age-adjusted recipients' telomere length is an independent biologic marker of TRM after HSCT.
Blood 09/2012; 120(16):3353-9. · 9.90 Impact Factor
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ABSTRACT: Recent studies have revealed the presence of pro-inflammatory and/or regulatory CD4(+) T cells within allografts promoting either graft rejection or tolerance. Histological evidence has identified the microvascular endothelium as the primary site of allograft damage as it is the first site of encounter with the recipient's immune system. The initial view of the human endothelial cell inducing an effector Th1 response leading to graft rejection has been extended by recent results which demonstrate the endothelial cell ability to generate other CD4(+) T cell sub-populations including Th17 and Treg cells. In the transplantation setting, the allo-reactivity of the endothelium with the CD4(+) T cell populations is likely to depend upon multiple factors including the vascular origin of the endothelial cell, the cytokine environment, the presence or absence of pro-inflammatory stimuli including ligands of Toll like receptors and alloantibodies. This review provides an update on the characteristics of the endothelial cell activation of the CD4(+) T cell response and an analysis of the factors, which can modify this activity in favor of either graft rejection or tolerance.
Human immunology 07/2012; · 2.55 Impact Factor
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ABSTRACT: Research on stem cell therapies for regenerative medicine is progressing rapidly. Although the use of autologous stem cells is a tempting choice, there are several instances in which they are either defective or not available in due time. Allogenic stem cells derived from healthy donors presents a promising alternative. Whether autologous or allogenic, recent advances have proven that stem cells are not as immune privileged as they were thought. Therefore understanding the interactions of these cells with the recipient immune system is paramount to their clinical application. Transplantation of stem cells induces humoral as well as cellular immune response. This review focuses on the humoral response elicited by stem cells upon their administration and consequences on the survival and maintenance of the graft. Current transplantation identifies pre- and post-transplantation anti-HLA antibodies as immune rejection and cell signaling effectors. These two mechanisms are likely to operate similarly in the context of SC therapeutics. Ultimately this knowledge will help to propose novel strategies to mitigate the allogenic barriers. Immunogenetics selection of the donor cell and immunomonitoring are key factors to allow the implementation of regenerative stem cell in the clinics.
Human immunology 07/2012; · 2.55 Impact Factor
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ABSTRACT: The role and the mechanisms by which β1 integrins regulate the survival and chemoresistance of T cell acute lymphoblastic leukemia (T-ALL) still are poorly addressed. In this study, we demonstrate in T-ALL cell lines and primary blasts, that engagement of α2β1 integrin with its ligand collagen I (ColI), reduces doxorubicin-induced apoptosis, whereas fibronectin (Fn) had no effect. ColI but not Fn inhibited doxorubicin-induced mitochondrial depolarization, cytochrome c release, and activation of caspase-9 and -3. ColI but not Fn also prevented doxorubicin from down-regulating the levels of the prosurvival Bcl-2 protein family member Mcl-1. The effect of ColI on Mcl-1 occurred through the inhibition of doxorubicin-induced activation of c-Jun N-terminal kinase (JNK). Mcl-1 knockdown experiments showed that the maintenance of Mcl-1 levels is essential for ColI-mediated T-ALL cell survival. Furthermore, activation of MAPK/ERK, but not PI3K/AKT, is required for ColI-mediated inhibition of doxorubicin-induced JNK activation and apoptosis and for ColI-mediated maintenance of Mcl-1 levels. Thus, our study identifies α2β1 integrin as an important survival pathway in drug-induced apoptosis of T-ALL cells and suggests that its activation can contribute to the generation of drug resistance.
Journal of Biological Chemistry 03/2012; 287(21):17065-76. · 4.77 Impact Factor
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Shanmugaapriya Sellathamby,
Kavitha M Lakshmi,
Marc Busson,
Auro Viswabandya,
Biju George,
Vikram Mathews,
Mammen Chandy, Dominique Charron,
Rajagopal Krishnamoorthy,
Ryad Tamouza,
Alok Srivastava
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ABSTRACT: In this study, the impact of polymorphisms in the genes of proinflammatory (IL-β, TNF-α, IL-6, IFN-γ), anti-inflammatory (transforming growth factor [TGF]-β, IL-10, IL-Ra), and other immunoregulatory factors (FcγRIIa, NOS3) along with the conventional risk factors on the rate of hematopoietic recovery and first episodes of bacterial, viral, or invasive fungal infections in 102 patients with β-thalassaemia major who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) with relatively uniform protocols at our center from June 1995 to June 2004 with a minimum follow-up of at least 2 years were studied retrospectively for 180 days after hematopoietic stem cell transplantation (HSCT). Our data show that (1) donor IL-1RN∗2/2 (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.17-5.09; P = .018) and FCγRIIA +4481G/G genotypes (HR, 3.1; 95% CI, 1.56-6.31; P = .001) increased the incidence of bacterial infection; (2) fungal infection was increased in recipients with whose donors had IFN-γ +874T/T genotype (HR, 3.8; 95% CI, 1.08-13.62; P = .037); (3) time to neutrophil recovery was shorter in splenectomized patients (HR, 3.1; 95% CI, 1.70-5.64; P < .001), donors without IL-10 -1082A, -819T, and -592A haplotype (HR, 1.6; 95% CI, 1.02-2.39; P = .039), and recipients with IFN-γ +874A/A genotype (HR, 1.6; 95% CI, 1.05-2.56; P = .029); and (4) time to platelet recovery was shorter in patients with IL-10 -1082A/A genotype (HR, 1.8; 95% CI, 1.14-2.68; P = .010) and with donors having TNF-α -308G/G genotypes (HR, 1.8; 95% CI, 1.06-2.93; P = .028). These data suggest that outcome after allogeneic stem cell transplantation could be affected by many factors. The mechanisms by which they bring about such impact needs further evaluation.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 01/2012; 18(8):1219-26. · 3.15 Impact Factor
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Naima Arji,
Marc Busson,
Ghali Iraqi,
Jamal Eddine Bourkadi,
Abdelaziz Benjouad,
Wahid Boukouaci,
Ouafae Lahlou,
Jouda Ben Amor,
Rajagopal Krishnamoorthy, Dominique Charron,
Rajae El Aouad,
Ryad Tamouza
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ABSTRACT: Both monocyte chemoattractant protein-1 (MCP-1), also designated officially as chemokine (C-C motif) ligand 2 (CCL2), and interleukin-12 p40 (IL-12 p40) molecules, encoded by polymorphic genes, are central components of the immune response to infection by Mycobacterium tuberculosis (Mtb). Their genetic diversity has previously been associated with the outcome of tuberculosis (TB) infection. We investigated whether the MCP-1 -2518 A/G and the IL-12B (p40) +1188 A/C polymorphisms influence susceptibility to or resistance against pulmonary tuberculosis (PTB) in a Moroccan population group.
Genomic DNA from 337 patients along with 204 healthy controls were genotyped for the above-mentioned genetic variations using polymerase chain reaction-based restriction fragment length polymorphism assay.
We found a higher prevalence of homozygous MCP-1 -2518 G allele in healthy individuals than in patients (pc = 0.04; odds ratio = 0.35; 95% confidence interval = 0.13 - 0.86), suggesting a potential protective effect, whereas analysis of IL-12B +1188 variation failed to reveal any such association.
Our results are in agreement with recent findings in Ghanaian patients, complying with the known genetic admixture of the Moroccan population.
The Journal of Infection in Developing Countries 01/2012; 6(1):73-8. · 1.19 Impact Factor
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Coralie Zumelzu,
Christelle Le Roux-Villet,
Pascale Loiseau,
Marc Busson,
Michel Heller,
Françoise Aucouturier,
Valérie Pendaries,
Nicole Lièvre,
Francis Pascal,
Marie-Dominique Brette,
Serge Doan, Dominique Charron,
Fréderic Caux,
Liliane Laroche,
Antoine Petit,
Catherine Prost-Squarcioni
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ABSTRACT: Epidermolysis bullosa acquisita (EBA) is a rare autoimmune bullous disease (AIBD). However, higher EBA incidence and predisposing genetic factor(s) involving an HLA haplotype have been suspected in some populations. This retrospective study assessed the overrepresentation of black patients with EBA, its link with HLA-DRB1*15:03, and their clinical and immunological characteristics. Between 2005 and 2009, 7/13 (54%) EBA and 6/183 (3%) other-AIBD patients seen consecutively in our department were black (P=10(-6)); moreover 7/13 (54%) black patients and 6/183 (3%) white patients had EBA (P=10(-6)). In addition, between 1983 and 2005, 12 black patients had EBA. Finally, among the 19 black EBA patients, most of them had very atypical clinical presentations, 9 were natives of sub-Saharan Africa, 1 from Reunion Island, 7 from the West Indies, and 2 were of mixed ancestry. HLA-DRB1*15:03 allelic frequencies were 50% for African patients, significantly higher than the control population (P<10(-3)), and 21% for the West Indians (nonsignificant). High EBA frequencies have already been reported in American blacks significantly associated with the HLA-DR2. In conclusion, black-skinned patients developing EBA seem to have a genetic predisposition, and EBA should be suspected systematically for every AIBD seen in this population.
Journal of Investigative Dermatology 08/2011; 131(12):2386-93. · 6.31 Impact Factor
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ABSTRACT: In organ transplantation, development of immunosuppressive treatment and improved diagnosis of allograft rejection has resulted in increased allograft survival in recent years. Nevertheless, rejection remains a major cause of graft loss and a better understanding of the characteristics of the allo-immune response is required to identify new diagnostic and therapeutic tools. The allogeneic immune response depends upon a major family of antigenic targets: the Major Histocompatibility Complex molecules (MHC) which are present on donor cells. These molecules are targets of both the humoral and cellular arms of the graft recipient's immune system: T lymphocytes which are implicated in acute cellular rejection and antibodies which are implicated in antibody-mediated rejection (AMR). Allo-recognition of allograft MHC antigens by either T cells or allo-antibodies is the primary event which can ultimately lead to graft rejection. Although immunosuppressive strategies have mainly focused on the T cell response and acute cellular rejection has therefore become relatively rare, antibody mediated rejection (AMR) remains resistant to conventional immunosuppressive treatment and results in frequent graft loss. Damage to the endothelium is a prominent histological feature of AMR underlining the involvement of endothelial cells in initiating the allo-immune response. Furthermore, endothelial cells express both HLA class I and class II molecules in the context of organ transplantation endowing them with the capacity to present antigen to the recipient T cells. The endothelium should therefore be viewed both as a stimulator of, and as a target for allo-immune responses. In this review, we will summarize current knowledge about the implication of endothelial cells in the allo-immune response in the context of organ transplantation.
Immunology letters 05/2011; 139(1-2):1-6. · 2.91 Impact Factor
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British Journal of Haematology 04/2011; 154(3):409-13. · 4.94 Impact Factor
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Benjamin Pariente,
Iulia Mocan,
Matthieu Camus,
Charles-Antoine Dutertre,
Julien Ettersperger,
Pierre Cattan,
Jean-Marc Gornet,
Nicolas Dulphy, Dominique Charron,
Marc Lémann,
Antoine Toubert,
Matthieu Allez
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ABSTRACT: The natural killer group 2 member D (NKG2D) is a stimulatory receptor expressed on a subset of mucosal and peripheral CD4+ T cells in patients with Crohn's disease (CD) and other inflammatory diseases. Ligand activation of NKG2D in patients induces CD4+ T cells to release T-helper (Th) 1 cytokines and become cytotoxic. We investigated the Th17 cytokines produced by T cells that express NKG2D in blood and intestinal mucosa samples from patients with CD.
We isolated CD4+ T cells from peripheral blood and lamina propria samples of patients with CD or ulcerative colitis (UC) and healthy individuals (controls). We analyzed the phenotype and functions of the CD4+NKG2D+ T cells and the cytokines they produce in response to NKG2D stimulation.
In patients with CD, CD4+ T cells that express NKG2D produced high levels of interleukin (IL)-17 and IL-22 and expressed high levels of CCR6, the IL-23 receptor, CD161, and RORC (a transcription factor that regulates expression of Th17 cytokines). CD4+ T cells that produced IL-17 expressed high levels of NKG2D and CD161. Costimulation of NKG2D and the T-cell receptor (TCR) significantly increased production of IL-17 and tumor necrosis factor α by CD4+ T cells, compared with activation of only the TCR. CD4+NKG2D+ T cells also responded to Th17 polarization.
NKG2D is a functional marker of CD4+ T cells that produce IL-17 in patients with CD, via costimulation of the TCR and NKG2D. Reagents developed to block NKG2D might reduce gastrointestinal inflammation in patients with CD.
Gastroenterology 04/2011; 141(1):217-26, 226.e1-2. · 11.68 Impact Factor
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Patrice Hemon,
Francette Jean-Louis,
Kiran Ramgolam,
Chrystelle Brignone,
Manuelle Viguier,
Hervé Bachelez,
Frédéric Triebel, Dominique Charron,
Fawzi Aoudjit,
Reem Al-Daccak,
Laurence Michel
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ABSTRACT: Melanoma is the most aggressive skin cancer in humans that often expresses MHC class II (MHC II) molecules, which could make these tumors eliminable by the immune system. However, this MHC II expression has been associated with poor prognosis, and there is a lack of immune-mediated eradication. The lymphocyte activation gene-3 (LAG-3) is a natural ligand for MHC II that is substantially expressed on melanoma-infiltrating T cells including those endowed with potent immune-suppressive activity. Based on our previous data showing the signaling capacity of MHC II in melanoma cells, we hypothesized that LAG-3 could contribute to melanoma survival through its MHC II signaling capacity in melanoma cells. In this study, we demonstrate that both soluble LAG-3 and LAG-3-transfected cells can protect MHC II-positive melanoma cells, but not MHC II-negative cells, from FAS-mediated and drug-induced apoptosis. Interaction of LAG-3 with MHC II expressed on melanoma cells upregulates both MAPK/Erk and PI3K/Akt pathways, albeit with different kinetics. Inhibition studies using specific inhibitors of both pathways provided evidence of their involvement in the LAG-3-induced protection from apoptosis. Altogether, our data suggest that the LAG-3-MHC II interaction could be viewed as a bidirectional immune escape pathway in melanoma, with direct consequences shared by both melanoma and immune cells. In the future, compounds that efficiently hinder LAG-3-MHC II interaction might be used as an adjuvant to current therapy for MHC II-positive melanoma.
The Journal of Immunology 03/2011; 186(9):5173-83. · 5.79 Impact Factor
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ABSTRACT: Organ transplantation represents a unique therapeutic option for irreparable organ dysfunction and rejection of transplants results from a breakdown in operational tolerance. Although endothelial cells (ECs) are the first target in graft rejection following kidney transplantation, their capacity to alloactivate and generate particular T lymphocyte subsets that could intervene in this process remains unknown. By using an experimental model of microvascular endothelium, we demonstrate that, under inflammatory conditions, human ECs induced proliferation of memory CD4(+)CD45RA(-) T cells and selectively amplified proinflammatory Th17 and suppressive CD45RA(-)HLA-DR(+)FoxP3(bright) regulatory CD4(+) T lymphocytes (Tregs). Although HLA-DR expression on resting microvascular ECs was sufficient to induce proliferation of memory CD4(+) T cells, Treg amplification was dependent on the interaction with CD54, highly expressed only under inflammatory conditions. Moreover, expansion of Th17 cells was dependent on IL-6 and STAT-3, and inhibition of either specifically impaired Th17, without altering Treg expansion. Collectively these data reveal that the HLA-DR(+) ECs regulate the local inflammatory allogeneic response, promoting either an IL-6/STAT-3-dependent Th17 response or a contact-CD54-dependent regulatory response according to the cytokine environment. Finally, these data open therapeutic perspectives in human organ transplantation based on targeting the IL-6/STAT-3 pathway and/or promoting CD54 dependent Treg proliferation.
Proceedings of the National Academy of Sciences 02/2011; 108(7):2891-6. · 9.68 Impact Factor
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ABSTRACT: Adult stem cells are critical for maintaining cellular homeostasis throughout life, yet the effects of age on their regenerative capacity are poorly understood. All lymphoid and myeloid blood cell lineages are continuously generated from hematopoietic stem cells present in human bone marrow. With age, significant changes in the function and composition of mature blood cells are observed. In this study, we report that age-related changes also occur in the human hematopoietic stem cell compartment. We find that the proportion of multipotent CD34(+) CD38(-) cells increases in the bone marrow of elderly (>70 years) individuals. CD34(+) CD38(+) CD90(-) CD45RA(+/-) CD10(-) and CD34(+) CD33(+) myeloid progenitors persist at the same level in the bone marrow, while the frequency of early CD34(+) CD38(+) CD90(-) CD45RA(+) CD10(+) and committed CD34(+) CD19(+) B-lymphoid progenitors decreases with age. In contrast to mice models of aging, transplantation experiments with immunodeficient NOD/SCID/IL-2Rγ null (NSG) mice showed that the frequency of NSG repopulating cells does not change significantly with age, and there is a decrease in myeloid lineage reconstitution. An age-related decrease in the capacity of CD34(+) cells to generate myeloid cells was also seen in colony-forming assays in vitro. Thus, with increasing age, human hematopoietic stem/progenitor cells undergo quantitative changes as well as functional modifications.
Aging cell 01/2011; 10(3):542-6. · 7.55 Impact Factor
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Wahid Boukouaci,
Marc Busson,
Catherine Fortier,
Kahina Amokrane,
Régis Peffault de Latour,
Marie Robin,
Rajagopal Krishnamoorthy,
Antoine Toubert, Dominique Charron,
Gérard Socié,
Ryad Tamouza
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ABSTRACT: Human leukocyte antigen-G (HLA-G) molecules play a prominent role in immune tolerance. Structurally similar to their classical HLA homologs, they are distinct by having high rate of polymorphism in the non-coding regions including a functionally relevant 14-base pair (bp) insertion/deletion (Ins/Del) allele in the 3' untranslated region (3'UTR), rarely examined in a hematopoietic stem cell transplantation (HSCT) setting. Here, we analyzed the potential impact of HLA-G Ins/Del dimorphism on the incidence of acute graft-versus-host disease (aGvHD), transplant-related mortality (TRM), overall survival (OS), and incidence of relapse after HSCT using bone marrow (BM) as stem cell source from HLA-matched donors.
One hundred fifty-seven sibling pairs, who had undergone HSCT, were studied for the distribution of the HLA-G 14 bp Ins/Del polymorphism using a polymerase chain reaction (PCR)-based technique. Potential genetic association with the incidence of aGvHD, TRM, and OS was analyzed by monovariate and multivariate analyses.
Monovariate analysis showed that the homozygous state for the 14-bp Ins allele is a risk factor for severe aGvHD (grade III and IV; P = 0.008), confirmed subsequently by multivariate analysis [hazard ratio (HR) = 3.5; 95% confidence interval (95%CI) = 1.3-9.5; P = 0.012]. We did not find any association between HLA-G polymorphism and the other studied complications.
Our data suggest that the HLA-G low expressor 14 bp Ins allele constitutes a risk factor for the incidence of severe aGvHD in patients who received BM as stem cell source.
Frontiers in immunology. 01/2011; 2:74.
