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2. 317.6: Anti-donor Human Leukocyte Antigen (HLA) Antibody Response After Vascularized Composite Allotransplantation: A Multicenter Study

Author

Palmina Petruzzo, Gaelle Wehrlen, Jean Kanitakis, Emmanuel Morelon, Lionel Badet, Bernard Devauchelle, Aram Gazarian, Claudia Sardu, Ozlenen Dogan, Dorota Kaminska, Simon Kay, Patrik Lassus, Bohdan Pomahac, Simon Talbot, Valerie Dubois, Olivier Thaunat, Hospices Civils de Lyon (HCL), University of Cagliari, Hôpital Edouard Herriot [CHU - HCL], Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Amiens-Picardie, CHirurgie, IMagerie et REgénération tissulaire de l’extrémité céphalique - Caractérisation morphologique et fonctionnelle - UR UPJV 7516 (CHIMERE), Université de Picardie Jules Verne (UPJV), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), Clinique du Parc, Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Laboratoire HLA [EFS - Auvergne-Rhônes-Alpes], and Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)

Subjects
Transplantation, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Introduction: The clinical significance of donor-specific anti-HLA antibodies (DSAs) in vascularized composite allotransplantation is not clear, even though their occurrence has been reported by several teams. The aim of the present multicenterc study was to assess the incidence of DSAs in upper extremity (UET) and face transplanted patients and their influence on patient outcomes.Methods and Results: Pre- and post-transplantation sera of 37 patients (23 UET, 13 face transplantations and 1 simultaneous UET and face transplantation) were screened in a single laboratory using a solid phase assay. The recipients included 29 men and 8 women, median age was 33 years. Their immunosuppressive treatment, number of HLA mismatches, number of acute rejection (AR) episodes with Banff score, occurrence of graft vasculopathy, chronic rejection and graft loss were collected. In addition, the histological impact of DSA was studied in a small cohort of these patients. For each patient from our cohort with de novo DSA, we randomly selected 2 biopsies taken before and 3 biopsies after the appearance of DSA. DSA were detected in 43.2% of the recipients (16/37), including 6 patients who had presented preformed DSA. The intensity of recipient humoral alloimmune response was estimated using the MFI of positive beads in solid-phase assay. This showed variability both among recipients and among the different DSA specificities of the same patient. From an overall perspective, the alloimmune response was not very strong (median MFI 1413). Donor and recipient age and gender as well as the immunosuppressive treatment were not statistically different between the recipients who developed DSA and those who did not do it. Interesting the number of AR and Banff score did not influence DSA occurrence. No significant correlation between the presence of DSA and chronic rejection, graft vasculopathy or graft loss was found. Five patients with DSA developed chronic rejection and 4 of them graft vasculopathy. In addition, 2 recipients with DSA experienced several episodes of atypical rejections. Longitudinal assessment showed that almost all preformed DSA disappear over time and almost 50% of de novo DSA also in those patients who developed chronic rejection and/or graft vasculopathy with graft loss. There were 5 cases of graft loss and 3 of which had developed DSA during their follow-up. The histopathological study performed on skin sections obtained after the appearance of DSA (routinely-stained and immunolabelled for CD34) did not show significant influx of inflammatory cells into the dermal capillaries endothelial, cell swelling, or microthrombosis.Conclusion: The study confirms that VCA is a sensitizing event for recipients. However, the evolution of DSA over time seems rather heterogeneous. Pre-formed DSAs tend to disappear rapidly and potentially no longer be deleterious, contrary to de novo DSA whose evolution and pathogenicity remain to be elucidated. Longer follow-up will allow to better assess the outcomes of the patients who developed DSA.

Published
2022

3. Role of HLA-B exon 1 in graft-versus-host disease after unrelated haemopoietic cell transplantation: a retrospective cohort study

Author

Effie W Petersdorf, Mary Carrington, Colm O'hUigin, Mats Bengtsson, Dianne De Santis, Valerie Dubois, Ted Gooley, Mary Horowitz, Katharine Hsu, J Alejandro Madrigal, Martin J Maiers, Mari Malkki, Caroline McKallor, Yasuo Morishima, Machteld Oudshoorn, Stephen R Spellman, Jean Villard, Phil Stevenson, Martin Maiers, Stephen Spellman, Jane Apperley, Peter Bardy, Ghislaine Bernard, Yves Bertrand, Adrian Bloor, Chiara Bonini, Stephane Buhler, Laura Bungener, Helen Campbell, Kristina Carlson, Ben Carpenter, Anne Cesbron, Christian Chabannon, Yves Chalandon, Jeremy Chapman, Réda Chebel, Patrice Chevallier, Gerda Choi, Matt Collin, Jan J Cornelissen, Charles Crawley, Lloyd D'Orsogna, Jean-Hugues Dalle, Eric Deconinck, Muriel DeMatteis, Mary Diviney, Anne Dormoy, Katia Gagne, Brenda Gibson, Maria Gilleece, David Gottlieb, John Gribben, Tayfun Güngör, Mike Haagenson, Cathie Hart, Rhonda Holdsworth, Ian Humphreys, Yoshihisa Kodera, Mickey Koh, Hélène Labussière-Wallet, Arjan C Lankester, Neubery Lardy, Sarah Lawson, Xavier Leleu, Stephen MacKinnon, Ram Malladi, Steven GE Marsh, Murray Martin, Neema P Mayor, I Grant McQuaker, Ellen Meijer, Satoko Morishima, Emmanouil Nikolousis, Kim Orchard, Jacob Passweg, Amit Patel, Katherine Patrick, Béatrice Pedron, Andy Peniket, Julia Perry, Eefke Petersen, Victoria Potter, Mike Potter, Rachel Protheroe, Nicole Raus, Carmen Ruiz de Elvira, Nigel Russell, Nicholaas PM Schaap, Urs Schanz, Harry Schouten, Roderick Skinner, John Snowden, Eric Spierings, Colin Steward, Eleni Tholouli, Alycia Thornton, Marcel Tilanus, Arnold van de Meer, Hendrik Veelkens, Paul Veys, Narelle Watson, Lyanne Weston, Keith Wilson, Marie Wilson, Robert Wynn, József Zsiros, University of Washington [Seattle], Harvard University [Cambridge], Frederick National Laboratory for Cancer Research (FNLCR), Uppsala Universitet [Uppsala], PathWest Murdoch / Fiona Stanley Hospital [Perth, WA, Australia] (PMFSH), Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Medical College of Wisconsin [Milwaukee] (MCW), Memorial Sloane Kettering Cancer Center [New York], Royal Free Hospital [London, UK], Center for International Blood and Marrow Transplant Research [Minneapolis, MN, USA] (CIBMTR), Aichi Medical University School of Medicine [Nagakute, Aichi, Japan] (AMUSM), Leiden University Medical Centre [Leyde, Pays-Bas], Leiden University, Geneva University Hospital (HUG), International Histocompatibility Working Group in Hematopoietic Cell Transplantation: Effie W Petersdorf, Mary Carrington, Colm O'hUigin, Mats Bengtsson, Dianne De Santis, Valerie Dubois, Ted Gooley, Mary Horowitz, Katharine Hsu, J Alejandro Madrigal, Martin Maiers, Mari Malkki, Caroline McKallor, Yasuo Morishima, Machteld Oudshoorn, Stephen Spellman, Jean Villard, Phil Stevenson, Jane Apperley, Peter Bardy, Ghislaine Bernard, Yves Bertrand, Adrian Bloor, Chiara Bonini, Stephane Buhler, Laura Bungener, Helen Campbell, Kristina Carlson, Ben Carpenter, Anne Cesbron, Christian Chabannon, Yves Chalandon, Jeremy Chapman, Réda Chebel, Patrice Chevallier, Gerda Choi, Matt Collin, Jan J Cornelissen, Charles Crawley, Lloyd D'Orsogna, Jean-Hugues Dalle, Eric Deconinck, Muriel DeMatteis, Mary Diviney, Anne Dormoy, Katia Gagne, Brenda Gibson, Maria Gilleece, David Gottlieb, John Gribben, Tayfun Güngör, Mike Haagenson, Cathie Hart, Rhonda Holdsworth, Ian Humphreys, Yoshihisa Kodera, Mickey Koh, Hélène Labussière-Wallet, Arjan C Lankester, Neubery Lardy, Sarah Lawson, Xavier Leleu, Stephen MacKinnon, Ram Malladi, Steven Ge Marsh, Murray Martin, Neema P Mayor, I Grant McQuaker, Ellen Meijer, Satoko Morishima, Emmanouil Nikolousis, Kim Orchard, Jacob Passweg, Amit Patel, Katherine Patrick, Béatrice Pedron, Andy Peniket, Julia Perry, Eefke Petersen, Victoria Potter, Mike Potter, Rachel Protheroe, Nicole Raus, Carmen Ruiz de Elvira, Nigel Russell, Nicholaas Pm Schaap, Urs Schanz, Harry Schouten, Roderick Skinner, John Snowden, Eric Spierings, Colin Steward, Eleni Tholouli, Alycia Thornton, Marcel Tilanus, Arnold van de Meer, Hendrik Veelkens, Paul Veys, Narelle Watson, Lyanne Weston, Keith Wilson, Marie Wilson, Robert Wynn, József Zsiros, Leiden University Medical Center (LUMC), GAGNE, Katia, CCA - Cancer Treatment and quality of life, AII - Inflammatory diseases, Hematology, CCA - Cancer biology and immunology, Petersdorf, E. W., Carrington, M., O'Huigin, C., Bengtsson, M., De Santis, D., Dubois, V., Gooley, T., Horowitz, M., Hsu, K., Madrigal, J. A., Maiers, M. J., Malkki, M., Mckallor, C., Morishima, Y., Oudshoorn, M., Spellman, S. R., Villard, J., Stevenson, P., Maiers, M., Spellman, S., Apperley, J., Bardy, P., Bernard, G., Bertrand, Y., Bloor, A., Bonini, C., Buhler, S., Bungener, L., Campbell, H., Carlson, K., Carpenter, B., Cesbron, A., Chabannon, C., Chalandon, Y., Chapman, J., Chebel, R., Chevallier, P., Choi, G., Collin, M., Cornelissen, J. J., Crawley, C., D'Orsogna, L., Dalle, J. -H., Deconinck, E., Dematteis, M., Diviney, M., Dormoy, A., Gagne, K., Gibson, B., Gilleece, M., Gottlieb, D., Gribben, J., Gungor, T., Haagenson, M., Hart, C., Holdsworth, R., Humphreys, I., Kodera, Y., Koh, M., Labussiere-Wallet, H., Lankester, A. C., Lardy, N., Lawson, S., Leleu, X., Mackinnon, S., Malladi, R., Marsh, S. G., Martin, M., Mayor, N. P., Mcquaker, I. G., Meijer, E., Morishima, S., Nikolousis, E., Orchard, K., Passweg, J., Patel, A., Patrick, K., Pedron, B., Peniket, A., Perry, J., Petersen, E., Potter, V., Potter, M., Protheroe, R., Raus, N., Ruiz de Elvira, C., Russell, N., Schaap, N. P., Schanz, U., Schouten, H., Skinner, R., Snowden, J., Spierings, E., Steward, C., Tholouli, E., Thornton, A., Tilanus, M., van de Meer, A., Veelkens, H., Veys, P., Watson, N., Weston, L., Wilson, K., Wilson, M., Wynn, R., Zsiros, J., RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, MUMC+: DA TI Staf (9), University of Zurich, and Petersdorf, Effie W

Subjects
Oncology, Male, Hematopoietic Stem Cell Transplantation/methods, [SDV]Life Sciences [q-bio], 2720 Hematology, Graft vs Host Disease, Histocompatibility Testing, 0302 clinical medicine, Graft vs Host Disease/genetics, immune system diseases, unrelated donor, Exons/genetics, graft-versus-host disease, Medicine, ddc:616, Hematopoietic Stem Cell Transplantation, Exons, Hematology, Middle Aged, 3. Good health, [SDV] Life Sciences [q-bio], surgical procedures, operative, 030220 oncology & carcinogenesis, Histocompatibility, HLA-B Antigens/genetics, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, EXPRESSION, Adult, medicine.medical_specialty, Adolescent, [SDV.IMM] Life Sciences [q-bio]/Immunology, 610 Medicine & health, Human leukocyte antigen, Lower risk, Risk Assessment, Article, Graft vs Host Disease/genetics/immunology, 03 medical and health sciences, Internal medicine, Journal Article, Humans, Retrospective Studies, RECEPTOR, business.industry, MORTALITY, RECOGNITION, Retrospective cohort study, Odds ratio, medicine.disease, Transplantation, Graft-versus-host disease, hematopoietic-cell transplantation, SEQUENCE-DERIVED PEPTIDES, 10036 Medical Clinic, HLA-B Antigens, 10032 Clinic for Oncology and Hematology, Multivariate Analysis, RESIDUES, HLA-B leader, business, 030215 immunology
Abstract

Background: The success of unrelated haemopoietic cell transplantation (HCT) is limited by graft-versus-host disease (GVHD), which is the main post-transplantation challenge when HLA-matched donors are unavailable. A sequence dimorphism in exon 1 of HLA-B gives rise to leader peptides containing methionine (Met; M) or threonine (Thr; T), which differentially influence natural killer and T-cell alloresponses. The main aim of the study was to evaluate the role of the leader dimorphism in GVHD after HLA-B-mismatched unrelated HCT. Methods: We did a retrospective cohort study of 33 982 patients who received an unrelated HCT done in Australia, Europe, Japan, North America, and the UK between Jan 1, 1988, and Dec 31, 2016. Data were contributed by participants of the International Histocompatibility Working Group in Hematopoietic Cell Transplantation. All cases were included and there were no exclusion criteria. Multivariate regression models were used to assess risks associated with HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 mismatching. Among the 33 982 transplantations, the risks of GVHD associated with HLA-B M and T leaders were established in 17 100 (50·3%) HLA-matched and 1457 (4·3%) single HLA-B-mismatched transplantations using multivariate regression models. Leader frequencies were defined in 2 004 742 BeTheMatch US registry donors. Findings: Between Jan 20, 2017, and March 11, 2019, we assessed 33 982 HCTs using multivariate regression models for the role of HLA mismatching on outcome. Median follow-up was 1841 days (IQR 909–2963). Mortality and GVHD increased with increasing numbers of HLA mismatches. A single HLA-B mismatch increased grade 3–4 acute GVHD (odds ratio [OR] 1·89, 95% CI 1·53–2·33; p

Published
2021

4. Eplet incompatibility in pediatric renal transplantation

Author

Pierre Cochat, Justine Bacchetta, Bruno Ranchin, Valerie Dubois, Aurelia Bertholet Thomas, Andreea Liana Rãchişan, and Anne-Laure Sellier-Leclerc

Subjects
Graft Rejection, Male, medicine.medical_specialty, Adolescent, Pediatric transplantation, Normal Distribution, 030232 urology & nephrology, Renal graft, Human leukocyte antigen, 030230 surgery, Gastroenterology, Epitopes, 03 medical and health sciences, 0302 clinical medicine, HLA Antigens, Isoantibodies, HLA-DQ Antigens, Internal medicine, Living Donors, medicine, Humans, Child, Transplantation, business.industry, Histocompatibility Testing, Graft Survival, Mean age, Kidney Transplantation, Histocompatibility, Pediatrics, Perinatology and Child Health, Cohort, Kidney Failure, Chronic, Female, Immunization, business, Software
Abstract

Eplet incompatibility appears to be a better predictor of the de novo appearance of DSA post-Tx than HLA antigen matching in adults. We evaluated the HLA Matchmaker® software (version 2.1) in our pediatric cohort to predict the appearance of DSA post-Tx. We included 70 pediatric patients (26 girls, 10 living donors, mean age 11.2 ± 3.9 years) after a first R-Tx (January 2010-August 2016), without prior immunization, having complete HLA typing (A, B, C, DRB1 and DQB1) and DSA follow-up for at least one year. The mean of HLA and eplet incompatibilities was 4.7 ± 1.3 and 15.5 ± 6.1, respectively, with a correlation coefficient r2 between these two variables of 0.34 (P < .001). The eplet load was 12.8 ± 5.0 in living donors vs 15.9 ± 6.2 in deceased donors (P = NS), 12.6 ± 6.1 in preemptive R-Tx (n = 14) vs 16.3 ± 5.9 for non-preemptive R-Tx (P = .04). Seven patients (10%) developed DSA during the 3.5 ± 1.2 years post-Tx. The eplet load was 13.7 ± 5.5 for those who developed DSA vs 15.7 ± 6.1 for the others (P = NS). In our single-center series of pediatric R-Tx with good HLA matching and lower eplet load than previously published series, eplet incompatibilities do not predict the development of DSA. The question of the HLA matching requirement and the daily interest of the HLA Matchmaker® software to help select the grafts remain open.

Published
2020

5. The role of donor hypertension and angiotensin II in the occurrence of early pancreas allograft thrombosis

Author

Christophe Masset, Julien Branchereau, Fanny Buron, Georges Karam, Maud Rabeyrin, Karine Renaudin, Florent Le Borgne, Lionel Badet, Xavier Matillon, Christophe Legendre, Denis Glotz, Corinne Antoine, Magali Giral, Jacques Dantal, Diego Cantarovich, DIVAT Consortium, Maria Brunet, Rémi Cahen, Ricardo Codas, Sameh Daoud, Valérie Dubois, Coralie Fournie, Arnaud Grégoire, Alice Koenig, Charlène Lévi, Emmanuel Morelon, Claire Pouteil-Noble, Thomas Rimmelé, Olivier Thaunat, Gilles Blancho, Agnès Chapelet, Clément Deltombe, Lucile Figueres, Raphael Gaisne, Claire Garandeau, Caroline Gourraud-Vercel, Maryvonne Hourmant, Clarisse Kerleau, Delphine Kervella, Aurélie Meurette, Simon Ville, Christine Kandell, Anne Moreau, Florent Delbos, Alexandre Walencik, Anne Devis, Lucile Amrouche, Dany Anglicheau, Olivier Aubert, Lynda Bererhi, Alexandre Loupy, Frank Martinez, Arnaud Méjean, Rébecca Sberro-Soussan, Anne Scemla, Marc-Olivier Timsit, Julien Zuber, Gillian Divard, and Carmen Lefaucheur

Subjects
body mass index (BMI), pre-procurement pancreas suitability score, pancreas transplantation, allograft thrombosis, high blood pressure, immunothrombosis, Immunologic diseases. Allergy, RC581-607
Abstract

BackgroundAbout 10–20% of pancreas allografts are still lost in the early postoperative period despite the identification of numerous detrimental risk factors that correlate with graft thrombosis.MethodsWe conducted a multicenter study including 899 pancreas transplant recipients between 2000 and 2018. Early pancreas failure due to complete thrombosis, long-term pancreas, kidney and patient survivals were analyzed and adjusted to donor, recipient and perioperative variables using a multivariate cause-specific Cox model stratified to transplant centers.ResultsPancreas from donors with history of hypertension (6.7%), as well as with high body mass index (BMI), were independently associated with an increased risk of pancreas failure within the first 30 post-operative days (respectively, HR= 2.57, 95% CI from 1.35 to 4.89 and HR= 1.11, 95% CI from 1.04 to 1.19). Interaction term between hypertension and BMI was negative. Donor hypertension also impacted long-term pancreas survival (HR= 1.88, 95% CI from 1.13 to 3.12). However, when pancreas survival was calculated after the postoperative day 30, donor hypertension was no longer a significant risk factor (HR= 1.22, 95% CI from 0.47 to 3.15). A lower pancreas survival was observed in patients receiving a pancreas from a hypertensive donor without RAAS (Renin Angiotensin Aldosterone System) blockers compared to others (50% vs 14%, p < 0.001). Pancreas survival was similar among non-hypertensive donors and hypertensive ones under RAAS blockers.ConclusionDonor hypertension was a significant and independent risk factor of pancreas failure. The well-known pathogenic role of renin-angiotensin-aldosterone system seems to be involved in the genesis of this immediate graft failure.

Published
2024
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6. HuMSC-EV induce monocyte/macrophage mobilization to orchestrate neovascularization in wound healing process following radiation injury

Author

Céline Loinard, Alexandre Ribault, Bruno Lhomme, Marc Benderitter, Stéphane Flamant, Sandrine Paul, Valérie Dubois, Ruenn Chai Lai, Sai Kiang Lim, and Radia Tamarat

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Cytology, QH573-671
Abstract

Abstract This study aims to investigate the mechanisms of human mesenchymal stem cell-derived extracellular vesicles (HuMSC-EV)-induced proangiogenic paracrine effects after radiation injury. HuMSC-EV were locally administered in mice hindlimb following 80-Gy X-ray irradiation and animals were monitored at different time points. HuMSC-EV improved neovascularization of the irradiated tissue, by stimulating angiogenesis, normalizing cutaneous blood perfusion, and increasing capillary density and production of proangiogenic factors. HuMSC-EV also stimulated vasculogenesis by promoting the recruitment and differentiation of bone marrow progenitors. Moreover, HuMSC-EV improved arteriogenesis by increasing the mobilization of monocytes from the spleen and the bone marrow and their recruitment into the muscle, with a pro-inflammatory potential. Importantly, monocyte depletion by clodronate treatment abolished the proangiogenic effect of HuMSC-EV. The critical role of Ly6C(hi) monocyte subset in HuMSC-EV-induced neovascularization process was further confirmed using Ccr2 −/− mice. This study demonstrates that HuMSC-derived EV enhances the neovascularization process in the irradiated tissue by increasing the production of proangiogenic factors, promoting the recruitment of vascular progenitor cells, and the mobilization of innate cells to the injured site. These results support the concept that HuMSC-EV might represent a suitable alternative to stem cells for therapeutic neovascularization in tissue repair.

Published
2023
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7. 16 th IHIW: Extending the number of resources and bioinformatics analysis for the investigation of HLA rare alleles

Author

F. F. Gonzalez-Galarza, S. J. Mack+, J. Hollenbach+, M. Fernandez-Vina?, M. Setterholm§, J. Kempenich§, S. G. E. Marsh¶, A. R. Jones, D. Middleton, the HLA Rare Allele Consortium1 (The HLA Rare Allele Consortium: Ana Alfirevic (Liverpool, UK), Michael Aubrey (Aurora, USA), Mats Bengtsson (Uppsala, Sweden), Maria da Graca Bicalho (Curitiba, Brazil), Irina Bohme (Dresden, Germany), Juliette Brown (London, Angelica Canossi (L'Aquila, Italy), Carlo Carcassi (Cagliari, Vaughan Carter (Newcastle, Steven Cate (Oklahoma, Chu Chen-Chung (Taipei, Taiwan), Frans Claas (Leiden, Netherlands), Noel Collins (Sheffield, John Crowley (Dublin, Ireland), Chris Darke (Cardiff, Natalia Diaz-Burlinson (London, Anne Dormoy (Besancon, France), Valerie Dubois (Lyon, Paul Dunn (Auckland, New Zealand), Ingrid Fae (Vienna, Austria), Gabriella Ficai (Genova, Gottfried Fischer (Vienna, Adrian Fleet (Adelaide, Australia), Katharina Fleischhauer (Milan, Sara Frison (Milan, Lucia Garbarino (Genova, Clara Godorezky (Mexico City, Mexico), Reyna Goodman (Cambrige, Zorana Grubic (Zagreb, Croatia), Franca Rosa Guerini (Milan, Milena Ivanova (Sofia, Bulgaria), Pavel Jindra (Pilsen, Czech Republic), Shirley Jobson (Birmingham, Gurvinder Kaur (New Delhi, Sridhar Kesireddy (Hyderabad, India), Edward KL Yang (Hualien, Sara Lai (Cagliari, Benedicte Lie (Oslo, Norway), Dario Ligeiro (Lisbon, Portugal), Ann-Margaret Little (Glasgow, Pascale Loiseau (Paris, Marja-Liisa Lokki (Helsinki, Finland), Elena Longhi (Milan, Alberto Malagoli (Brescia, Miryiam Martinetti (Pavia, Emeline Masson (Paris, Sibelle Mattar (Curitiba, Maria Elisa Moraes (Rio de Janeiro, Victor Morales (Buenos Aires, Argentina), Barbara Murgia (Genova, Joannis Mytilineos (Ulm, Sonia Nesci (Pesaro, Giuseppina Ozzella (Rome, Chryssa Papasteriades (Athens, Greece), Juha Perasaari (Helsinki, Shalini Pereira (Seattle, Francesca Poli (Milan, Katherine Poole (Leeds, Bernardino Porfirio (Florence, Kay Poulton (Manchester, Gisele Rampim (Sao Paulo, Fernanda Ribas (Curitiba, Lucie Richard (Montreal, Canada), Dave Roelen (Leiden, Carley Shaut (Portland, Linda Smith (Perth, Maggie Sprague (Seattle, Franco Tavarozzi (London, Sofia Tavoularis (Ottawa, Manuela Testi (Rome, Jean- Marie Tiercy (Geneva, Switzerland), Margareth Torres (Sao Paulo, Hien Tran (Heidelberg, Shankarkumar Umapathy (Mumbai, Tiziana Valentini (Rome, Michael Varney (Melbourne, Cinzia Vecchiato (Bolzano, Petra Venigova (Pilsen, Silvia Vidal (Barcelona, Spain), Blanka Vidan-Jeras (Ljubljana, Solvenia), Alan Walkinshaw (Glasgow, John Ward (Bristol, Campbell Witt (West Australia, Georgena Wohlwend (Seattle, Elizabeth Wroe (Bristol, Chanfu Zhu (Jinan, China), Renata Zunec (Zagreb, Croatia). © 2012 Blackwell Publishing Ltd International Journal of Immunogenetics, 2013, and 60-65 Resources for the investigation of rare alleles 65

Subjects
HLA rare alleles, HLA allele frequencies
Abstract

Continuing a project presented at the 15th International HLA and Immunogenetics Workshop (IHIWS) on the rarity of HLA alleles, we sought to expand the number of data sources and bioinformatics tools available in the Allele Frequencies Net Database website (AFND, www.allelefrequencies.net). In this 16th IHIWS Rare Alleles project, HLA alleles described in the latest IMGT/HLA Database (release 3.8.0) were queried against different sources including data from registries (stem cell) and from 74 different laboratories around the world. We demonstrated that approximately 40% of the alleles officially named in the IMGT/HLA Database have been reported only once across all different sources. To facilitate the large-scale analysis of rare alleles, we have produced an online tool called the Rare Allele Detector that simplifies the detection of alleles that are considered to be 'very rare', 'rare' or 'frequent'. Tools and associated data can be accessed via the www.allelefrequencies.net website.

Published
2013

8. Integrating biological HLA-DPB1 mismatch models to predict survival after unrelated hematopoietic cell transplantation

Author

Annalisa Ruggeri, Liesbeth C. de Wreede, Carlheinz R. Müller, Pietro Crivello, Edouard F. Bonneville, Effie W. Petersdorf, Gerard Socié, Valérie Dubois, Riitta Niittyvuopio, Juha Peräsaari, Ibrahim Yakoub-Agha, Jan J. Cornelissen, Lotte Wieten, Tobias Gedde-Dahl, Edouard Forcade, Charles R. Crawley, Steven G.E. Marsh, Virginie Gandemer, Eleni Tholouli, Claude-Eric Bulabois, Anne Huynh, Goda Choi, Eric Deconinck, Maija Itäla-Remes, Stig Lenhoff, Mats Bengtsson, Jan-Erik Johansson, Gwendolyn van Gorkom, Jorinde D. Hoogenboom, Luca Vago, Vanderson Rocha, Chiara Bonini, Christian Chabannon, and Katharina Fleischhauer

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2022
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9. Class I/Class II HLA Evolutionary Divergence Ratio Is an Independent Marker Associated With Disease-Free and Overall Survival After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia

Author

Anne-Marie Daull, Valérie Dubois, Hélène Labussière-Wallet, Fabienne Venet, Fiorenza Barraco, Sophie Ducastelle-Lepretre, Marie-Virginie Larcher, Marie Balsat, Lila Gilis, Gaëlle Fossard, Hervé Ghesquières, Maël Heiblig, Florence Ader, and Vincent Alcazer

Subjects
acute myeloid leukemia, hematopoietic (stem) cell transplantation (HCT), HLA Evolutionary divergence, graft-versus-host disease (GVHD), graft-versus-leukemia (GVL), immune reconstitution, Immunologic diseases. Allergy, RC581-607
Abstract

Class I Human Leukocyte Antigen (HLA) evolutionary divergence (HED) is a metric which reflects immunopeptidome diversity and has been associated with immune checkpoint inhibitor responses in solid tumors. Its impact and interest in allogeneic hematopoietic stem cell transplantation (HCT) have not yet been thoroughly studied. This study analyzed the clinical and immune impact of class I and II HED in 492 acute myeloid leukemia (AML) recipients undergoing HCT. The overall cohort was divided into a training (n=338) and a testing (n=132) set. Univariate cox screening found a positive impact of a high class I HED and a negative impact of a high class II HED on both disease-free (DFS) and overall survival (OS). These results were combined in a unique marker, class I/class II HED ratio, and assessed in the testing cohort. The final multivariate cox model confirmed the positive impact of a high versus low class I/class II HED ratio on both DFS (Hazard Ratio (HR) 0.41 [95% CI 0.2-0.83]; p=0.01) and OS (HR 0.34 [0.19-0.59]; p

Published
2022
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10. A New Score to Determine the Probability of Finding An HLA Identical Unrelated Donor: A Promising Efficient Time and Cost Saving Method

Author

Valerie Dubois, Marie L Balere, Mohamad Sobh, Stephane Morisset, Helene Labussiere, Marie Y. Detrait, Franck E. Nicolini, Sylvie Rey, Valerie Mialou, Yves Bertrand, and Mauricette Michallet

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Abstract

Abstract 4188 Introduction: We recently demonstrated that a delayed time to find a compatible donor and also to proceed to allogeneic-HSCT can worsen the disease outcome (Michallet et al. ASH 2010). When a patient is presenting at our hospital for unrelated allogeneic-HSCT a donor search on the Bone Marrow Donor Worldwide (BMDW) registry is done, this query is limited to only 2-digits HLA typing of -A, -B, -DRB1 or -DQB1 loci. The identification of a compatible unrelated donor can be very long and expensive because of the limited HLA typing information in the registries. Tiercy et al. developed a computerized software that predicts the chance to find a suitable donor (BMT 2007, 40; 515–522) and the French transplant registry has recently developed a software called “Easy Match” that predicts the number of compatible donors for a given patient. Aims: To refine and accelerate the process of donor search by combining the results of Tiercy score and EasyMatch applied on patients already received allogeneic-HSCT and define a new score for donor finding probability, in order to be time- and cost-efficient. Material and methods: We retrospectively analyzed 104 adult and 34 pediatric patients who underwent allogeneic-HSCT between 2009 and 2011 after finding an unrelated donor (identical or not) or cord blood units. Firstly, we analyzed the HLA characteristics of each patient as previously described by Tiercy et al. to provide a HLA score with low, intermediate or high probability to identify a suitable identical donor. Then, we used the EasyMatch software which realize a “qualitative” analysis that consist on checking that each HLA recipient phenotype was found among all possible pair wise combinations of 2 haplotypes of the different sets of haplotypes. Various “quantitative” analyses calculated the likelihood associated to each recipient phenotype for a given set of HLA genes, in a given population, at low versus high resolution typing. The EasyMatch software gives for each patient a number of potential donors sharing the same phenotype as the patient. Results: Our 138 patients were classified in 5 different categories (A to E) according to the combined results of the HLA score (Tiercy) and the EasyMatch software (Table). The results of the combination of the two methods associated to the characteristics of our population, allowed the definition of a new scoring system applicable to each patient. Score 0 (group A): 0% of chances to identify a 10/10 identical donor for the recipient. The choice of the source will be defined considering the HLA characteristics of the recipient; in case of class I rare allele or rare HLA-BC linkage disequilibrium; a cord blood unit will be easier and more rapidly available. A complementary help should be given by an associated analysis with 4-digit haplotypes as defined by Maiers (Human Immunology 2007, 68; 779–788). Score 1 (groups B and C): about 50% of chances to identify a suitable 10/10 identical donor. Score 2 (groups D and E): from 75 to 100% of chances to identify a suitable 10/10 identical donor. In conclusion, the use of this new scoring system allows time and cost spare. In case of low chance to find a donor, physicians can have a fast redirection to find another treatment alternative in order to maintain optimal results. Disclosures: No relevant conflicts of interest to declare.

Published
2011

11. Missing self triggers NK cell-mediated chronic vascular rejection of solid organ transplants

Author

Alice Koenig, Chien-Chia Chen, Antoine Marçais, Thomas Barba, Virginie Mathias, Antoine Sicard, Maud Rabeyrin, Maud Racapé, Jean-Paul Duong-Van-Huyen, Patrick Bruneval, Alexandre Loupy, Sébastien Dussurgey, Stéphanie Ducreux, Vannary Meas-Yedid, Jean-Christophe Olivo-Marin, Héléna Paidassi, Romain Guillemain, Jean-Luc Taupin, Jasper Callemeyn, Emmanuel Morelon, Antonino Nicoletti, Béatrice Charreau, Valérie Dubois, Maarten Naesens, Thierry Walzer, Thierry Defrance, and Olivier Thaunat

Subjects
Science
Abstract

‘Missing self’ is a mode of natural killer (NK) cell activation aimed to detect the lack of HLA-I molecules on infected or neoplastic cells. Here, the authors show that mismatch between donor HLA-I and cognate receptors on recipient NK cells mediates microvascular inflammation-associated graft rejection, a pathology that is preventable by mTOR inhibition.

Published
2019
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12. Highly Variable Sialylation Status of Donor-Specific Antibodies Does Not Impact Humoral Rejection Outcomes

Author

Thomas Barba, Jean Harb, Stéphanie Ducreux, Alice Koenig, Virginie Mathias, Maud Rabeyrin, Eric Pouliquen, Antoine Sicard, Dimitri Chartoire, Emilie Dugast, Thierry Defrance, Emmanuel Morelon, Sophie Brouard, Valérie Dubois, and Olivier Thaunat

Subjects
antibody-mediated rejection, DSA, sialylation, glycosylation, solid organ transplantation, Immunologic diseases. Allergy, RC581-607
Abstract

Clinical outcome in antibody-mediated rejection (AMR) shows high inter-individual heterogeneity. Sialylation status of the Fc fragment of IgGs is variable, which could modulate their ability to bind to C1q and/or Fc receptors. In this translational study, we evaluated whether DSA sialylation influence AMR outcomes. Among 938 kidney transplant recipients for whom a graft biopsy was performed between 2004 and 2012 at Lyon University Hospitals, 69 fulfilled the diagnosis criteria for AMR and were enrolled. Sera banked at the time of the biopsy were screened for the presence of DSA by Luminex. The sialylation status of total IgG and DSA was quantified using Sambucus nigra agglutinin-based chromatography. All patients had similar levels of sialylation of serum IgGs (~2%). In contrast, the proportion of sialylated DSA were highly variable (median = 9%; range = 0–100%), allowing to distribute the patients in two groups: high DSA sialylation (n = 44; 64%) and low DSA sialylation (n = 25; 36%). The two groups differed neither on the intensity of rejection lesions (C4d, ptc, and g; p > 0.05) nor on graft survival rates (Log rank test, p = 0.99). in vitro models confirmed the lack of impact of Fc sialylation on the ability of a monoclonal antibody to trigger classical complement cascade and activate NK cells. We conclude that DSA sialylation status is highly variable but has not impact on DSA pathogenicity and AMR outcome.

Published
2019
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13. Salvage use of allogeneic hematopoietic stem cell transplantation after reduced intensity conditioning from unrelated donors in multiple myeloma. A study by the Plasma Cell Disorders subcommittee of the European Group for Blood and Marrow Transplant Chronic Malignancies Working Party

Author

Mohamad Sobh, Mauricette Michallet, Valérie Dubois, Simona Iacobelli, Linda Koster, Anja Van Biezen, Nathalie Fegueux, Reza Tabrizi, Jürgen Finke, Jean El-Cheikh, Martin Schipperus, Ellen Meijer, Peter von dem Borne, Eefke Petersen, Nigel Russell, Eleni Tholouli, Jakob Passweg, Frédéric Garban, Johan Maertens, Patrice Chevalier, Natacha Maillard, Liisa Volin, Sylvie Francois, Bruno Lioure, Yves Beguin, Eliane Gluckman, Annalisa Ruggeri, Laurent Garderet, and Nicolaus Kröger

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2017
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14. Unrelated alternative donor transplantation for severe acquired aplastic anemia: a study from the French Society of Bone Marrow Transplantation and Cell Therapies and the EBMT Severe Aplastic Anemia Working Party

Author

Raynier Devillier, Jean-Hugues Dalle, Austin Kulasekararaj, Maud D’aveni, Laurence Clément, Alicja Chybicka, Stéphane Vigouroux, Patrice Chevallier, Mickey Koh, Yves Bertrand, Mauricette Michallet, Marco Zecca, Ibrahim Yakoub-Agha, Jean-Yves Cahn, Per Ljungman, Marc Bernard, Pascale Loiseau, Valérie Dubois, Sébastien Maury, Gérard Socié, Carlo Dufour, and Regis Peffault de Latour

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Unrelated allogeneic transplantation for severe aplastic anemia is a treatment option after immunosuppressive treatment failure in the absence of a matched sibling donor. Age, delay between disease diagnosis and transplantation, and HLA matching are the key factors in transplantation decisions, but their combined impact on patient outcomes remains unclear. Using the French Society of Bone Marrow Transplantation and Cell Therapies registry, we analyzed all consecutive patients (n=139) who underwent a first allogeneic transplantation for idiopathic severe aplastic anemia from an unrelated donor between 2000 and 2012. In an adjusted multivariate model, age over 30 years (Hazard Ratio=2.39; P=0.011), time from diagnosis to transplantation over 12 months (Hazard Ratio=2.18; P=0.027) and the use of a 9/10 mismatched unrelated donor (Hazard Ratio=2.14; P=0.036) were independent risk factors that significantly worsened overall survival. Accordingly, we built a predictive score using these three parameters, considering patients at low (zero or one risk factors, n=94) or high (two or three risk factors, n=45) risk. High-risk patients had significantly shorter survival (Hazard Ratio=3.04; P

Published
2016
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15. Impact of donor-specific anti-HLA antibodies on graft failure and survival after reduced intensity conditioning-unrelated cord blood transplantation: a Eurocord, Société Francophone d’Histocompatibilité et d’Immunogénétique (SFHI) and Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) analysis

Author

Annalisa Ruggeri, Vanderson Rocha, Emeline Masson, Myriam Labopin, Renato Cunha, Lena Absi, Ali Boudifa, Brigitte Coeffic, Anne Devys, Muriel De Matteis, Valérie Dubois, Daniel Hanau, Françoise Hau, Isabelle Jollet, Dominique Masson, Beatrice Pedron, Pascale Perrier, Christophe Picard, Annie Ramouneau-Pigot, Fernanda Volt, Dominique Charron, Eliane Gluckman, and Pascale Loiseau

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Graft failure is a major complication after unrelated cord blood transplantation. Presence of HLA-antibodies before cord blood transplantation may impact graft failure. 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 Luminex™ platform. Results were interpreted as mean fluorescence intensity (MFI) against donor-specific mismatch. 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%: 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). 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 an HLA mismatched cord blood unit. Whenever possible it is important to avoid selecting a unit for which the patient has donor specific anti-HLA antibodies.

Published
2013
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