Pub Date : 2026-01-10DOI: 10.1016/j.ajt.2026.01.006
Muhammad M Mohiuddin,David Kalfa
{"title":"Pediatric Cardiac Xenotransplantation: A Cautious Approach as Bridge to Allotransplantation.","authors":"Muhammad M Mohiuddin,David Kalfa","doi":"10.1016/j.ajt.2026.01.006","DOIUrl":"https://doi.org/10.1016/j.ajt.2026.01.006","url":null,"abstract":"","PeriodicalId":123,"journal":{"name":"American Journal of Transplantation","volume":"28 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
We report the case of a kidney transplant recipient (2011) who developed persistent elevation of liver enzymes beginning in 2015. Extensive investigations including standard Hepatitis E virus PCR failed to identify a cause. In 2019, she developed decompensated cirrhosis and underwent liver-kidney transplantation in 2021. Post-transplant, liver function tests remained abnormal. Given suspicion of an unidentified pathogen, metagenomic next-generation sequencing was performed on the graft and identified rat hepatitis E virus. Retrospective testing of native liver and serum samples confirmed infection since 2015. Ribavirin therapy resulted in normalization of liver enzymes and viral clearance.
{"title":"Occult rat Hepatitis E Virus Infection as a Cause of Cirrhosis and Post-Transplant Recurrence: Insights into the Role of Metagenomics.","authors":"Jacques Fourgeaud,Nicolas Veyrenche,Illan Laloum,Jean-Philippe Jais,Camille Roger,Marion Rabant,Vincent Mallet,Aurélie Beaufrère,Hélène Fontaine,Marianne Leruez-Ville,François Durand,Dany Anglicheau","doi":"10.1016/j.ajt.2026.01.005","DOIUrl":"https://doi.org/10.1016/j.ajt.2026.01.005","url":null,"abstract":"We report the case of a kidney transplant recipient (2011) who developed persistent elevation of liver enzymes beginning in 2015. Extensive investigations including standard Hepatitis E virus PCR failed to identify a cause. In 2019, she developed decompensated cirrhosis and underwent liver-kidney transplantation in 2021. Post-transplant, liver function tests remained abnormal. Given suspicion of an unidentified pathogen, metagenomic next-generation sequencing was performed on the graft and identified rat hepatitis E virus. Retrospective testing of native liver and serum samples confirmed infection since 2015. Ribavirin therapy resulted in normalization of liver enzymes and viral clearance.","PeriodicalId":123,"journal":{"name":"American Journal of Transplantation","volume":"50 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-10DOI: 10.1016/j.ajt.2026.01.003
Silke E. de Boer, Erzsi Tegzess, Daan Kremer, Frederike J. Bemelman, Maarten H.L. Christiaans, Luuk B. Hilbrands, Aiko P.J. de Vries, Dorottya K. de Vries, Jacqueline van de Wetering, Hendrikus J.A.N. Kimenai, Arjan D. van Zuilen, Cyril Moers, Stefan P. Berger, Jan Stephan F. Sanders
Older patients (≥65 years) account for nearly one-third of the kidney transplant waiting list, with high waitlist mortality that could be prevented by early transplantation, even with (very) old donor kidneys. Yet, data on outcomes of old deceased-donor kidneys are sparse.
{"title":"Comparable outcomes for old, older and very old deceased donors in old kidney transplant recipients","authors":"Silke E. de Boer, Erzsi Tegzess, Daan Kremer, Frederike J. Bemelman, Maarten H.L. Christiaans, Luuk B. Hilbrands, Aiko P.J. de Vries, Dorottya K. de Vries, Jacqueline van de Wetering, Hendrikus J.A.N. Kimenai, Arjan D. van Zuilen, Cyril Moers, Stefan P. Berger, Jan Stephan F. Sanders","doi":"10.1016/j.ajt.2026.01.003","DOIUrl":"https://doi.org/10.1016/j.ajt.2026.01.003","url":null,"abstract":"Older patients (≥65 years) account for nearly one-third of the kidney transplant waiting list, with high waitlist mortality that could be prevented by early transplantation, even with (very) old donor kidneys. Yet, data on outcomes of old deceased-donor kidneys are sparse.","PeriodicalId":123,"journal":{"name":"American Journal of Transplantation","volume":"94 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-08DOI: 10.1016/j.ajt.2025.12.287
Jonathan S Bromberg,Suphamai Bunnapradist,Zachary P Demko,Philippe Gauthier
{"title":"Letter to the Editor re: Valenzuela et al. 2025 STAR working group report on dd-cfDNA validation.","authors":"Jonathan S Bromberg,Suphamai Bunnapradist,Zachary P Demko,Philippe Gauthier","doi":"10.1016/j.ajt.2025.12.287","DOIUrl":"https://doi.org/10.1016/j.ajt.2025.12.287","url":null,"abstract":"","PeriodicalId":123,"journal":{"name":"American Journal of Transplantation","volume":"30 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145947421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-08DOI: 10.1016/j.ajt.2025.12.286
Carrie A Schinstock,Howard Gebel,Idoia Gimferrer,Marlena Habal,Sebastiaan Heidt,Michelle J Hickey,Annette M Jackson,Vasilis Kosmoliaptsis,Roslyn B Mannon,Maria Meneghini,Michael Mengel,Anna Morris,Maarten Naesens,Elaine Reed,Aleksandar Senev,Olivier Thaunat,Nicole Valenzuela,Chris Wiebe,Anat R Tambur,
The Sensitization in Transplantation: Assessment of Risk (STAR) initiative aims to translate HLA laboratory data into clinical practice and identify key knowledge gaps to guide future research. The STAR working group has held three consensus meetings and published reports that have influenced clinical care. In 2025, the group focused on five evolving areas: donor-derived cell-free DNA (dd-cfDNA) tests, innate immunity in allograft rejection, immunogenicity and antigenicity, HLA antibody quantification, and non-HLA antibodies. Three years of work culminated in two webinars and a February 2025 community meeting summarized in this report. The group outlined considerations for integrating dd-cfDNA tests into practice, proposed a definition for genetic prediction of NK-cell missing self, and discussed monocyte activation via the SIRPα-CD47 pathway. They reviewed molecular mismatch approaches, limitations, and immune-recognition complexities. Finally, they provided updates on HLA antibody quantification, non-HLA antibodies, and ongoing studies addressing critical knowledge gaps.
{"title":"Sensitization in Organ Transplantation: Assessment of Risk (STAR) 2025 Meeting Group Report.","authors":"Carrie A Schinstock,Howard Gebel,Idoia Gimferrer,Marlena Habal,Sebastiaan Heidt,Michelle J Hickey,Annette M Jackson,Vasilis Kosmoliaptsis,Roslyn B Mannon,Maria Meneghini,Michael Mengel,Anna Morris,Maarten Naesens,Elaine Reed,Aleksandar Senev,Olivier Thaunat,Nicole Valenzuela,Chris Wiebe,Anat R Tambur, ","doi":"10.1016/j.ajt.2025.12.286","DOIUrl":"https://doi.org/10.1016/j.ajt.2025.12.286","url":null,"abstract":"The Sensitization in Transplantation: Assessment of Risk (STAR) initiative aims to translate HLA laboratory data into clinical practice and identify key knowledge gaps to guide future research. The STAR working group has held three consensus meetings and published reports that have influenced clinical care. In 2025, the group focused on five evolving areas: donor-derived cell-free DNA (dd-cfDNA) tests, innate immunity in allograft rejection, immunogenicity and antigenicity, HLA antibody quantification, and non-HLA antibodies. Three years of work culminated in two webinars and a February 2025 community meeting summarized in this report. The group outlined considerations for integrating dd-cfDNA tests into practice, proposed a definition for genetic prediction of NK-cell missing self, and discussed monocyte activation via the SIRPα-CD47 pathway. They reviewed molecular mismatch approaches, limitations, and immune-recognition complexities. Finally, they provided updates on HLA antibody quantification, non-HLA antibodies, and ongoing studies addressing critical knowledge gaps.","PeriodicalId":123,"journal":{"name":"American Journal of Transplantation","volume":"5 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145947422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-07DOI: 10.1016/j.ajt.2025.12.285
Soha Mcheik,Hui Wang,Xiaolan Ding,Hao Wei Li,Megan Sykes
Tolerance induction would prevent xenograft rejection while avoiding high levels of immunosuppression. Mixed chimerism is an attractive approach to xenotolerance induction, as it tolerizes T, B and natural killer (NK) cells. However, the species-specific interaction between CD47 and signal regulatory protein alpha (SIRPα) is ineffective in the pig to human combination, and may limit pig cell and organ engraftment. Prior studies showed that human CD47 (hCD47) expression on porcine cells can inhibit phagocytosis by primate macrophages. We have now tested the effect of hCD47 expression on destruction of pig splenocytes in a human immune system (HIS) mouse model. Although the hCD47 transgene enhanced the survival of opsonized and non-opsonized porcine splenocytes in both HIS mice and non-reconstituted immunodeficient (NSG) mice, macrophage-mediated destruction of hCD47-transgenic (hCD47-tg) pig cells still occurred in HIS mice. In longer-term studies, higher levels of pig chimerism were achieved in HIS mice receiving hCD47-tg compared to control pig bone marrow (BM) cells. Taken together, these results indicate that transgenic expression of hCD47 may reduce macrophage-mediated xenograft rejection in clinical xenotransplantation, but that additional strategies are needed to fully overcome human macrophage-mediated destruction of pig cells.
{"title":"Transgenic expression of hCD47 on pig cells provides only partial protection against human macrophage-mediated destruction in human immune system (HIS) mice.","authors":"Soha Mcheik,Hui Wang,Xiaolan Ding,Hao Wei Li,Megan Sykes","doi":"10.1016/j.ajt.2025.12.285","DOIUrl":"https://doi.org/10.1016/j.ajt.2025.12.285","url":null,"abstract":"Tolerance induction would prevent xenograft rejection while avoiding high levels of immunosuppression. Mixed chimerism is an attractive approach to xenotolerance induction, as it tolerizes T, B and natural killer (NK) cells. However, the species-specific interaction between CD47 and signal regulatory protein alpha (SIRPα) is ineffective in the pig to human combination, and may limit pig cell and organ engraftment. Prior studies showed that human CD47 (hCD47) expression on porcine cells can inhibit phagocytosis by primate macrophages. We have now tested the effect of hCD47 expression on destruction of pig splenocytes in a human immune system (HIS) mouse model. Although the hCD47 transgene enhanced the survival of opsonized and non-opsonized porcine splenocytes in both HIS mice and non-reconstituted immunodeficient (NSG) mice, macrophage-mediated destruction of hCD47-transgenic (hCD47-tg) pig cells still occurred in HIS mice. In longer-term studies, higher levels of pig chimerism were achieved in HIS mice receiving hCD47-tg compared to control pig bone marrow (BM) cells. Taken together, these results indicate that transgenic expression of hCD47 may reduce macrophage-mediated xenograft rejection in clinical xenotransplantation, but that additional strategies are needed to fully overcome human macrophage-mediated destruction of pig cells.","PeriodicalId":123,"journal":{"name":"American Journal of Transplantation","volume":"263 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-07DOI: 10.1016/j.ajt.2025.12.288
Lukas Weidmann,Petra Hruba,Eva Girmanova,Dusan Harmacek,Katerina Jaklova,Kerstin Hübel,Elena Rho,Kai Castrezana Lopez,Ariana Gaspert,Birgit Maria Helmchen,Florian Westphal,Britta George,Seraina von Moos,Ludek Voska,Ondrej Viklicky,Thomas Schachtner
Chronic-active T-cell-mediated rejection (caTCMR) remains debated and molecular diagnostics might aid risk-stratification. This retrospective two-center observational study analyzed 26 kidney allograft biopsies with caTCMR comparing them to 40 borderline/acute TCMR-cases (without caTCMR) and 308 subthreshold/negative controls after excluding microvascular inflammation (MVI) at/above threshold and overlapping pathologies. All biopsies received transcriptomic evaluation through microarray-based gene expression profiling. caTCMR-cases with acute TCMR (n=8) showed higher molecular TCMR activity (median TCMRprob 0.54 [0.30-0.83]) than "pure" caTCMR (n=11; TCMRprob 0.03 [0.01-0.28], p=0.012) or caTCMR with borderline TCMR (n=7; TCMRprob 0.01 [0.01-0.77], p=0.036). TCMRprob was low in subthreshold/negative controls but elevated in acute TCMR, BK virus nephropathy- and pyelonephritis-cases (side cohort). Molecular sign-outs classified 4/11 (36%) "pure" caTCMR-cases as molecular TCMR. Within the TCMR continuum (26 caTCMR plus 40 borderline/acute TCMR), i-, t- and ti-lesions were associated in univariable analyses with TCMRprob >0.2, while i-IFTA/t-IFTA correlated with molecular chronicity. 7/26 (27%) caTCMR- and 7/40 (18%) borderline/acute TCMR-cases showed mixed molecular rejection activity above thresholds. In conclusion, significant molecular TCMR activity was present in a subset of caTCMR-cases and was associated with higher i/t/ti scores and, at times, molecular AMR signals, even with MVI<2. To confirm these preliminary observations, future studies and external validation are needed.
{"title":"Molecular Rejection Signals in Chronic-Active T-Cell-Mediated Rejection: Histological Associations and Potential Clinical Implications.","authors":"Lukas Weidmann,Petra Hruba,Eva Girmanova,Dusan Harmacek,Katerina Jaklova,Kerstin Hübel,Elena Rho,Kai Castrezana Lopez,Ariana Gaspert,Birgit Maria Helmchen,Florian Westphal,Britta George,Seraina von Moos,Ludek Voska,Ondrej Viklicky,Thomas Schachtner","doi":"10.1016/j.ajt.2025.12.288","DOIUrl":"https://doi.org/10.1016/j.ajt.2025.12.288","url":null,"abstract":"Chronic-active T-cell-mediated rejection (caTCMR) remains debated and molecular diagnostics might aid risk-stratification. This retrospective two-center observational study analyzed 26 kidney allograft biopsies with caTCMR comparing them to 40 borderline/acute TCMR-cases (without caTCMR) and 308 subthreshold/negative controls after excluding microvascular inflammation (MVI) at/above threshold and overlapping pathologies. All biopsies received transcriptomic evaluation through microarray-based gene expression profiling. caTCMR-cases with acute TCMR (n=8) showed higher molecular TCMR activity (median TCMRprob 0.54 [0.30-0.83]) than \"pure\" caTCMR (n=11; TCMRprob 0.03 [0.01-0.28], p=0.012) or caTCMR with borderline TCMR (n=7; TCMRprob 0.01 [0.01-0.77], p=0.036). TCMRprob was low in subthreshold/negative controls but elevated in acute TCMR, BK virus nephropathy- and pyelonephritis-cases (side cohort). Molecular sign-outs classified 4/11 (36%) \"pure\" caTCMR-cases as molecular TCMR. Within the TCMR continuum (26 caTCMR plus 40 borderline/acute TCMR), i-, t- and ti-lesions were associated in univariable analyses with TCMRprob >0.2, while i-IFTA/t-IFTA correlated with molecular chronicity. 7/26 (27%) caTCMR- and 7/40 (18%) borderline/acute TCMR-cases showed mixed molecular rejection activity above thresholds. In conclusion, significant molecular TCMR activity was present in a subset of caTCMR-cases and was associated with higher i/t/ti scores and, at times, molecular AMR signals, even with MVI<2. To confirm these preliminary observations, future studies and external validation are needed.","PeriodicalId":123,"journal":{"name":"American Journal of Transplantation","volume":"29 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-07DOI: 10.1016/j.ajt.2025.12.284
Jay A Fishman,Allan D Kirk,Seyed M Hosseini-Moghaddam
Costimulatory blockade has emerged as a promising alternative to conventional immunosuppression with the potential to reduce chronic allograft injury and minimize drug-related toxicities including nephrotoxicity, cardiometabolic complications, and malignancies. Belatacept, the most extensively studied agent, has been associated with improved allograft function and reduced donor-specific antibody formation while associated with increased risk of acute, early graft rejection and increased risk for infections due to cytomegalovirus (CMV), Epstein-Barr virus (EBV), and Pneumocystis jirovecii. These effects may reflect the impact of costimulatory blockade on naïve T-cell activation while relatively sparing memory responses. Susceptibility to infections is, therefore, influenced by prior infectious exposures and the maintenance of immune memory in the face of diverse adjunctive immunosuppressive programs. Next-generation approaches, including Fc-silent anti-CD154 antibodies and CD28-directed therapies, are in early clinical trials with infectious complications incompletely defined. Recently, immunosuppression for clinical xenotransplantation has included costimulatory blockade as a component of generally complex immunosuppressive regimens; intensive microbiological surveillance will provide insights into any associated xenozoonotic infections. Successful integration of costimulatory blockade in allotransplantation and clinical xenotransplantation require further prospective trials coupled with robust microbiological surveillance.
{"title":"Co-Stimulatory Blockade and Infectious Risk in Solid Organ Transplantation.","authors":"Jay A Fishman,Allan D Kirk,Seyed M Hosseini-Moghaddam","doi":"10.1016/j.ajt.2025.12.284","DOIUrl":"https://doi.org/10.1016/j.ajt.2025.12.284","url":null,"abstract":"Costimulatory blockade has emerged as a promising alternative to conventional immunosuppression with the potential to reduce chronic allograft injury and minimize drug-related toxicities including nephrotoxicity, cardiometabolic complications, and malignancies. Belatacept, the most extensively studied agent, has been associated with improved allograft function and reduced donor-specific antibody formation while associated with increased risk of acute, early graft rejection and increased risk for infections due to cytomegalovirus (CMV), Epstein-Barr virus (EBV), and Pneumocystis jirovecii. These effects may reflect the impact of costimulatory blockade on naïve T-cell activation while relatively sparing memory responses. Susceptibility to infections is, therefore, influenced by prior infectious exposures and the maintenance of immune memory in the face of diverse adjunctive immunosuppressive programs. Next-generation approaches, including Fc-silent anti-CD154 antibodies and CD28-directed therapies, are in early clinical trials with infectious complications incompletely defined. Recently, immunosuppression for clinical xenotransplantation has included costimulatory blockade as a component of generally complex immunosuppressive regimens; intensive microbiological surveillance will provide insights into any associated xenozoonotic infections. Successful integration of costimulatory blockade in allotransplantation and clinical xenotransplantation require further prospective trials coupled with robust microbiological surveillance.","PeriodicalId":123,"journal":{"name":"American Journal of Transplantation","volume":"1 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-06DOI: 10.1016/j.ajt.2026.01.001
Marcus R Pereira
{"title":"Human-to-human rabies transmission via solid organ transplantation from a donor with undiagnosed rabies-United States, October 2024-February 2025.","authors":"Marcus R Pereira","doi":"10.1016/j.ajt.2026.01.001","DOIUrl":"10.1016/j.ajt.2026.01.001","url":null,"abstract":"","PeriodicalId":123,"journal":{"name":"American Journal of Transplantation","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145931536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-06DOI: 10.1016/j.ajt.2025.12.283
Paolo Malvezzi, Anna Martínez-Lacalle, Elena Crespo, Alba Torija, Farida Imerzoukene, Maria Meneghini, Laura Donadeu, Delphine Kervella, Claudia Carrera, Irina B Torres, Jorge Iván Zamora, Mariona Juvé, Cristina Font-Miñarro, Anne Bourdin, Celine Dard, Thomas Jouve, Eduard Palou, Francesc Moreso, Lionel Rostaing, Oriol Bestard
Highly sensitized kidney transplant candidates face limited access to compatible organs due to persistent anti-human leukocyte antigen (HLA) antibodies (Abs) and memory B cell (mBc) responses, which are generally not concomitantly targeted by current desensitization therapies. In this single-arm phase 1b/2 trial (NCT05145296), 5 highly sensitized kidney transplant candidates (calculated panel-reactive Ab >99%) were treated with belatacept and daratumumab to evaluate safety and mechanistic efficacy. Serum anti-HLA Ab levels, HLA-specific mBc, and bone marrow (BM)-residing long-lived plasma cells (PCs) were analyzed using single antigen beads, functional B cell assays, and spectral flow cytometry. The regimen was well-tolerated, with no serious adverse events attributable to study drugs. Three of 4 evaluable patients showed substantial serologic response by means of elimination and reductions in mean fluorescence intensity Abs and titers, mainly anti-HLA class I. HLA-specific mBc and CD38+ PC were significantly depleted in responders in peripheral blood and BM. Multidimensional profiling revealed depletion of CD38+ natural killer, T follicular helper, and PC in both peripheral blood and BM, which was accompanied by a reduction in calculated panel-reactive Ab levels, primarily in class I Abs. Dual targeting of T/B cell costimulation and PC using belatacept and daratumumab is a safe and mechanistically effective approach for desensitization in highly sensitized kidney transplant candidates. These findings support further investigation in larger trials.
{"title":"Dual targeting of B cell compartments using belatacept and daratumumab in highly sensitized kidney transplant candidates: A mechanistic proof-of-concept desensitization trial.","authors":"Paolo Malvezzi, Anna Martínez-Lacalle, Elena Crespo, Alba Torija, Farida Imerzoukene, Maria Meneghini, Laura Donadeu, Delphine Kervella, Claudia Carrera, Irina B Torres, Jorge Iván Zamora, Mariona Juvé, Cristina Font-Miñarro, Anne Bourdin, Celine Dard, Thomas Jouve, Eduard Palou, Francesc Moreso, Lionel Rostaing, Oriol Bestard","doi":"10.1016/j.ajt.2025.12.283","DOIUrl":"10.1016/j.ajt.2025.12.283","url":null,"abstract":"<p><p>Highly sensitized kidney transplant candidates face limited access to compatible organs due to persistent anti-human leukocyte antigen (HLA) antibodies (Abs) and memory B cell (mBc) responses, which are generally not concomitantly targeted by current desensitization therapies. In this single-arm phase 1b/2 trial (NCT05145296), 5 highly sensitized kidney transplant candidates (calculated panel-reactive Ab >99%) were treated with belatacept and daratumumab to evaluate safety and mechanistic efficacy. Serum anti-HLA Ab levels, HLA-specific mBc, and bone marrow (BM)-residing long-lived plasma cells (PCs) were analyzed using single antigen beads, functional B cell assays, and spectral flow cytometry. The regimen was well-tolerated, with no serious adverse events attributable to study drugs. Three of 4 evaluable patients showed substantial serologic response by means of elimination and reductions in mean fluorescence intensity Abs and titers, mainly anti-HLA class I. HLA-specific mBc and CD38<sup>+</sup> PC were significantly depleted in responders in peripheral blood and BM. Multidimensional profiling revealed depletion of CD38<sup>+</sup> natural killer, T follicular helper, and PC in both peripheral blood and BM, which was accompanied by a reduction in calculated panel-reactive Ab levels, primarily in class I Abs. Dual targeting of T/B cell costimulation and PC using belatacept and daratumumab is a safe and mechanistically effective approach for desensitization in highly sensitized kidney transplant candidates. These findings support further investigation in larger trials.</p>","PeriodicalId":123,"journal":{"name":"American Journal of Transplantation","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145931541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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