Le service de Recherche en Hémato-Immunologie (SRHI) du Commissariat à l'Energie Atomique et aux Energies alternatives a le plaisir de vous annoncer la 9ème Conférence Internationale sur la Molécule HLA-G qui se déroulera au sein de la Fondation Singer-Polignac les 4 et 5 juillet 2022.
C’est en 1998 qu’a été initié ce cycle de réunions triennales qui remportent un succès croissant auprès des scientifiques nationaux et internationaux.
Cette molécule dont le Pr Carosella et son équipe sont à l’origine de la découverte, joue un rôle capital dans la tolérance fœto-maternelle, dans la greffe d’organes, mais aussi, hélas, dans la dissémination tumorale. Les recherches menées jusqu’ici ont permis des progrès importants dans les approches thérapeutiques. HLA-G est en effet considérée aujourd’hui comme un point de contrôle immunitaire fondamental dans la réponse immunitaire anti-tumorale et son rôle dans les maladies inflammatoires et auto-immunes a également été démontré.
July 4, 2022
Plenary Session 1 : HLA-G
Chairpersons: Edgardo D. Carosella, Vera Rebmann
Ouverture du colloque par E.D. Carosella (France)
- Roberta RIZZO (Italy) “Role of HLA-G molecules in SARS-CoV-2 infection"
- Barbara SELIGER (Germany) “Role of HLA-G in tumors and upon COVID-19 infection”
- Anatolij HORUSZKO (USA) “Tolerogenic properties of HLA-G and its receptors in relation to transplant acceptance”
- Nathalie ROUAS-FREISS (France) “HLA-G/ILT2/ILT4 Immune Checkpoint: Function and Clinical Applications”
SYMPOSIUM I : HLA-G in CANCER
Chairpersons: Joël LEMAOULT, Fabio MORANDI
- Investigating HLA-G for accurate detection of the colorectal cancer risk and prognosis using data science tools : different speeds for meaningful outcomes!
Nadia Boujelbene, Marwa Hasni, Sabrine Dhouioui, Kalthoum Tizaoui, Hadda-Imene Ouzari, Safa Bhar Layeb, Inès Zemni, Inès Zidi
- Comprehensive analysis of classical HLA Class I and non classical HLA-F and HLA-G in colon cancer
Hehuan Zhu, Jessica Rolands, Eiman Ahmed, Wouter Hendrickx, Davide Bedognetti, and Peter J K Kuppen
- Evaluation of the specificity of the 4H84 antibody by bioinformatics methods
Kevin Martinez, Fernando Riccillo, Marcela N. Garcia
- Methods for Establishing a Renal Cell Carcinoma Tumor Spheroid Model with Immune Infiltration for Immunotherapeutic Studies
Leonard Lugand, Guillaume Mestrallet, Rebecca Laboureur, Clement Dumont, Fatiha Bouhidel, Malika Djouadou, Alexandra Masson-Lecomte, Francois Desgrandchamps, Stéphane Culine, Edgardo D. Carosella, Nathalie Rouas-Freiss, Joel LeMaoult
- HLA-G expression in transitional carcinoma of the bladder, in Argentine patients, and its relationship with the level of invasion and survival
Damián Moavro, Pablo Colaci, Marcela N. García
PLENARY SESSION 2
HLA-G IMMUNE FUNCTION
Chairpersons: Nathalie ROUAS-FREISS, Anatolij HORUZSKO
- Silvia GREGORI (Italy) “HLA-G-expressing DC-10 a biomarker of tolerance.”
- Katsumi MAENAKA (Japan) “Structural aspects and antibody binding of HLA-G isoforms”
- Laurence AMIOT (France) "HLA-G is mainly expressed by mast cells in the fibrotic regions of liver, lung and kidney”
- Fabio MORANDI (Italy) “Interactions between HLA-G and other immune checkpoints”
PLENARY SESSION 3
HLA-G, COVID and PARASITE INFECTIONS
Chairpersons: Fabio Morandi
- Daria BORTOLOTTI (Italy) "SARS-CoV-2 infection in placental tissues: altered expression of HLA-G molecules”
- Hana ROHN (Germany) “Systematic analysis of HLA-G in COVID-19 disease”
- David COURTIN (France) “LILRB1 and LILRB2 expression and susceptibility to malaria”
SYMPOSIUM II: HLA-G and DISEASE
Chairpersons: Antoine DURRBACH, Eduardo A. DONADI
- Combined plasma levels of IL-10 and testosterone, but not soluble HLA-G5, predict the risk of death in CONVID-19 patients
Giada Amodio, Paolo Capogrosso, Marina Pontillo, Michela Tassara, Luca Boeri, Cristina Carenzi, Daniele Cignoli, Anna Maria Ferrara, Giuseppe A. Ramirez, Cristina Tresoldi, Massimo Locatelli, Luca Santoleri, Antonella Castagna, Alberto Zangrillo, Francesco De Cobelli, Moreno Tresoldi, Giovanni Landoni, Patrizia Rovere-Querini, Fabio Ciceri, Francesco Montorsi, Andrea Salonia, Silvia Gregori
Pre-clinical development and characterization of a decitabine-induced regulatory HLA-G + CD4 + -T cell enriched cell product against GVHD
M. Lysandrou, D. Kefala, P. Christofi, P.G. Papayanni, C. Pieridou, N. Savvopoulos, A.-L. Chatzidaniil, M. Kyriakou, P. Costeas, A. Papadopoulou, E. Yannaki, A. Spyridonidis
Wound healing by allogenic transplantation of umbilical cord mesenchymal stem cells in different species
Ailén Iribarne, María Belén Palma, Camila Seoane Rocha, Laura Andrini, Fernando Riccillo, Guillermo Buero, Marcos Torres, Santiago Bruno, Pablo Pelinski, Santiago Miriuka, Edgardo D. Carosella, Marcela N. Garcia
HLA-G and CD152 expression levels encourage the use of umbilical cord tissue-derived mesenchymal stromal cells as an alternative for immunosuppressive therapy
Bernardo Zoehler, Letícia Fracaro, Lidiane Maria Boldrini Leite, José Samuel da Silva, Paul Travers, Paulo Roberto Slud Brofman, Alexandra Cristina Senegaglia and Maria da Graça Bicalho
Proinflammatory cytokine and hypoxic condition stimuli enhances the immunomodulatory property of tissue specific mesenchymal stem cells
Rawat Sonali, Mohanty Sujata, Gupta Suchi
HLA-J, a non-pseudogene as a new prognostic marker for therapy response and survival in breast cancer
Würfel FM, Wirtz RM, Winterhalter C, Taffurelli M, Santini D, Mandrioli A, Veltrup E, Ruebner M, Fasching PA, Würfel W, Zamagni C
HLA I class expression as a new prognostic marker of successful implantation
Margarita Shengelia, Bespalova O, Ivashchenko T
July 5, 2022
PLENARY SESSION 4
HLA-G in CANCER
Chairpersons: Silvia GREGORI, François DESGRANDCHAMPS
- Vera REBMANN(Germany) “The clinical relevance of soluble HLA-G and HLA-G bearing extracellular vesicles in breast cancer and their potential to modulate T cell phenotypes”
- Diana LE ROUX(France) “HLA-G isoforms and their new role in tumours development”
- Christophe HENNEQUIN (France) “Immuno and Radiotherapy”
- Joël LE MAOULT (France) “ILT2-expressing cells in urologic cancers”
SYMPOSIUM III: HLA-G in ALLOGRAFT and MSC
Chairpersons: Diego DELGADO, Vera REBMANN
HLA-G gene editing in tumor cell lines as a novel tool in cancer therapies
María Belén Palma, Diana Tronik-Le Roux, Camila Seoane Rocha, Ailen Iribarne, Alejandro La Greca, Lucía N. Moro, Marina Daouya, Isabelle Poras, Edgardo D. Carosella, Marcela N. García, Santiago G. Miriuka
Redirection of immune cells specificity against HLA-G: anti HLA-G CAR T cells
Marie Escande, Espie David, Anna François, Giroux Benoit, Lecomte Martin, Langlade-Demoyen Pierre, Donnadieu Emmanuel, Loustau Maria, Caumartin Julien
ILT2-positive CD8+ T cells in clear-cell renal cell carcinoma: potential implications for cancer immunotherapy
C. Dumont, L. Lugand, R. Laboureur, J. Vérine, A. Masson-Lecomte, S. Culine, F. Desgandschamps, E.D. Carosella, J. LeMaoult, N. Rouas-Freiss
Cytotoxic functions of CD8+ ILT2+ cells in clear cell renal cell carcinoma
Rebecca Laboureur, Léonard Lugand, Clément Dumont, Fatiha Bouhidel, Malika Djouadou, François Desgandschamps, Alexandra Masson-Lecomte, Edgardo D. Carosella, Joël LeMaoult, Nathalie Rouas-Freiss
Advances in cancer immunotherapy development:new VHH-based immune checkpoint inhibitors targeting the receptor ILT4
Raphaëlle Dréan, Gabriel Aymé, Alix Jaquier, Odessa Fayet, Martin Lecomte, Julien Caumartin, Maria Loustau, Pierre Lafaye
PLENARY SESSION 5
HLA-G in PREGNANCY and TRANSPLANTATION
Chairpersons: Diego DELGADO
- Michael EIKMANS (Netherlands) “The role of HLA-G in women with recurrent pregnancy loss”
- Thomas Vauvert F. HVIID (Denmark) “An update on HLA-G and HLA-F in reproduction”
- Olivier BRUGIÈRE (France) “Prediction of chronic lung allograft dysfunction by measurement of circulating cytotoxic CD4+CD57+ILT2+ T cells, selectively inhibited by the immune check-point HLA-G”
15:00 - Pause
PLENARY SESSION 6
HLA-G, REGULATION and EXPRESSION
Chairpersons: Philippe MOREAU, Thomas V.F. HVIID
- Eduardo A. DONADI (Brazil) “Atomistic studies on HLA-G: major isoforms and interactions with receptors and with transcription factor”
- Julie DI CRISTOFARO (France) “HLA 1b haplotype, from clinics to genetic evolution”
- Antonio ARNAIZ-VILLENA(Spain) "Evolution of HLA-G, HLA-haplotypes and disease association”
- Erick CASTELLI (Brazil) "HLA-G worldwide genetic diversity and evolutionary aspects"
Closing remarks by Anatolij HORUSZKO
Résumés de communication
The subject of this presentation is the predominant expression of HLA-G in mast cells in fibrosis zones regardless of the affected organ : liver, lung and kidney.
My presentation will describe the interactions between HLA-G and other immune checkpoint molecules, with particular emphasis on PD-1/PD-L1. In addition, I will present and discuss recent data describing the expression of HLA-G and PD-1/PD-L1 on extracellular vesicles isolated from bone marrow of cancer patients and helathy donors.
Background: Placental malaria (PM) is associated with a higher susceptibility of infants to malaria infection. A hypothesis of immune tolerance has been suggested but no clear explanation has been provided to date. In the present study, we investigated the involvement of inhibitory receptors LILRB1 and LILRB2 in PM-induced immune tolerance. Method: Infants of women with or without PM were followed-up from birth to 24 months of age. The frequency of immune cell subsets was quantified by flow cytometry. LILRB1 or LILRB2 expression was assessed on cells collected at 18 and 24 months of age. Findings: Infants born to women with PM had a higher risk of developing symptomatic malaria than those born to women without PM, and such infants displayed a lower frequency of non-classical monocytes that overexpressed LILRB2. Interpretation: The long-lasting effect of PM on infants’ monocytes was notable, raising questions about the capacity of ligands such as Rifins or HLA-I molecules to bind to LILRB1 and LILRB2 and to modulate immune responses.
In the context of pregnancy, the fetus inherits genes from both the father and the mother and it is therefore semi-allogeneic to the mother’s immune system. Maintenance of healthy pregnancy requires the maternal immune system to tolerize the fetus. For this reason, several immune regulatory mechanisms are at play at the fetal-maternal interface, which represent the location where fetal trophoblasts in the placenta come into contact with maternal immune cells.
HLA-G is an immune modulating molecule present on extravillous trophoblasts (EVT) at the fetal- maternal interface. The soluble form of HLA-G can also be detected in various body fluids, such as amniotic fluid and blood of pregnant women, but also in male seminal plasma. Genetic variations in the HLA-G gene may be associated with the level of the HLA-G protein product.
Recurrent pregnancy loss (RPL) affects 1-2% of couples who are trying to conceive. Around 70% of the couples do not know the underlying cause for this recurring problem, leaving them with a burden of uncertainty. At some point, some couples may maintain a healthy pregnancy to term, but in those cases the principal mechanism remains elusive as well.
In this lecture, I will go into the findings regarding HLA-G expression and genotype in pregnant women with a history of RPL, evaluated in the placenta and in the mother’s blood circulation. I will also elaborate on a culture system of trophoblasts, isolated from placenta tissue during gestation, which can be differentiated to HLA-G-positive EVT to study interaction with maternal immune cells. I will speculate on how recent investigations may provide further insight on the pathophysiology of pregnancy complications and whether information regarding HLA-G may represent a biomarker for
Julie Di Cristofaro
HLA-G is a tolerogenic molecule. We showed an impact of HLA-G alleles in Lung Transplant outcome : anti-HLA allo-immunization risk, overall survival and chronic rejection (CLAD).
HLA-G*01:04 allele was associated to lower levels of sHLA-G at D0 and M3 (p=0.03), impaired long term survival (p=0.001), increased CLAD occurrence (p=0.03) and to the production of de novo DSA at M3 (p=0.01).
HLA-G*01:04 allele is LD with the HLA-H deletion and HLA*11 allele.
Currently, 19 HLA-H alleles with a distinct sequence in the exons are described. These alleles display open reading frames ranging from 18 to 362 amino-acids (AA). Of these 19 alleles, two (HLA-H*02:07 and H*02:14) putatively encode a complete, membrane-bound HLA protein
Potential tolerogenic function of the H*02:07 protein is supported by its association, through its full Linkage Disequilibrium (LD) with the HLA-A*11 allele, with higher risk of lung cancer.
HLA-H transcriptional activity was characterized in Peripheral Blood Mononuclear Cells (PBMC) and Human Bronchial Epithelial Cell (HBEC)
We hypothesize that HLA-H contributes to immune homeostasis, similarly to tolerogenic molecules HLA-G, -E and -F and that HLA-H*02:07 is expressed as a functional, immune-tolerant, membrane-bound HLA molecule.
We use a HLA null human erythroblast cell line transduced with HLA-H*02:07 cDNA to demonstrate that HLA-H*02:07 encodes a membrane-bound protein. Additionally, using a cytotoxicity assay, our results support that K562 HLA-H*02:07 inhibits human effector IL-2 activated PBMC and human IL-2 independent NK92-MI cell line activity.
Finally, through in silico genotyping of the Denisovan genome and haplotypic association with Denisovan-derived HLA-A*11, we also show that H*02:07 is of archaic origin. Hence admixture with archaic humans brought a functional HLA-H allele into modern European and Asian populations.
Antonio ARNAIZ-VILLENA (Spain)
Classical HLA genes and disease association has been studied at least since 1967 and no firm pathogenic mechanisms have been yet established. HLA-G immune modulation gene (and also -E and -F) are starting the same arduous way: statistics and allele association are the subject trendings with the same few results obtained by HLA classical genes i. e.: no pathogenesis may be discovered after many years of a great amount of researchers effort. Thus, we believe it is necessary to follow different research methodologies to approach this problem, like a sound one based on how evolution has worked maintaining together a cluster of immunity related genes (the MHC) in a relatively short chromosome area since amniotes to human at least: this evolution may be quite reliably studied during about 40 million years by analyzing the evolution of MHC-G and its receptors. Also,in addition to establishing new in vitro models, it is necessary to take into account other neighbouring genes that imply the study of full or part of MHC haplotypes involving several loci/alleles instead of single ones. This need of change or implement is already learnt from the long and in part fruitless HLA and disease statistical association history.
My presentation will address our current knowledge regarding the HLA-G genetic diversity (SNPs and haplotypes) in worldwide populations, the different HLA-G lineages we have detected, and the functional aspects of frequent polymorphisms (ligand/receptor binding, allele-expression levels, and alternative splicing).
Research Director and international expert at the French alternative energies and atomic energy Commission (CEA)
Head of the Hemato-Immunology Department, Institut Universitaire d’Hématologie, Hospital Saint-Louis, Paris
Vice-President of the Board of Directors of C.E.P.H. - Centre d'Etude du Polymorphisme Humain - Fondation Jean DAUSSET
MD, PhD in Haematology laboratory of Rennes and teacher researcher at the University of Rennes 1. For its medical part, she is a medical biologist at the Hematology Laboratory of the CHU of Rennes, she makes the diagnosis of hemopathies by cytology and flow cytometry.She actually works in “Infection, Immunity and Environmental Factors in Liver” team of Institute of Research in Environmental and Occupational Health. Her research initially focused on HLA-G in hematologic malignancies and then dendritic cells is now shifted on HLA-G and liver, especially on mast cells and fibrosis.
Senior Researcher/Quality Control Operator
UOSD Cell Factory – IRCCS Istituto Giannina Gaslini
Research in Tumor immunology and Development of Advanced Therapeutic Medicinal Products Dr. Morandi is a Senior Researcher and operates in the Quality Control area of Cell Factory “G.Gaslini” at IRCCS Giannina Gaslini in Genoa, Italy. He is author of several publications in the field of i) tumor immunology ii) mechanisms of regulation of immune response in physiological and pathological conditions. In the last years, he studied HLA-G and other HLA-Ib molecules, adenosinergic ectoenzymes and extracellular vesicles. Dr. Morandi graduated in Biology and then he get a Specialization in Clinical Pathology at the University of Genoa. He competed a research fellowship at IST/S.Martino Hospital and then at IRCCS Giannina Gaslini, in Genoa, Italy.
Dr. D. Courtin is a senior researcher at the French National Institute For Sustainable Development (IRD) in the Mother and Child in tropical area (MERIT) research unit, Paris, France. He co-leads the host genetic adaptation team and is IRD correspondent in Ghana.
Research : He devoted his PhD thesis work to the study of human genetic susceptibility to human African trypanosomiasis and his post-doctoral training was performed on antibody responses directed to merozoite candidate vaccine antigens associated with malaria protection. Since his recruitment at the IRD in 2008, his research programs aim to identify genetic and immunological factors involved in host susceptibility to tropical parasitic diseases: malaria, helminthiasis and Human African Trypanosomiasis. Currently, he is involved in immunogenetic programs in Africa (Benin, Cote d’Ivoire, Ghana and Guinea) leading to new insights on the relevance of HLA-G and its receptors in human susceptibility to tropical parasitic diseases.
-Coordinator of a research group on NK cell and tumor biology at the Institute for Transfusion Medicine, University Hospital Essen.
-Research : The research interests are focused on the immune biology of atypical HLA class I molecules (HLA-G, HLA-E and HLA-F) and other immune checkpoint molecules (PD-1, PDL1, and PDL-2), both on the cell surface or as soluble molecules with emphasis placed on their translational potential and implmentation in clinical practice in settings of transplantation and cancer. During the last five years, she and her team explored primarily the clinical and functional potential of EV (extracellular vesicles) and EV subpopulations harbouring certain immune checkpoint molecules like HLA-G.
Joël LE MAOULT
Senior researcher at the Department of Immunology
Leiden University Medical Center - The Netherlands
Research in Reproductive Immunology and HLA-G
Dr. Eikmans is group leader of the Reproductive Immunology research line at his department (https://immunology.lumc.nl/).
He is the author of scientific publications in the field of reproductive immunology and of transplantation. Research of his group is aimed at understanding in healthy pregnancy how the pregnant woman immunologically tolerates her baby, and what mechanisms account for
complications to occur in aberrant pregnancy.
Dr. Eikmans is co-founder and member of the core group of the Reproductive Immunology Network Netherlands (RiNet) (https://rinet.nl/), a national initiative to gain more insight in the role of the immune system in pregnancy and to come to better treatment of patients in
the area of reproduction, pregnancy, and birth.
He graduated in Molecular Biology and Medical Biology at the University of Leiden in The Netherlands. After that he conferred a PhD at the Dept of Pathology (LUMC) and completed a research fellowship at the Massachusetts General Hospital, Boston MA.
Centre for Immune Regulation and Reproductive Immunology (CIRRI), The ReproHealth Research
Consortium ZUH, Department of Clinical Biochemistry, Zealand University Hospital, and Department of Clinical Medicine, University of Copenhagen, Roskilde, Denmark
Research: Our research activities focus on: (1) regulation of the immune system, especially in relation to immunosuppression and tolerance, (2) reproductive immunology, and (3) cancer immunology. In reproductive medicine, our aims are to further clarify the role of HLA class Ib molecules (HLA-G, HLA-F and HLA-E) at the feto-maternal interface and their tolerance-inducing function by the interaction with maternal
immune cells. Our aim in cancer research is to elucidate the impact of HLA class Ib expression by tumour cells on the tumour microenvironment and the prognosis of the patient. The research may contribute to an improved understanding of disease mechanisms and therapeutic targets in infertility, certain pregnancy complications and cancer.
Olivier Brugière is involved in the lung transplant program of Foch hospital (Suresnes France) as a referent LTx physician. He developed a translational research focused on chronic allograft dysfunction and the role of the tolerogenic HLA-G molecule in lung graft acceptance (collaboration with the Immunology laboratory of Saint-Louis hospital, SHRI, Paris, France).
Eduardo A. DONADI
Dr Julie Di Cristofaro, French Blood Center, Marseilles, France Major scientific interests are related to:
- Human genetic diversity
- HLA Ib evolution, expression and function
- Molecular biology applied to red blood cell antigens and HLA typing
- Markers to optimize patients' care in blood transfusion and transplant contexts
Physician and Doctor by Complutense University of Madrid.He studied Immunology and Immunogenetics with Profs Roitt and Festenstein in London for 9 years.He has published more than 400 scientific papers in international magazines. He has carried out research on Immunology ,Population Genetics and Anthropology.He has also described HLA-G new alleles and polymorphisms both in human and primates and has been awarded by the Spanish Senate because he elaborated together with Prof Dausset and others the successful Transplant Law in Spain. At present he is Full Professor at Complutense University.
Senior researcher at the Pathology Department, School of Medicine, São Paulo State University (Unesp), Brazil.
Dr. Castelli graduated in Biomedical Sciences from the São Paulo State University (Unesp), Brazil, with a master's degree in Pathology from Unesp and a Ph.D. degree from the University of São Paulo, USP, Brazil.
Dr. Castelli is the section editor (bioinformatics) from DNA and Cell Biology (ISSN 1557-7430) and a member of the editorial board of Human Immunology (ISSN 0198-8859).
Member of the SNP-HLA Reference Consortium (SHLARC), an initiative to share and promote MHC-centric analyses in genomics and improve HLA imputation from SNP-Array data.
He is the author of publications in the area of HLA and KIR polymorphisms, evolutive aspects of HLA and KIR genes, HLA polymorphisms associated with infectious diseases, and bioinformatic tools tailored to HLA genes and highly polymorphic genes. He has published more than 47 articles related to HLA-G, including the description of its genetic structure, its haplotypes, and polymorphisms associated with diseases.