Service de Recherches en Hémato-Immunologie
Présentation
Le Service de Recherches en Hémato-Immunologie (SRHI) a pour mission l'étude des mécanismes de tolérance immunitaire des greffes tissulaires (solides et liquides), ainsi que des mécanismes immunologiques d'échappement tumoral à la surveillance de l'hôte. Les travaux menés par le SRHI depuis 1992 ont été à l'origine de la description de la fonction de la molécule HLA-G. Le SRHI a établi sa position de leader international sur ce sujet, fédéré de nombreux laboratoires de plusieurs pays, et organisé autour de HLA-G des congrès internationaux et ateliers de travail en 1998, 2000, 2003, 2006, 2009 et 2012 présidés par E.D. Carosella.
Le Service s'organise autour de deux laboratoires :
Immunogénétique et Expression des Gènes (LIEG)
Chef d'équipe : Dr Edgardo D. Carosella
- Groupe de recherche sur la régulation de l’expression des gènes de la réponse immune
- Groupe de recherche sur les mécanismes de la tolérance immunitaire
Immunologie de la Transplantation (LIT)
Chef d'équipe : Dr Nathalie Rouas-Freiss
Thèmes de recherche
Les recherches menées par le LIEG s'articulent autour des thèmes suivants :
- Fonctions immunologiques de la molécule HLA-G dans les mécanismes d'immune tolérance. Caractérisation des différentes configurations structurales de la molécule HLA-G et de leurs récepteurs, étude fonctionnelle ;
- Etude de la fonction et de la pertinence physio-pathologique de la molécule HLA-G au cours de pathologies inflammatoires, virales, et auto-immunes ;
- Implication de la molécule HLA-G dans la greffe des cellules souches et embryonnaires et son application en médecine régénérative ;
- Régulation et expression des gènes de la molécule HLA-G.
En ce qui concerne le LIT :
Notre équipe mène des travaux sur la fonction immunologique de la molécule HLA-G et ses implications en pathologies, notamment en transplantation et en cancérologie. Dans le contexte des tumeurs solides, nous avons démontré (I) l'expression de HLA-G dans les tumeurs de mélanome, du sein et de l'ovaire corrélée avec l'inflammation et l'agressivité de la tumeur. (II) l'induction d'expression d'HLA-G par des facteurs environnementaux tels que les cytokines. Et (III) l'implication fonctionnelle de l'expression de HLA-G permettant à la cellule tumorale d'échapper à l'action des cellules immunes. La progression d’une tumeur HLA-G+ a pu être enrayée in vivo chez la souris après blocage de HLA-G par un anticorps. Dans le contexte des tumeurs liquides, la forme soluble HLA-G inhibe (I) la croissance des clones érythroïdes malins de patients atteints de polycythemia vera, et (II) la prolifération de cellules B lymphomateuses et myélomateuses (Brevet N° PCT/FR2009/000965) révélant pour la première fois un rôle inattendu de HLA-G en tant qu'agent antitumoral au cours d'hémopathies. Ainsi, l'activité de HLA-G serait dépendante de la cellule tumorale selon qu'elle exprime ou non un récepteur inhibiteur capable de lier HLA-G. Bien que constituant un moyen pour les tumeurs solides d'échapper à l'immunosurveillance par le biais d'une inhibition de la réponse antitumorale, HLA-G peut être en mesure d'inhiber la croissance des tumeurs liquides exprimant un de ses récepteurs.
Dans le contexte de la transplantation, nous avons mené deux approches montrant (I) la corrélation clinique entre l’expression de HLA-G au niveau de transplants tolérés cardiaques, pulmonaires, hépatiques et rénaux et une acceptation de la greffe chez ces patients. Le lien entre l'expression de HLA-G et la tolérance observée chez les patients a pu être montré à travers l'activité immunosuppressive de molécules HLA-G purifiées à partir du plasma de patients tolérant leurs greffes. Une corrélation positive a été établie entre l'acceptation de la greffe, HLA-G, et des paramètres reliés à HLA-G tels que l'IL-10, les formes solubles CD4 et CD8 et la présence de cellules T suppressives CD3+CD4low or CD3+ CD8low. (II) l’induction in vivo de la sécrétion de HLA-G chez des patients transplantés rénaux traités par un nouvel immunosuppresseur, le Belatacept*. Les patients exprimant HLA-G pourraient ainsi bénéficier d’un traitement immunosuppresseur restreint réduisant ainsi les effets secondaires indésirables. De plus, l’utilisation de HLA-G ou de dérivés constituerait une nouvelle thérapie anti-rejet. A cet égard, les cellules souches mésenchymateuses ont montré leur efficacité thérapeutique en traitement adjuvant dans la greffe de moelle osseuse et en médecine régénératrice chez des patients irradiés. Nous avons récemment décrit que l’effet immunosuppresseur de ces cellules est dû à son expression de HLA-G. Notre objectif est donc de poursuivre ses travaux en analysant le potentiel thérapeutique de ces cellules en greffe et en réparation osseuse dans le cadre d'une participation à un consortium européen.
[hal-00690715] Expression of functional soluble human leucocyte antigen-G molecules in lymphoproliferative disorders.
Date: 24 avr 2012 - 12:39
Desc: Membrane-bound and soluble human leucocyte antigen-G (sHLA-G) molecules display immunotolerant properties favouring tumour cell escape from immune surveillance. sHLA-G molecules have been detected in several tumour pathologies; this study aimed to evaluate sHLA-G expression in lymphoproliferative disorders. sHLA-G plasma level was significantly increased in 110 of 178 newly diagnosed lymphoid proliferations cases i.e. 59% of chronic lymphocytic leukaemia, 65% of B non-Hodgkin lymphomas (NHL) and 58% of T-NHL. To assess the mechanisms involved in this secretion, the differential effect of cytokines was tested in in vitro cultures of NHL cells. A significant induction of sHLA-G level was shown in T-NHL in contrast with B-NHL and normal equivalent cells, after cytokine stimulation with (i) interferongamma (IFNgamma), interleukin-2 (IL-2) and granulocyte-macrophage colony-stimulating factor, (ii) IL-10 and (iii) transforming growth factor beta. An impact of microenvironment on sHLA-G expression was found in B-NHL as shown by the in vitro effect of addition of normal monocytes. Finally, a functional effect of sHLA-G molecules purified from pathologic plasma was demonstrated by their strong capacity to inhibit T-cell proliferation at concentrations currently observed during these disorders. These results suggest that functional sHLA-G molecules are upregulated in lymphoproliferative disorders which can support their potential immunomodulatory role during this pathology.
[hal-02412773] The p53-inducible TSAP6 gene product regulates apoptosis and the cell cycle and interacts with Nix and the Myt1 kinase
Date: 15 déc 2019 - 22:06
Desc: The p53 tumor suppressor protein plays a crucial role in tumorigenesis by controlling cell-cycle progression and apoptosis. We have previously described a transcript designated tumor suppressor activated pathway-6 (TSAP6) that is up-regulated in the p53-inducible cell line, LTR6. Cloning of the murine and human full-length TSAP6 cDNA revealed that it encodes a 488-aa protein with five to six transmembrane domains. This gene is the murine and human homologue of the recently published rat pHyde. Antibodies raised against murine and human TSAP6 recognize a 50- to 55-kDa band induced by p53. Analysis of the TSAP6 promoter identified a functional p53-responsive element. Functional studies demonstrated that TSAP6 antisense cDNA diminished levels of the 50- to 55-kDa protein and decreased significantly the levels of p53-induced apoptosis. Furthermore, TSAP6 small interfering RNA inhibited apoptosis in TSAP6-overexpressing cells. Yeast two-hybrid analysis followed by GST/in vitro-transcribed/translated pull-down assays and in vivo coimmunoprecipitations revealed that TSAP6 associated with Nix, a proapoptotic Bcl-2-related protein and the Myt1 kinase, a negative regulator of the G(2)/M transition. Moreover, TSAP6 enhanced the susceptibility of cells to apoptosis and cooperated with Nix to exacerbate this effect. Cell-cycle studies indicated that TSAP6 could augment Myt1 activity. Overall, these data suggest that TSAP6 may act downstream to p53 to interface apoptosis and cell-cycle progression.
[hal-00271643] Maternal traces of deep common ancestry and asymmetric gene flow between Pygmy hunter-gatherers and Bantu-speaking farmers.
Date: 9 avr 2008 - 19:03
Desc: Two groups of populations with completely different lifestyles-the Pygmy hunter-gatherers and the Bantu-speaking farmers-coexist in Central Africa. We investigated the origins of these two groups and the interactions between them, by analyzing mtDNA variation in 1,404 individuals from 20 farming populations and 9 Pygmy populations from Central Africa, with the aim of shedding light on one of the most fascinating cultural transitions in human evolution (the transition from hunting and gathering to agriculture). Our data indicate that this region was colonized gradually, with an initial L1c-rich ancestral population ultimately giving rise to current-day farmers, who display various L1c clades, and to Pygmies, in whom L1c1a is the only surviving clade. Detailed phylogenetic analysis of complete mtDNA sequences for L1c1a showed this clade to be autochthonous to Central Africa, with its most recent branches shared between farmers and Pygmies. Coalescence analyses revealed that these two groups arose through a complex evolutionary process characterized by (i) initial divergence of the ancestors of contemporary Pygmies from an ancestral Central African population no more than approximately 70,000 years ago, (ii) a period of isolation between the two groups, accounting for their phenotypic differences, (iii) long-standing asymmetric maternal gene flow from Pygmies to the ancestors of the farming populations, beginning no more than approximately 40,000 years ago and persisting until a few thousand years ago, and (iv) enrichment of the maternal gene pool of the ancestors of the farming populations by the arrival and/or subsequent demographic expansion of L0a, L2, and L3 carriers.
[hal-02879515] Comprehensive landscape of immune-checkpoints uncovered in clear cell renal cell carcinoma reveals new and emerging therapeutic targets.
Date: 23 juin 2020 - 22:59
Desc: Clear cell renal cell carcinoma (ccRCC) constitutes the most common renal cell carcinoma subtype and has long been recognized as an immunogenic cancer. As such, significant attention has been directed toward optimizing immune-checkpoints (IC)-based therapies. Despite proven benefits, a substantial number of patients remain unresponsive to treatment, suggesting that yet unreported, immunosuppressive mechanisms coexist within tumors and their microenvironment. Here, we comprehensively analyzed and ranked forty-four immune-checkpoints expressed in ccRCC on the basis of in-depth analysis of RNAseq data collected from the TCGA database and advanced statistical methods designed to obtain the group of checkpoints that best discriminates tumor from healthy tissues. Immunohistochemistry and flow cytometry confirmed and enlarged the bioinformatics results. In particular, by using the recursive feature elimination method, we show that HLA-G, B7H3, PDL-1 and ILT2 are the most relevant genes that characterize ccRCC. Notably, ILT2 expression was detected for the first time on tumor cells. The levels of other ligand-receptor pairs such as CD70:CD27; 4-1BB:4-1BBL; CD40:CD40L; CD86:CTLA4; MHC-II:Lag3; CD200:CD200R; CD244:CD48 were also found highly expressed in tumors compared to adjacent non-tumor tissues. Collectively, our approach provides a comprehensible classification of forty-four IC expressed in ccRCC, some of which were never reported before to be co-expressed in ccRCC. In addition, the algorithms used allowed identifying the most relevant group that best discriminates tumor from healthy tissues. The data can potentially assist on the choice of valuable immune-therapy targets which hold potential for the development of more effective anti-tumor treatments.
[cea-04516156] Novel landscape of HLA-G isoforms expressed in clear cell renal cell carcinoma patients
Date: 18 juin 2024 - 18:30
Desc: Immune checkpoints are powerful inhibitory molecules that promote tumor survival. Their blockade is now recognized as providing effective therapeutic benefit against cancer. Human leukocyte antigen G (HLA-G), a recently identified immune checkpoint, has been detected in many types of primary tumors and metastases, in malignant effusions as well as on tumor-infiltrating cells, particularly in patients with clear cell renal cell carcinoma (ccRCC). Here, in order to define a possible anticancer therapy, we used a molecular approach based on an unbiased strategy that combines transcriptome determination and immunohistochemical labeling, to analyze in-depth the HLA-G isoforms expressed in these tumors. We found that the expression of HLA-G is highly variable among tumors and distinct areas of the same tumor, testifying a marked inter- and intratumor heterogeneity. Moreover, our results generate an inventory of novel HLA-G isoforms which includes spliced forms that have an extended 5′-region and lack the transmembrane and alpha-1 domains. So far, these isoforms could not be detected by any method available and their assessment may improve the procedure by which tumors are analyzed. Collectively, our approach provides the first extensive portrait of HLA-G in ccRCC and reveals data that should prove suitable for the tailoring of future clinical applications.
Autres contacts
Institut Universitaire d'Hématologie (IUH)
Hôpital St Louis - Pavillon Lailler
1, avenue Claude Vellefaux
75475 PARIS CEDEX 10