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1. Qualitative, rather than quantitative, differences between HLA‐DQ alleles affect HLA‐DQ immunogenicity in organ transplantation

Author

Maguire, Chelsea, primary, Crivello, Pietro, additional, Fleischhauer, Katharina, additional, Isaacson, Dylan, additional, Casillas, Aurora, additional, Kramer, Cynthia S. M., additional, Copley, Hannah C., additional, Heidt, Sebastiaan, additional, Kosmoliaptsis, Vasilis, additional, Meneghini, Maria, additional, Gmeiner, Michael, additional, Schold, Jesse, additional, Louzoun, Yoram, additional, and Tambur, Anat R., additional

Published
2024
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2. Early years postgraduate surgical training programmes in the UK are failing to meet national quality standards: An analysis from the ASiT/BOTA Lost Tribe prospective cohort study of 2,569 surgical trainees

Author

Glasbey, James C., Harries, Rhiannon L., Beamish, Andrew J., Gokani, Vimal J., Mohan, Helen, Williams, Adam P., Fleming, Simon, Chai, Aaron, Singh, Abhinav, Stoneham, Adam C.S., Lunt, Adam J., Rehman, Adeeb H., Dhahri, Adeel A., Yvon, Adrien R.A., Dutta, Agneish, Abou-Foul, Ahmad K., Abdelrahman, Ahmed, Daoub, Ahmed, Sanalla, Ahmed, de Gea Rico, Aitor, Konarski, Alastair, Ward, Alex E., Wilkin, Alex J., Winter, Alexandra K., Arnaout, Ali, Bakhsh, Ali, Esfandiari, Alireza, Hardy, Alistair W., Khan, Amad N., Thacoor, Amitabh, Gavrila, Ana D., Nedea, Anca-Mihaela, Fontalis, Andreas, Hall, Andrew J., Williamson, Andrew J., Kosti, Angeliki, Harlinska, Anna, Adimonye, Anthony, Egglestone, Anthony, Thaventhiran, Anthony J., Myatt, Antonia, Vusirikala, Anuhya, Rawashdeh, Arab S., Paramasivan, Arjun C., Cotton, Arthur E., Scrimshire, Ashley B., Ramesh, Ashwanth C., Krishnamoorthy, Ashwin K., Ahmed, Asif, Abdul-Hamid, Ayeshah, Khan, Ayushah, Oremule, Babatunde, Ho, Beatrice, Barkham, Ben, Collard, Ben, Edgar, Ben F., Drake, Benjamin, John, Bethan E., Gordon, Catherine R., Rossborough, Catherine, Park, Chang Y., Seretis, Charalampos, Johnson, Charles H.N., Gill, Charn, Serino, Chiara, Ogbuokiri, Chinomso I., Swords, Chloe, Kang, Chong Y., McKinnon, Chris, Brown, Christopher E., Manning, Christopher J., Marusza, Christopher J., Jones, Christopher P., Forde, Cillian T., Wilson, Claire L., Koh, Claudia, Horgan, Conal, Lin, Daniel J., Ashmore, Daniel L., Ness, Daniel, Akhtar, Daniel O., Doherty, Daniel T., Scholfield, Daniel W., Ensor, David C., Bratt, David G., Spence, David J.R., Thomson, David R., Ferguson, David W., Apparau, Denish, Navaratnam, Devaraj M., Mai, Dinh, Rutherford, Duncan G., Karam, Edward, Wu, Eiling, Zimmermann, Eleanor F., Douka, Eleftheria, Flatt, Elinor, Kane, Elizabeth G., Thornhill, Elizabeth L., Gammeri, Emanuele, Littlehales, Emma G., Valsamis, Epaminondas M., Hankin, Erin J., Meenan, Erin R.M., Botha, Etienne N., Khalid, Farhan, Patel, Fatema, Power, Fiachra R., Rutherford, Fiona M., Saeed, Fozia, Guest, Francesca L., Barbosa, Francisco J., Cameron, Fraser G., Raja, Furqan R., Thiruchandran, Gajendiran, Munbauhal, Gavish, Dovey, Gemma E., Hogg, Gemma E., Dovell, George E., Matheron, George, Hill, George T., Layton, Georgia R., Jong, Georgiana G.S., Hicks, Georgina, Millward, Graham J., Shaw, Grahame A., Stamp, Gregory F.W., Parwaiz, Hammad, Chong, Han Hong, Copley, Hannah C., Lennox-Warburton, Hannah C., Emerson, Hannah M., Dean, Harry F., Eltyeb, Hazim, Chu, Howard O., Sadien, Iannish, Mohamed, Imran M., Parwaiz, Iram, Drummond, Isabella M.H., Pearce, Jack C.H., Ahmed, Jacob J., Koris, Jacob, Rait, Jaideep S., Bailey, James A., Cohen, James A., Kennedy, James A., Olivier, James B., Bailey, James, Archer, James E., Stewart, James J., de Barros, James N.J.Monteiro, Allen, James R., O'Brien, James W., James, McGhee, T., Quarcoopome, Jared N., Winyard, Jasmine C., Roberts, Jason L., Barwell, Jennifer S., Rodrigues, Jeremy, Chapman, Jessica A.R., Fairbanks, Jessica Y., Voll, Jessika, Lim, Jie Q., Chang, Jin H., Bovis, Joanna L., Ferns, John, Tam, Johnson Pok Him, Herron, Jonathan B.T., Macdonald, Jonathan D.R., Ducey, Jonathan R., DIxon, Joseph W., Luck, Joshua T., Hewage, Kalon, Yakoub, Kamal M., Bhopal, Kamran F., Vejsbjerg, Karen A., Aboelmagd, Karim, Bera, Katarzyna D., Hamlett, Katharine E., Fok, Katherine E., Hurst, Katherine V., Gillams, Kathryn L., Siggens, Katie L., Young, Katie, Burns, Kenneth M., Burke, Kerry A., Seebah, Kevin, Shah, Khalid A., Bentick, Kieran R., Majid, Kiran, Davies, Kirsty L., Tan, Krystal, Baryeh, Kwaku W., Phillips, Laura A.F., Ellerton, Laura N., Giet, Leeying J., Monaghan, Liam, Ka Cheung, Lok, Shen, Louise L., Paramore, Louise, Arrowsmith, Lucy J., Attwell, Lukas A., Thornton, Luke, Xu, Luting, Leadon, Madeline L., Natarajan, Madhavi, Houlihan, Maria C.R., Cheah, Marisa, Sagmeister, Markus L., Abubakar, Maryam, Flynn, Matthew F., Harris, Matthew, Stone, Matthew J., Young, Matthew J., Gray, Matthew P., Horner, Matthew P., Schembri, Matthew, Trail, Matthew, Joy, Melvin, Rice, Michael J., Thomas, Michael P., Poon, Michael T.C., Stoddart, Michael T., Fong, Michelle L., Foster, Mitchell T., Mohamud, Mohamed F., Hoque, Mohammed N., Remtulla, Mohammedabbas, Javed Karim, Mohsin, Rezacova, Monika, Siddiqui, Muhammad B., Iqbal, Muhammad R., Mensa, Mussa, McCauley, Nadine, Bauer, Natasha J., Walker, Nathan, Hakim, Navid A., Knight, Ngonidzashe, O'Hara, Niall, Fawcett, Nicholas A., Wong, Nicholas, Allen, Nicola F.D., Husnoo, Nilofer, Vallabh, Nimisha, Srikandarajah, Nisaharan, Chidumije, Nnaemeka, Elamin, Obaiy, Akinlaja, Odunayo O., Griffiths, Olga, Brown, Oliver D., Shastri, Oliver, Cameron, Olivia J., Kenyon, Olivia, Javed, Omar A., Sogaolu, Opeyemi O., Birmpili, Panagiota, Haylock-Vize, Patricia, Green, Patrick A., Carroll, Patrick J., Yang, Peiming, Beak, Philip, Persson, Pia, Tam, Pok Him Johnson, Waqar, Rabia, Morley, Rachael L., Bowden, Rachel Clare, Eyre, Rachel L., Pankhania, Rahul M., Sahemey, Rajpreet S., Kabariti, Rakan, Rawashdeh, M., Arab, Rawashdeh S., Rollett, Rebecca A., Nicholas, Rebecca S., Morgan, Rebecca V., Limb, Richard, Robinson, Richard Mark, Hayes, Richard S., Daureeawoo, Ridwan, Cooke, Robert A., Espey, Robert A.J., Chessman, Robert, Whitham, Robert D.J., Payne, Robert E., Staruch, Robert, Alho, Roberto J.R., Gordon, Robin, Cuthbert, Rory, Harrison, Roseanna B., Scott, Rupert A., Parks, Ruth M., Cheong, Ryan C.T., Hillier-Smith, Ryan L., Moffatt, Ryan, Rehman, Saad, Ambren, Sabah, Abdulal, Sabria, Kulkarni, Sagar, Hopwood, Sam, Greenfield, Samantha H., Mehta, Samir K., Haines, Samuel, AlSaati, Sarah A., Williams, Sarah A., El-Badawy, Sarah, Barlow, Sarah L., Pywell, Sarah, Pollock, Sarah-jayne, Lampridis, Savvas, Nazarian, Scarlet, Rezvani, Sean, Scattergood, Sean, Toescu, Sebastian M., Hotonu, Sesi, Shaikh, Shafaque, Rupani, Shamil, Hasan, Shumaila, Pradeep, Shwetha, Cole, Simon J., Growcott, Siona A., Bedoya, Sofia E., Ike, Sonia I., Bodnarescu, Stefan V., Seppings, Stella C., Poyntz, Stephanie A., Jordan, Stevan J., Iqbal, Sundas, Das, Suparna, Chatterjee-Woolman, Suravi, Shumon, Syed, Morrison, Tamsin E.M., Sibartie, Tara, Aboelmagd, Tariq, Russell, Thomas B., Seddon, Thomas C., Stringfellow, Thomas D., Goldsmith, Thomas, Banks, Thomas H.F., Tolley, Thomas, Oputa, Tobenna J., Kanzara, Todd T., Challoner, Tom, Urbonas, Tomas, Richards, Tomos B., Morrison-Jones, Victoria J., Garikapati, Vivek, Al-Azzani, Waheeb A.K., Zahra, Wajiha, Ho, Weiguang, Al-Dhahir, Wesam, Gibson, William G.W., Grant, Yasmin, Hijazi, Yasser, Chiang, Yayganeh, Gundkalli, Zobia K., Seymour, Zoe M., and Panayi, Zoe

Published
2018
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3. Molecular HLA mismatching for prediction of primary humoral alloimmunity and graft function deterioration in paediatric kidney transplantation

Author

Süsal, Caner (ORCID 0000-0003-2521-8201 & YÖK ID 351800), Kim, Jon Jin; Fichtner, Alexander; Copley, Hannah C.; Gragert, Loren; Dello Strologo, Luca; Oh, Jun; Pape, Lars; Weber, Lutz T.; Weitz, Marcus; Koenig, Jens; Krupka, Kai; Toenshoff, Burkhard; Kosmoliaptsis, Vasilis, Koç University Transplant Immunology Research Centre of Excellence (TIREX), Koç University Hospital, School of Medicine, Süsal, Caner (ORCID 0000-0003-2521-8201 & YÖK ID 351800), Kim, Jon Jin; Fichtner, Alexander; Copley, Hannah C.; Gragert, Loren; Dello Strologo, Luca; Oh, Jun; Pape, Lars; Weber, Lutz T.; Weitz, Marcus; Koenig, Jens; Krupka, Kai; Toenshoff, Burkhard; Kosmoliaptsis, Vasilis, Koç University Transplant Immunology Research Centre of Excellence (TIREX), Koç University Hospital, and School of Medicine

Abstract

Introduction: Rejection remains the main cause of allograft failure in paediatric kidney transplantation and is driven by donor-recipient HLA mismatching. Modern computational algorithms enable assessment of HLA mismatch immunogenicity at the molecular level (molecular-mismatch, molMM). Whilst molMM has been shown to correlate with alloimmune outcomes, evidence demonstrating improved prediction performance against traditional antigen mismatching (antMM) is lacking. Methods: We analysed 177 patients from the CERTAIN registry (median follow-up 4.5 years). molMM scores included Amino-Acid-Mismatch-Score (AAMS), Electrostatic-Mismatch-Score (EMS3D) and netMHCIIpan (netMHC1k: peptide binding affinity <= 1000 nM; netMHC: binding affinity <= 500 nM plus rank <2%). We stratified patients into high/low-risk groups based on risk models of DSA development. Results: Donor-specific HLA antibodies (DSA) predominantly targeted the highest scoring molMM donor antigen within each HLA locus. MolMM scores offered superior discrimination versus antMM in predicting de novo DSA for all HLA loci; the EMS3D algorithm had particularly consistent performance (area under the receiver operating characteristic curve (AUC) >0.7 for all HLA loci vs. 0.52-0.70 for antMM). ABMR (but not TCMR) was associated with HLA-DQ molMM scores (AAMS, EMS3D and netMHC). Patients with high-risk HLA-DQ molMM had increased risk of graft function deterioration (50% reduction in baseline eGFR (eGFR50), adjusted HR: 3.5, 95% CI 1.6-8.2 high vs. low EMS3D). Multivariable modelling of the eGFR50 outcome using EMS3D HLA-DQ stratification showed better discrimination (AUC EMS3D vs. antMM at 2 years: 0.81 vs. 0.77, at 4.5 years: 0.72 vs. 0.64) and stratified more patients into the low-risk group, compared to traditional antMM. Conclusion: Molecular mismatching was superior to antigen mismatching in predicting humoral alloimmunity. Molecular HLA-DQ mismatching appears to be a significant prognostic factor for graft functio, European Union (EU); Horizon 2020; Research and Innovation Programme; The CERTAIN registry received funding from Astellas and Novartis. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. All authors declare no other competing interests. The authors gratefully acknowledge the funding of the CERTAIN Registry by a grant from the Dietmar Hopp Stiftung, the European Society for Paediatric Nephrology (ESPN) and The German Society for Paediatric Nephrology (GPN). JKi acknowledges funding from a MRC NIHR fellowship (MR/V037900/1). VK acknowledges funding from an NIHR Fellowship (PDF-2016-09-065) and as a Paul I. Terasaki Scholar. VK acknowledges funding from the National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU, Grant number: NIHR203332) in Organ Donation and Transplantation at the University of Cambridge in collaboration with Newcastle University and in partnership with NHS Blood and Transplant (NHSBT). The views expressed are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research, the Department of Health or National Health Service Blood and Transplant.

Published
2023

4. Molecular HLA mismatching for prediction of primary humoral alloimmunity and graft function deterioration in paediatric kidney transplantation

Author

Kim, Jon Jin, Fichtner, Alexander, Copley, Hannah C, Gragert, Loren, Süsal, Caner, Dello Strologo, Luca, Oh, Jun, Pape, Lars, Weber, Lutz T, Weitz, Marcus, König, Jens, Krupka, Kai, Tönshoff, Burkhard, Kosmoliaptsis, Vasilis, and Apollo - University of Cambridge Repository

Subjects
HLA mismatch, eplets, antibody mediated rejection (ABMR), Histocompatibility Testing, Immunology, Medizin, kidney transplantation, Antibodies, molecular mismatch, Risk Factors, HLA-DQ Antigens, Immunology and Allergy, Humans, Transplantation, Homologous, donor specific HLA antibodies, Child, predictive modeling
Abstract

Peer reviewed: True, INTRODUCTION: Rejection remains the main cause of allograft failure in paediatric kidney transplantation and is driven by donor-recipient HLA mismatching. Modern computational algorithms enable assessment of HLA mismatch immunogenicity at the molecular level (molecular-mismatch, molMM). Whilst molMM has been shown to correlate with alloimmune outcomes, evidence demonstrating improved prediction performance against traditional antigen mismatching (antMM) is lacking. METHODS: We analysed 177 patients from the CERTAIN registry (median follow-up 4.5 years). molMM scores included Amino-Acid-Mismatch-Score (AAMS), Electrostatic-Mismatch-Score (EMS3D) and netMHCIIpan (netMHC1k: peptide binding affinity ≤1000 nM; netMHC: binding affinity ≤500 nM plus rank 0.7 for all HLA loci vs. 0.52-0.70 for antMM). ABMR (but not TCMR) was associated with HLA-DQ molMM scores (AAMS, EMS3D and netMHC). Patients with high-risk HLA-DQ molMM had increased risk of graft function deterioration (50% reduction in baseline eGFR (eGFR50), adjusted HR: 3.5, 95% CI 1.6-8.2 high vs. low EMS3D). Multivariable modelling of the eGFR50 outcome using EMS3D HLA-DQ stratification showed better discrimination (AUC EMS3D vs. antMM at 2 years: 0.81 vs. 0.77, at 4.5 years: 0.72 vs. 0.64) and stratified more patients into the low-risk group, compared to traditional antMM. CONCLUSION: Molecular mismatching was superior to antigen mismatching in predicting humoral alloimmunity. Molecular HLA-DQ mismatching appears to be a significant prognostic factor for graft function deterioration in paediatric kidney transplantation.

Published
2023
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5. Corrigendum: Molecular HLA mismatching for prediction of primary humoral alloimmunity and graft function deterioration in paediatric kidney transplantation

Author

Kim, Jon Jin, primary, Fichtner, Alexander, additional, Copley, Hannah C., additional, Gragert, Loren, additional, Süsal, Caner, additional, Strologo, Luca Dello, additional, Oh, Jun, additional, Pape, Lars, additional, Weber, Lutz T., additional, Weitz, Marcus, additional, König, Jens, additional, Krupka, Kai, additional, Tönshoff, Burkhard, additional, and Kosmoliaptsis, Vasilis, additional

Published
2023
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6. Molecular HLA mismatching for prediction of primary humoral alloimmunity and graft function deterioration in paediatric kidney transplantation

Author

Kim, Jon Jin, primary, Fichtner, Alexander, additional, Copley, Hannah C., additional, Gragert, Loren, additional, Süsal, Caner, additional, Dello Strologo, Luca, additional, Oh, Jun, additional, Pape, Lars, additional, Weber, Lutz T., additional, Weitz, Marcus, additional, König, Jens, additional, Krupka, Kai, additional, Tönshoff, Burkhard, additional, and Kosmoliaptsis, Vasilis, additional

Published
2023
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9. Refined HLA-DPB1 mismatch with molecular algorithms predicts outcomes in hematopoietic stem cell transplantation

Author

Zou, Jun, primary, Kongtim, Piyanuch, additional, Oran, Betül, additional, Kosmoliaptsis, Vasilis, additional, Carmazzi, Yudith, additional, Ma, Junsheng, additional, Li, Liang, additional, Rondon, Gabriela, additional, Srour, Samer, additional, Copley, Hannah C., additional, Partlow, David, additional, Ciurea, Stefan O., additional, Greenbaum, Uri, additional, Ma, Qing, additional, Shpall, Elizabeth J., additional, Champlin, Richard E., additional, and Cao, Kai, additional

Published
2021
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13. Corrigendum: Molecular HLA mismatching for prediction of primary humoral alloimmunity and graft function deterioration in paediatric kidney transplantation.

Author

Jon Jin Kim, Fichtner, Alexander, Copley, Hannah C., Gragert, Loren, Süsal, Caner, Strologo, Luca Dello, Jun Oh, Pape, Lars, Weber, Lutz T., Weitz, Marcus, König, Jens, Krupka, Kai, Tönshoff, Burkhard, and Kosmoliaptsis, Vasilis

Subjects
KIDNEY transplantation, ALLOIMMUNITY, PEDIATRICS, FORECASTING
Published
2023
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14. HLA-DQ mismatches lead to more unacceptable antigens, greater sensitization, and increased disparities in repeat transplant candidates

Author

Isaacson, Dylan, Schold, Jesse D., Gmeiner, Michael W., Copley, Hannah C., Kosmoliaptsis, Vasilis, Tambur, Anat R., Isaacson, Dylan, Schold, Jesse D., Gmeiner, Michael W., Copley, Hannah C., Kosmoliaptsis, Vasilis, and Tambur, Anat R.

Abstract

Background In single-center studies, HLA-DQ mismatches stimulate the most pathogenic donor-specific antibodies. However, because of limitations of transplant registries, this cannot be directly confirmed with registry-based analyses. Methods We evaluated patients in the Scientific Registry of Transplant Recipients who were relisted after renal graft failure with new, unacceptable antigens corresponding to the HLA typing of their previous donor (UA-PD) as a proxy for donor-specific antibodies. Linear regression was applied to estimate the effects of HLA mismatches on UA-PD and the effects of UA-PD on calculated panel reactive antibody (cPRA) values for 4867 kidney recipients from 2010 to 2021. Results Each additional HLA-DQ mismatch increased the probability of UA-PD by 25.2% among deceased donor transplant recipients and by 28.9% among living donor transplant recipients, significantly more than all other HLA loci (P<0.05). HLA-DQ UA-PD increased cPRA by 29.0% in living donor transplant recipients and by 23.5% in deceased donor transplant recipients, significantly more than all loci except for HLA-A in deceased donor transplant recipients (23.1%). African American deceased donor transplant recipients were significantly more likely than Hispanic and White recipients to develop HLA-DQ UA-PD; among living donor transplant recipients, African American or Hispanic recipients were significantly more likely to do so compared with White recipients. Models evaluating interactions between HLA-DR/DQ mismatches revealed largely independent effects of HLA-DQ mismatches on HLA-DQ UA-PD. Conclusions HLA-DQ mismatches had the strongest associations with UA-PD, an effect that was greatest in African American and Hispanic recipients. cPRA increases with HLA-DQ UA-PD were equivalent or larger than any other HLA locus. This suggests a need to consider the effects of HLA-DQ in kidney allocation.

15. Refined HLA-DPB1 mismatch with molecular algorithms predicts outcomes in hematopoietic stem cell transplantation.

Author

Zou J, Kongtim P, Oran B, Kosmoliaptsis V, Carmazzi Y, Ma J, Li L, Rondon G, Srour S, Copley HC, Partlow D, Ciurea SO, Greenbaum U, Ma Q, Shpall EJ, Champlin RE, and Cao K

Subjects
Algorithms, Epitopes, T-Lymphocyte, HLA-DP beta-Chains, Histocompatibility Testing, Humans, Unrelated Donors, Graft vs Host Disease etiology, Graft vs Host Disease prevention & control, Hematopoietic Stem Cell Transplantation adverse effects
Abstract

HLA-DPB1 mismatches between donor and recipient are commonly seen in allogeneic hematopoietic stem cell transplantation from an unrelated donor. HLA-DPB1 mismatch, conventionally determined by the similarity of the T-cell epitope (TCE), is associated with an increased risk of acute graft-versus-host disease (GVHD) and a decreased risk of disease relapse. We investigated the clinical impact of HLA-DPB1 molecular mismatch quantified by mismatched eplets (ME) and the Predicted Indirectly Recognizable HLA Epitopes Score (PS) in a cohort of 1,514 patients receiving hematopoietic stem cell transplants from unrelated donors matched at HLA-A, -B, -C, -DRB1/3/4/5, and - DQB1 loci. HLA-DPB1 alloimmunity in the graft-versus-host direction, determined by high graft-versus-host ME/PS, was associated with a reduced risk of relapse (hazard ratio [HR]=0.83, P=0.05 for ME) and increased risk of grade 2-4 acute GVHD (HR=1.44, P<0.001 for ME), whereas high host-versus-graft ME/PS was only associated with an increased risk of grade 2-4 acute GVHD (HR=1.26, P=0.004 for ME). Notably, in the permissive mismatch subgroup classified by TCE grouping, high host-versus-graft ME/PS was associated with an increased risk of relapse (HR=1.36, P=0.026 for ME) and grade 2-4 acute GVHD (HR=1.43, P=0.003 for PS-II). Decision curve analysis showed that graftversus- host ME outperformed other models and provided the best clinical net benefit for the modification of acute GVHD prophylaxis regimens in patients with a high risk of developing clinically significant acute GVHD. In conclusion, molecular assessment of HLA-DPB1 mismatch enables separate prediction of host-versus-graft or graft-versus-host alloresponse quantitatively and allows further refinement of HLA-DPB1 permissiveness as defined by conventional TCE grouping.

Published
2022
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