367 results on '"Gennery, Ar"'
Search Results
2. T-lymphocyte depleted transplants for inborn errors of immunity
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Slatter, MA, primary, Maschan, MA, additional, and Gennery, AR, additional
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- 2023
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3. Hematopoietic stem cell transplantation for adolescents and adults with inborn errors of immunity: an EBMT IEWP study
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Albert MH, Sirait T, Eikema DJ, Bakunina K, Wehr C, Suarez F, Fox ML, Mahlaoui N, Gennery AR, Lankester AJ, Beier R, Bernardo ME, Bigley V, Lindemans CA, OBurns S, Carpenter B, Dybko J, Gungor T, Hauck F, Lum SH, Balashov D, Meisel R, Moshous D, Schulz A, Speckmann C, Slatter MA, Strahm B, Uckan-Cetinkaya D, Meyts I, Vallee TC, Wynn R, Neven B, Morris EC, EBMT IEWP, ESID
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- 2022
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4. Defining the systemic immune landscape in children at an increased risk of posttransplant lymphoproliferative disease: The immunology of thymectomy and childhood cardiac transplant (ITHACA) study
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Offor UT, Long HM, Filby A, Ognjanovic M, Simmonds J, Parry G, Khushnood A, Reinhardt Z, Gennery AR, Bacon CM, Bomken S
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- 2022
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5. Neonatal thymectomy in children-accelerating the immunologic clock?
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Deyà-Martinez A, Flinn AM, and Gennery AR
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immunosenescence ,T-lymphocyte ,Thymus ,neonatal thymectomy ,immunodeficiency - Abstract
The thymus is critical for central tolerance and diverse T-lymphocyte repertoire development, to provide lifelong defense against pathogens while maintaining self-tolerance. Peak thymic output occurs in utero, during infancy, and in early childhood, diminishing throughout life. Infants with congenital heart disease requiring sternotomy often undergo thymectomy to clear the surgical field. The long-term effects of early thymectomy are just being appreciated. Many patients remain asymptomatic despite immunologic findings mirroring those of immunosenescence. Few develop increased infection or lymphoreticular malignancy risk. When considering the effects of infant thymectomy, patients with partial DiGeorge syndrome or hypomorphic recombination-activating gene (RAG) mutations may be instructive. These patients are lymphocytopenic, with increased early-onset infection and autoimmunity risk that is not seen in most patients who underwent thymectomy during infancy. The thymic structure of patients with partial DiGeorge syndrome or hypomorphic RAG is abnormal, with disrupted architecture inclining to perturbation of central tolerance. Similar findings may be seen in patients with myasthenia gravis, although disrupted peripheral tolerance may play a greater role in autoimmunity development. In conclusion, thymectomy during infancy may increase future risk of infection or autoimmunity, with premature immunosenescence mediated through disruption of central and peripheral tolerance mechanisms initiated by early cessation or diminution of thymic output. Ideally, some thymic tissue should be preserved at the time of surgery.
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- 2020
6. Childrenʼs participation in clinical research: factors influencing parental consent
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Elemraid, MA, Pollard, K, Thomas, MF, Simmister, C, Spencer, DA, Rushton, SP, Gennery, AR, and Clark, JE
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- 2012
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7. Bone marrow transplantation does not correct the hyper IgE syndrome
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Gennery, AR, Flood, TJ, Abinun, M, and Cant, AJ
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- 2000
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8. Hematopoietic stem cell transplantation in patients with gain-of-function signal transducer and activator of transcription 1 mutations
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Leiding, JW, Okada, S, Hagin, D, Abinun, M, Shcherbina, A, Balashov, DN, Kim, VHD, Ovadia, A, Guthery, SL, Pulsipher, M, Lilic, D, Devlin, LA, Christie, S, Depner, M, Fuchs, S, van Royen-Kerkhof, A, Lindemans, C, Petrovic, A, Sullivan, KE, Bunin, N, Kilic, SS, Arpaci, F, de la Calle-Martin, O, Martinez-Martinez, L, Aldave, JC, Kobayashi, M, Ohkawa, T, Imai, K, Iguchi, A, Roifman, CM, Gennery, AR, Slatter, M, Ochs, HD, Morio, T, Torgerson, TR, Inborn Errors Working Party, European Soc Blood Marrow, and Primary Immune Deficiency
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surgical procedures, operative ,hemophagocytic lymphohistiocytosis ,gain of function ,graft-versus-host disease ,chronic mucocutaneous candidiasis ,Hematopoietic stem cell transplantation ,graft rejection ,Janus kinase ,signal transducer and activator of transcription - Abstract
Background: Gain-of-function (GOF) mutations in signal transducer and activator of transcription 1 (STAT1) cause susceptibility to a range of infections, autoimmunity, immune dysregulation, and combined immunodeficiency. Disease manifestations can be mild or severe and life-threatening. Hematopoietic stem cell transplantation (HSCT) has been used in some patients with more severe symptoms to treat and cure the disorder. However, the outcome of HSCT for this disorder is not well established. Objective: We sought to aggregate the worldwide experience of HSCT in patients with GOF-STAT1 mutations and to assess outcomes, including donor engraftment, overall survival, graft-versus-host disease, and transplant-related complications. Methods: Data were collected from an international cohort of 15 patients with GOF-STAT1 mutations who had undergone HSCT-using a variety of conditioning regimens and donor sources. Retrospective data collection allowed the outcome of transplantation to be assessed. In vitro functional testing was performed to confirm that each of the identified STAT1 variants was in fact a GOF mutation. Results: Primary donor engraftment in this cohort of 15 patients with GOF-STAT1 mutations was 74%, and overall survival was only 40%. Secondary graft failure was common (50%), and posttransplantation event-free survival was poor (10% by 100 days). Asubset of patients had hemophagocytic lymphohistiocytosis before transplant, contributing to their poor outcomes. Conclusion: Our data indicate that HSCT for patients with GOF-STAT1 mutations is curative but has significant risk of secondary graft failure and death.
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- 2018
9. 132 Improved survival and outcome of HLA-mismatched donor hematopoietic stem cell transplantation in children with primary immunodeficiencies using new graft manipulation strategies in the UK
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Elfeky, R, primary, Shah, RM, additional, Unni, MNM, additional, Rao, K, additional, Chiesa, R, additional, Amrolia, P, additional, Worth, A, additional, Flood, T, additional, Abinun, M, additional, Nademi, Z, additional, Hambleton, S, additional, Cant, AJ, additional, Gilmour, K, additional, Adams, S, additional, Ahsan, G, additional, Barge, D, additional, Gennery, AR, additional, Qasim, W, additional, Slatter, M, additional, and Veys, P, additional
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- 2018
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10. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype
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Toubiana, J., Okada, S., Hiller, J., Oleastro, M., Lagos Gomez, M., Aldave Becerra, J. C., Ouachee-Chardin, M., Fouyssac, F., Girisha, K. M., Etzioni, A., Van Montfrans, J., Camcioglu, Y., Kerns, L. A., Belohradsky, B., Blanche, S., Bousfiha, A., Rodriguez-Gallego, C., Meyts, I., Kisand, K., Reichenbach, J., Renner, E. D., Rosenzweig, S., Grimbacher, B., van de Veerdonk, F. L., Traidl-Hoffmann, C., Picard, C., Marodi, L., Morio, T., Kobayashi, M., Lilic, D., Milner, J. D., Holland, S., Casanova, J. -L., Puel A, Cypowyj S, Thumerelle C, Toulon A, Bustamante J, Tahuil N, SALHI, DALILA, Boiu S, Chopra C, Di Giovanni D, Bezrodnik L, Boutros J, Thomas C, Lacuesta G, Jannier S, Korganow AS, Paillard C, Boutboul, Bué M, Marie-Cardine A, Bayart S, Migaud M, Weiss, Karmochkine M, Garcia-Martinez JM, Stephan JL, Bensaid P, Jeannoel GP, Witte T, Baumann U, Harrer T, Navarrete C, ACOSTA HUGHES, BENJAMIN, Firinu, Pignata C, Picco P, Mendoza D, Lugo Reyes SO, Torres Lozano C, Ortega-Cisneros M, Cortina M, Mesdaghi M, Nabavi M, Español T, Martínez-Saavedra MT, Rezaei N, Zoghi S, Pac M, Barlogis V, Revon-Rivière G, Haimi-Cohen Y, Spiegel R, Miron D, Bouchaib J, Blancas-Galicia L, Toth B, Drexel B, Rohrlich PS, Lesens O, Hoernes M, Drewe E, Abinum M, Sawalle-Belohradsky J, Kindle G, Depner M, Milani L, Nikopensius T, Remm M, Talas UG, Tucker M, Willis M, Leonard S, Meuwissen H, Ferdman RM, CORBO UGULINO, WALLACE, Desai MM, Taur P, Badolato R, Soltesz B, Schnopp C, Jansson AF, Ayvaz D, Shabashova N, Chernyshova L, Bondarenko A, Moshous D, Neven B, Boubidi C, Ailal F, Giardino G, Del Giacco S, Bougnoux ME, Imai K, Okawa T, Mizoguchi Y, Ozaki Y, Takeuchi M, Hayakawa A, Lögering B, Reich K, Buhl T, Eyerich K, Schaller M, Arkwright PD, Gennery AR, Cant AJ, Warris A, Henriet S, Mekki N, Barbouche R, Ben Mustapha I, Bodemer, Polak M, Grimprel E, Burgel PR, Fischer A, Hermine O, Debré M, Kocacyk D, Dhalla F, Patel SY, Moens L, Haerynck F, Dullaers, Hoste L, Sanal O, Kilic SS, Roesler J, Lanternier F, Lortholary O, Fieschi C, Church JA, Roifman C, Yuenyongviwat A, Peterson P, Boisson-Dupuis S, Abel L, Marciano BE, Netea MG., Toubiana, J., Okada, S., Hiller, J., Oleastro, M., Lagos Gomez, M., Aldave Becerra, J. C., Ouachee-Chardin, M., Fouyssac, F., Girisha, K. M., Etzioni, A., Van Montfrans, J., Camcioglu, Y., Kerns, L. A., Belohradsky, B., Blanche, S., Bousfiha, A., Rodriguez-Gallego, C., Meyts, I., Kisand, K., Reichenbach, J., Renner, E. D., Rosenzweig, S., Grimbacher, B., van de Veerdonk, F. L., Traidl-Hoffmann, C., Picard, C., Marodi, L., Morio, T., Kobayashi, M., Lilic, D., Milner, J. D., Holland, S., Casanova, J. -L., Puel, A, Cypowyj, S, Thumerelle, C, Toulon, A, Bustamante, J, Tahuil, N, Salhi, Dalila, Boiu, S, Chopra, C, Di Giovanni, D, Bezrodnik, L, Boutros, J, Thomas, C, Lacuesta, G, Jannier, S, Korganow, A, Paillard, C, Boutboul, Bué, M, Marie-Cardine, A, Bayart, S, Migaud, M, Weiss, Karmochkine, M, Garcia-Martinez, Jm, Stephan, Jl, Bensaid, P, Jeannoel, Gp, Witte, T, Baumann, U, Harrer, T, Navarrete, C, ACOSTA HUGHES, Benjamin, Firinu, Pignata, C, Picco, P, Mendoza, D, Lugo Reyes, So, Torres Lozano, C, Ortega-Cisneros, M, Cortina, M, Mesdaghi, M, Nabavi, M, Español, T, Martínez-Saavedra, Mt, Rezaei, N, Zoghi, S, Pac, M, Barlogis, V, Revon-Rivière, G, Haimi-Cohen, Y, Spiegel, R, Miron, D, Bouchaib, J, Blancas-Galicia, L, Toth, B, Drexel, B, Rohrlich, P, Lesens, O, Hoernes, M, Drewe, E, Abinum, M, Sawalle-Belohradsky, J, Kindle, G, Depner, M, Milani, L, Nikopensius, T, Remm, M, Talas, Ug, Tucker, M, Willis, M, Leonard, S, Meuwissen, H, Ferdman, Rm, CORBO UGULINO, Wallace, Desai, Mm, Taur, P, Badolato, R, Soltesz, B, Schnopp, C, Jansson, Af, Ayvaz, D, Shabashova, N, Chernyshova, L, Bondarenko, A, Moshous, D, Neven, B, Boubidi, C, Ailal, F, Giardino, G, Del Giacco, S, Bougnoux, Me, Imai, K, Okawa, T, Mizoguchi, Y, Ozaki, Y, Takeuchi, M, Hayakawa, A, Lögering, B, Reich, K, Buhl, T, Eyerich, K, Schaller, M, Arkwright, Pd, Gennery, Ar, Cant, Aj, Warris, A, Henriet, S, Mekki, N, Barbouche, R, Ben Mustapha, I, Bodemer, Polak, M, Grimprel, E, Burgel, Pr, Fischer, A, Hermine, O, Debré, M, Kocacyk, D, Dhalla, F, Patel, Sy, Moens, L, Haerynck, F, Dullaers, Hoste, L, Sanal, O, Kilic, S, Roesler, J, Lanternier, F, Lortholary, O, Fieschi, C, Church, Ja, Roifman, C, Yuenyongviwat, A, Peterson, P, Boisson-Dupuis, S, Abel, L, Marciano, Be, and Netea, Mg.
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Male ,0301 basic medicine ,Pediatrics ,Clinical Trials and Observations ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,medicine.disease_cause ,Biochemistry ,Gastroenterology ,Cohort Studies ,STAT5 Transcription Factor ,Medicine ,Chronic mucocutaneous candidiasis ,Child ,Hematology ,biology ,Progressive multifocal leukoencephalopathy ,Candidiasis, Chronic Mucocutaneous ,Candidiasis ,Orvostudományok ,Middle Aged ,Phenotype ,STAT1 Transcription Factor ,Staphylococcus aureus ,Child, Preschool ,Female ,STAT3 Transcription Factor ,Adult ,Heterozygote ,medicine.medical_specialty ,Adolescent ,Aged ,Genetic Predisposition to Disease ,Humans ,Infant ,Young Adult ,Genetic Association Studies ,Mutation ,Immunology ,Cell Biology ,Chronic Mucocutaneous ,Klinikai orvostudományok ,Herpesviridae ,Mycobacterium tuberculosis ,03 medical and health sciences ,Internal medicine ,Journal Article ,ddc:610 ,Preschool ,Key Points AD STAT1 GOF is the most common genetic cause of inherited CMC and is not restricted to a specific age or ethnic group. STAT1 GOF underlies a variety of infectious and autoimmune features, as well as carcinomas and aneurysms associated with a poor outcome ,Type 1 diabetes ,Cytopenia ,business.industry ,medicine.disease ,biology.organism_classification ,030104 developmental biology ,business - Abstract
Contains fulltext : 172671.pdf (Publisher’s version ) (Closed access) Since their discovery in patients with autosomal dominant (AD) chronic mucocutaneous candidiasis (CMC) in 2011, heterozygous STAT1 gain-of-function (GOF) mutations have increasingly been identified worldwide. The clinical spectrum associated with them needed to be delineated. We enrolled 274 patients from 167 kindreds originating from 40 countries from 5 continents. Demographic data, clinical features, immunological parameters, treatment, and outcome were recorded. The median age of the 274 patients was 22 years (range, 1-71 years); 98% of them had CMC, with a median age at onset of 1 year (range, 0-24 years). Patients often displayed bacterial (74%) infections, mostly because of Staphylococcus aureus (36%), including the respiratory tract and the skin in 47% and 28% of patients, respectively, and viral (38%) infections, mostly because of Herpesviridae (83%) and affecting the skin in 32% of patients. Invasive fungal infections (10%), mostly caused by Candida spp. (29%), and mycobacterial disease (6%) caused by Mycobacterium tuberculosis, environmental mycobacteria, or Bacille Calmette-Guerin vaccines were less common. Many patients had autoimmune manifestations (37%), including hypothyroidism (22%), type 1 diabetes (4%), blood cytopenia (4%), and systemic lupus erythematosus (2%). Invasive infections (25%), cerebral aneurysms (6%), and cancers (6%) were the strongest predictors of poor outcome. CMC persisted in 39% of the 202 patients receiving prolonged antifungal treatment. Circulating interleukin-17A-producing T-cell count was low for most (82%) but not all of the patients tested. STAT1 GOF mutations underlie AD CMC, as well as an unexpectedly wide range of other clinical features, including not only a variety of infectious and autoimmune diseases, but also cerebral aneurysms and carcinomas that confer a poor prognosis.
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- 2016
11. Transplantation in patients with SCID: mismatched related stem cells or unrelated cord blood?
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Fernandes, Jf, Rocha, V, Labopin, M, Neven, B, Moshous, D, Gennery, Ar, Friedrich, W, Porta, F, Diaz de Heredia, C, Wall, D, Bertrand, Y, Veys, P, Slatter, M, Schulz, A, Chan, Kw, Grimley, M, Ayas, M, Gungor, T, Ebell, W, Bonfim, C, Kalwak, K, Taupin, P, Blanche, S, Gaspar, Hb, Landais, P, Fischer, A, Gluckman, E, Cavazzana Calvo, M, Eurocord, Inborn Errors Working Party of European Group for Blood, Marrow Transplantation: Ahmed, A, Auiti, A, Biffi, A, Cant, A, Fasth, A, Gennery, A, Hassan, A, Lankester, A, O'Mera, A, Plabani, A, Rovelli, A, Salmon, A, Scarselli, A, Thrasher, A, Van Royen, A, Villa, A, Wawer, A, Wahadneh, A, Worth, A, Belohradsky, B, Wolska, B, Gaspar, B, Bonfirm, C, Booth, C, Klein, C, Messina, C, Peters, C, Steward, C, Lindemans, C, Schuetz, C, de Heredia Rubio CD, Bensoussan, D, Gleadow, D, Lilic, D, Gambineri, Eleonora, Smith, E, Aerts, F, Caracseghi, F, Roberts, G, Davies, G, Al Mousa, H, Jossanc, H, Ozsahim, H, Hirsch, I, Meyts, I, Tezcan, I, Mueller, I, Andresc, I, Boelens, J, Fernandes, J, Folloni, J, Keuhl, J, Reichenbach, J, Stary, J, Wachowiak, J, Xu Bayford, J, Cunha, Jm, Ehlert, J, Rao, K, Sykora, K, Andais, L, Brown, L, Dal Cortivo, L, Griffith, L, Notarangelo, L, Abinun, M, Albert, M, Bierings, M, Bouchet, M, Cavazzana, M, Hirschfield, M, Cowan, M, Hoenig, M, Loubser, M, Roncarolo, M, Sauer, M, Schneider, M, Verstegen, M, Schroeder, M, Essink, M, Yesilipek, M, Entz Werle, N, Mahlaoui, N, Schlautmann, N, Taylor, N, Vanroyen, N, Walffraat, N, Sanal, O, Amrolia, P, Bordigoni, P, De Coppi, P, Frange, P, Orchard, P, Sedlacek, P, Shaw, P, Stephensky, P, Bacchetta, R, Bredius, R, Formankova, R, Gale, R, Seger, R, Wynn, R, Corbacioglu, S, Ehl, S, Hacein Bey, S, Hambleton, S, Mohsen, S, Mueller, S, Pai, Sy, Espanol, T, Flood, T, Guengoer, T, Bordon, V, Ormoor, V, Pashano, V, Courteille, V, Czogala, W, Qasim, W, Camci, Y, and Nademi, Z.
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Male ,medicine.medical_specialty ,Transplantation Conditioning ,medicine.medical_treatment ,Immunology ,Graft vs Host Disease ,Kaplan-Meier Estimate ,Cord Blood Stem Cell Transplantation ,Hematopoietic stem cell transplantation ,Biochemistry ,Gastroenterology ,SCID HSCT ,Internal medicine ,medicine ,Humans ,Proportional Hazards Models ,Retrospective Studies ,Preparative Regimen ,Severe combined immunodeficiency ,business.industry ,Umbilical Cord Blood Transplantation ,Incidence ,Hematopoietic Stem Cell Transplantation ,Infant, Newborn ,Infant ,Cell Biology ,Hematology ,medicine.disease ,Surgery ,Transplantation ,Treatment Outcome ,Child, Preschool ,Histocompatibility ,Cord blood ,Female ,Severe Combined Immunodeficiency ,business - Abstract
Pediatric patients with SCID constitute medical emergencies. In the absence of an HLA-identical hematopoietic stem cell (HSC) donor, mismatched related-donor transplantation (MMRDT) or unrelated-donor umbilical cord blood transplantation (UCBT) are valuable treatment options. To help transplantation centers choose the best treatment option, we retrospectively compared outcomes after 175 MMRDTs and 74 UCBTs in patients with SCID or Omenn syndrome. Median follow-up time was 83 months and 58 months for UCBT and MMRDT, respectively. Most UCB recipients received a myeloablative conditioning regimen; most MMRDT recipients did not. UCB recipients presented a higher frequency of complete donor chimerism (P = .04) and faster total lymphocyte count recovery (P = .04) without any statistically significance with the preparative regimen they received. The MMRDT and UCBT groups did not differ in terms of T-cell engraftment, CD4+ and CD3+ cell recoveries, while Ig replacement therapy was discontinued sooner after UCBT (adjusted P = .02). There was a trend toward a greater incidence of grades II-IV acute GVHD (P = .06) and more chronic GVHD (P = .03) after UCBT. The estimated 5-year overall survival rates were 62% ± 4% after MMRDT and 57% ± 6% after UCBT. For children with SCID and no HLA-identical sibling donor, both UCBT and MMRDT represent available HSC sources for transplantation with quite similar outcomes.
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- 2012
12. ARTEMIS AND LIGASE 4 ARE DISPENSABLE FOR THE GENERATION OF HUMAN INDUCED PLURIPOTENT STEM CELLS
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Felgentreff, K, Weinacht, Kg, Gennery, Ar, Dobbs, K, Giliani, Silvia Clara, Matzig, T, Schambach, A, Baum, C, and Notarangelo, Ld
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- 2012
13. IL-21 is the primary common gamma chain-binding cytokine requiredfor human B-cell differentiation in vivo
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Recher, M, Berglund, Lj, Avery, Dt, Cowan, Mj, Gennery, Ar, Smart, J, Peake, J, Wong, M, Pai, Sy, Baxi, S, Walter, Je, Palendira, U, Tangye, Ga, Rice, M, Brothers, S, Al Herz, W, Oettgen, H, Eibel, H, Puck, Jm, Cattaneo, F, Ziegler, Jb, Giliani, Silvia Clara, Tangye, Sg, and Notarangelo, L. D.
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- 2011
14. Mutation update for the CSB/ERCC6 and CSA/ERCC8 genes involved in the Cockayne syndrome
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Laugel V, Dalloz C, Durand M, Sauvanaud F, Kristensen U, Vincent MC, Pasquier L, Odent S, Cormier-Daire V, Gener B, Tobias ES, Tolmie JL, Martin-Coignard D, Drouin-Garraud V, Heron D, Journel H, Raffo E, Vigneron J, Lyonnet S, Murday V, Gubser-Mercati D, Funalot B, Brueton L, Sanchez Del Pozo J, Muxf1oz E, Gennery AR, Salih M, Noruzinia M, Prescott K, Ramos L, Stark Z, Fieggen K, Chabrol B, Sarda P, Edery P, Bloch-Zupan A, Fawcett H, Pham D, Egly JM, Lehmann AR, Sarasin A, and Dollfus H.
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- 2010
15. GvHD-associated cytokine polymorphisms do not associate with Omenn syndrome rather than T-B- SCID in patients with defects in RAG genes
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Haq IJ, Steinberg LJ, Hoenig M, van der Burg M, Villa A, Cant AJ, Middleton PG, and Gennery AR.
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- 2007
16. Omenn's syndrome occurring in patients without mutations in recombination activating genes
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Gennery AR, Hodges E, Williams AP, Harris S, Villa A, Angus B, Cant AJ, Smith JL. Clin Immunol. 116:246-256, and 2005
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- 2005
17. CAMPATH-1M T-cell depleted BMT for SCID: long-term follow-up of 19 children treated 1987–98 in a single center.
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Gennery, AR, Dickinson, AM, Brigham, K, Barge, D, Spickett, GP, Curtis, A, Spencer, V, Jackson, A, Cavanagh, G, Carter, V, Palmer, P, Flood, TJ, Cant, AJ, and Abinun, M
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IMMUNODEFICIENCY , *IMMUNITY , *BONE marrow transplantation , *BONE marrow purging , *JUVENILE diseases - Abstract
Background: SCID can be cured by BMT. Depletion of mature T cells from BM has enabled HLA non-identical stem-cell transplantation. We report the outcome of 30 patients treated with 37 T-cell depleted BMT procedures using CAMPATH-1M in vitro between 1987-98 in a single center. Methods: Immune reconstitution and quality-of-life were assessed in 19 longterm survivors. All but two received pre-transplant conditioning. T- and B-cell chimerism, numbers and function were analyzed during a median follow-up of 5.3 years (range 1.33-12). Results: The overall engraftment rate was 59%, six children required repeated BMT and the survival rate was 63%. All have donor T cells, 58% normal T-cell numbers and 74% normal T-cell function. Of 17 evaluated, 16 patients (94%) have normal IgM and IgG levels, and production of specific Abs to protein Ags, but only 5/16 (31%) have a good response to pneumococcal polysaccharide. Early and late post-BMT complications were rare and there were no delayed deaths. Only one child continues on long-term i.v. Ig 4-years post-BMT. Eleven children died (37%). Discussion: CAMPATH-1M T-cell depleted BMT for SCID resulted in 63% survival. Deaths of 11 children were mainly due to pre-existing infections. Seventeen of 19 long-term survivors have normal immune function and good quality-of-life. [ABSTRACT FROM AUTHOR]
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- 2001
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18. Validity of using Hospital Episode Statistics data on monitoring disease trends.
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Elemraid MA, Pollard K, Thomas MF, Gennery AR, Eastham KM, Rushton SP, Hampton F, Singleton P, Gorton R, Spencer DA, Clark JE, and North East of England Paediatric Respiratory Infection Study Group
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- 2011
19. Hematopoietic stem cell transplantation corrects the immunologic abnormalities associated with immunodeficiency-centromeric instability-facial dysmorphism syndrome.
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Gennery AR, Slatter MA, Bredius RG, Hagleitner MM, Weemaes C, Cant AJ, and Lankester AC
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Immunodeficiency-centromeric instability-facial dysmorphism syndrome, characterized by variable immunodeficiency, centromeric instability, and facial anomalies caused by epigenetic dysregulation resulting in hypomethylation, is caused in many patients by mutations in DNMT3B, a DNA methyltransferase gene; associated infections are a major cause of serious sequelae and death. Hematopoietic stem cell transplantation may improve the clinical course in immunodeficiency-centromeric instability-facial dysmorphism syndrome. We report 3 unrelated patients with persistent infections and intestinal complications who successfully underwent hematopoietic stem cell transplantation after nonmyeloablative or myeloablative conditioning regimens using HLA-matched donors. In all cases, donor chimerism led to resolution of intestinal complications and infections, growth improvement, and correction of the immunodeficiency. [ABSTRACT FROM AUTHOR]
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- 2007
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20. Neonatal bone marrow transplantation for severe combined immunodeficiency.
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Kane L, Gennery AR, Crooks BNA, Flood TJ, Abinun M, Cant AJ, Kane, L, Gennery, A R, Crooks, B N, Flood, T J, Abinun, M, and Cant, A J
- Abstract
Aims: To evaluate outcome following neonatal bone marrow transplantation (BMT) for severe combined immunodeficiency (SCID) when there is a family history of a previously affected sibling, and to compare results with those published for in utero BMT.Methods: A retrospective review of cases referred and transplanted between 1987 and 1999, focusing on infectious and graft versus host disease (GvHD) complications after BMT, and T and B lymphocyte function. Thirteen patients received 18 stem cell transplants: four whole marrow, one cord blood, 10 parental T cell depleted (TCD) haplo-identical, and three TCD unrelated donor BMT. Nine were conditioned with busulphan and cyclophosphamide.Results: All are alive and well (six months to 11.5 years after BMT). Six had grade I-II acute GvHD and two chronic GvHD (now resolved). Three had a top up BMT for poor T cell function, one had a third BMT for graft failure and chronic GvHD, and one had a third BMT for graft failure. Twelve have good in vitro proliferation to T cell mitogens, and all have normal serum IgA levels. Three receive intravenous immunoglobulin; for one of these, it is less than one year since BMT. Nine are above the 2nd centile, and 10 of 12 old enough to be assessed have normal neurodevelopment.Conclusion: These results are better than those published for in utero BMT for SCID. Early postnatal BMT should be the preferred option in neonatal SCID. [ABSTRACT FROM AUTHOR]- Published
- 2001
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21. Haematopoietic stem cell transplantation for CTLA-4 insufficiency across Europe: an EBMT Inborn Errors Working Party study.
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Tsilifis C, Speckmann C, Lum SH, Fox TA, Soler AM, Mozo Y, Corral D, Ewins AM, Hague R, Oikonomopoulou C, Kałwak K, Drabko K, Wynn R, Morris EC, Elcombe S, Bigley V, Lougaris V, Malagola M, Hauck F, Sedlacek P, Laberko A, Tjon JML, Buddingh EP, Wehr C, Grimbacher B, Gennery AR, Lankester AC, Albert MH, Neven B, and Slatter MA
- Abstract
Background: Cytotoxic T-lymphocyte antigen-4 (CTLA-4) insufficiency causes a primary immune regulatory disorder characterised by lymphoproliferation, dysgammaglobulinaemia, and multi-organ autoimmunity including cytopenias and colitis., Objective: To examine the outcome of HSCT for CTLA-4 insufficiency and study the impact of pre-HSCT CTLA-4-Ig therapy and pre-HSCT immune dysregulation on survival and immunological outcome., Methods: Retrospective study of HSCT for CTLA-4 insufficiency and 2q33.2-3 deletion from the Inborn Errors Working Party of EBMT. Primary endpoints were overall survival (OS) and disease- and chronic GvHD-free survival (DFS). Secondary endpoint was immunological outcome assessed by Immune Dysregulation Disease Activity (IDDA) score., Results: Forty patients were included over a 25-year period. Pre-HSCT, 60% received CTLA-4-Ig and IDDA was 23.3 (3.9-84.0). Median age at HSCT was 14.2 (1.3-56.0) years. Patients received PBSC (58%) or marrow (43%) from MUD (75%), MMUD (12.5%) or MFD (12.5%). Median follow-up was 3 years (0.6-15 years) and 3-year OS was 76.7% (58-87%) and DFS was 74.4% (54.9-86.0%). At latest follow-up, 28/30 surviving patients are in disease-free remission with median IDDA reduction of 16. Probability of OS and DFS was greater in patients with lower disease activity pre-HSCT (IDDA<23, p=0.002 and p=0.006, respectively). CTLA-4-Ig receipt did not influence OS or DFS. Cause of death was transplant-related in 7/8 patients., Conclusion: This is the largest retrospective study of HSCT for CTLA-4 insufficiency to date. HSCT is an effective therapy to prevent ongoing disease progression and morbidity, with improving survival rates over time and in patients with lower pre-HSCT disease activity., (Copyright © 2024. Published by Elsevier Inc.)
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- 2024
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22. Hereditary C1q Deficiency is Associated with Type 1 Interferon-Pathway Activation and a High Risk of Central Nervous System Inflammation.
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Triaille C, Rao NM, Rice GI, Seabra L, Sutherland FJH, Bondet V, Duffy D, Gennery AR, Fournier B, Bader-Meunier B, Troedson C, Cleary G, Buso H, Dalby-Payne J, Ranade P, Jansen K, De Somer L, Frémond ML, Chavan PP, Wong M, Dale RC, Wouters C, Quartier P, Khubchandani R, and Crow YJ
- Subjects
- Humans, Female, Male, Adult, Child, Adolescent, Young Adult, Signal Transduction, Middle Aged, Inflammation genetics, Interferon-alpha, Child, Preschool, Retrospective Studies, Complement C1q genetics, Complement C1q metabolism, Interferon Type I metabolism
- Abstract
Hereditary C1q deficiency (C1QDef) is a rare monogenic disorder leading to defective complement pathway activation and systemic lupus erythematosus (SLE)-like manifestations. The link between impairment of the complement cascade and autoimmunity remains incompletely understood. Here, we assessed type 1 interferon pathway activation in patients with C1QDef. Twelve patients with genetically confirmed C1QDef were recruited through an international collaboration. Clinical, biological and radiological data were collected retrospectively. The expression of a standardized panel of interferon stimulated genes (ISGs) in peripheral blood was measured, and the level of interferon alpha (IFNα) protein in cerebrospinal fluid (CSF) determined using SIMOA technology. Central nervous system (encompassing basal ganglia calcification, encephalitis, vasculitis, chronic pachymeningitis), mucocutaneous and renal involvement were present, respectively, in 10, 11 and 2 of 12 patients, and severe infections recorded in 2/12 patients. Elevated ISG expression was observed in all patients tested (n = 10/10), and serum and CSF IFNα elevated in 2/2 patients. Three patients were treated with Janus-kinase inhibitors (JAKi), with variable outcome; one displaying an apparently favourable response in respect of cutaneous and neurological features, and two others experiencing persistent disease despite JAKi therapy. To our knowledge, we report the largest original series of genetically confirmed C1QDef yet described. Additionally, we present a review of all previously described genetically confirmed cases of C1QDef. Overall, individuals with C1QDef demonstrate many characteristics of recognized monogenic interferonopathies: particularly, cutaneous involvement (malar rash, acral vasculitic/papular rash, chilblains), SLE-like disease, basal ganglia calcification, increased expression of ISGs in peripheral blood, and elevated levels of CSF IFNα., (© 2024. The Author(s).)
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- 2024
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23. Allogeneic Hematopoietic Stem Cell Transplantation in Immunodeficiency-Centromeric Instability-Facial Dysmorphism (ICF) Syndrome: an EBMT/ESID Inborn Errors Working Party Study.
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Berghuis D, Mehyar LS, Abu-Arja R, Albert MH, Barnum JL, von Bernuth H, Elfeky R, Lewalle P, Laberko A, Ghosh S, Slatter MA, Weemaes CMR, Yesilipek A, Sirait T, Neven B, Gennery AR, and Lankester AC
- Subjects
- Humans, Child, Preschool, Child, Male, Female, Infant, Adolescent, Young Adult, Immunologic Deficiency Syndromes therapy, Immunologic Deficiency Syndromes diagnosis, Transplantation Conditioning methods, Treatment Outcome, Primary Immunodeficiency Diseases therapy, Primary Immunodeficiency Diseases diagnosis, Hematopoietic Stem Cell Transplantation methods, Transplantation, Homologous, Graft vs Host Disease etiology, Graft vs Host Disease diagnosis
- Abstract
Immunodeficiency-Centromeric instability-Facial dysmorphism (ICF) syndrome is an inborn error of immunity characterized by progressive immune dysfunction and multi-organ disease usually treated with antimicrobial prophylaxis and immunoglobulin substitution. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment, but data on outcome are scarce. We provide a detailed description of disease characteristics and HSCT outcome in an international cohort of ICF syndrome patients. Eighteen patients (including all four genotypes) were enrolled. Main HSCT indications were infections (83%), enteropathy/failure to thrive (56%), immune dysregulation (22%) and myelodysplasia/haematological malignancy (17%). Two patients underwent pre-emptive HSCT after early diagnosis. Patients were transplanted between 2003-2021, at median age 4.3 years (range 0.5-19), after myeloablative or reduced-intensity conditioning, from matched sibling or matched family donors, matched unrelated or mismatched donors in 39%, 50% and 12% of cases respectively. Overall survival was 83% (all deaths occurred within the first 5 months post-HSCT; mean follow-up 54 months (range 1-185)). Acute GvHD occurred in 35% of patients, severe (grade III) in two (12%), while none developed chronic GvHD. At latest follow-up (median 2.2 years (range 0.1-14)), complete donor chimerism was achieved in 15/17 surviving patients. All survivors demonstrated normalized T and B cell numbers. Immunoglobulin substitution independence was achieved in all but two patients. All survivors recovered from pre-transplant infections, enteropathy/failure to thrive and immune dysregulation. All three patients transplanted at young age (≤ 3 years), after early diagnosis, survived. The favourable clinical and immunological HSCT outcome in this cohort of patients supports the timely use of this curative treatment in ICF syndrome., (© 2024. The Author(s).)
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- 2024
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24. Outcomes of HLA-mismatched HSCT with TCRαβ/CD19 depletion or post-HSCT cyclophosphamide for inborn errors of immunity.
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Lum SH, Albert MH, Gilbert P, Sirait T, Algeri M, Muratori R, Fournier B, Laberko A, Karakukcu M, Unal E, Ayas M, Yadav SP, Fisgin T, Elfeky R, Fernandes J, Faraci M, Cole T, Schulz A, Meisel R, Zecca M, Ifversen M, Biffi A, Diana JS, Vallée T, Giardino S, Ersoy GZ, Moshous D, Gennery AR, Balashov D, Bonfim C, Locatelli F, Lankester A, Neven B, and Slatter M
- Subjects
- Humans, Child, Child, Preschool, Female, Male, Infant, Adolescent, Retrospective Studies, Young Adult, Lymphocyte Depletion, Transplantation Conditioning methods, HLA Antigens immunology, Adult, Treatment Outcome, Infant, Newborn, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation methods, Cyclophosphamide therapeutic use, Cyclophosphamide administration & dosage, Receptors, Antigen, T-Cell, alpha-beta, Antigens, CD19, Graft vs Host Disease etiology, Graft vs Host Disease prevention & control
- Abstract
Abstract: HLA-mismatched transplants with either in vitro depletion of CD3+ T-cell receptor (TCR)αβ/CD19 (TCRαβ) cells or in vivo T-cell depletion using posttransplant cyclophosphamide (PTCY) have been increasingly used for patients with inborn errors of immunity (IEIs). We performed a retrospective multicenter study via the EBMT registry on 306 children with IEIs undergoing their first transplant between 2010 and 2019 from an HLA-mismatched donor using TCRαβ (n = 167) or PTCY (n = 139). The median age for hematopoietic stem cell transplantation (HSCT) was 1.2 years (range, 0.03-19.6 years). The 3-year overall survival (OS) was 78% (95% confidence interval (CI), 71-84) after TCRαβ and 66% (57-74) after PTCY (P = .013). Pre-HSCT morbidity score (hazard ratio [HR], 2.27; 1.07-4.80, P = .032) and non-busulfan/treosulfan conditioning (HR, 3.12; 1.98-4.92, P < .001) were the only independent predictors of unfavorable OS. The 3-year event-free survival (EFS) was 58% (50%-66%) after TCRαβ and 57% (48%-66%) after PTCY (P = .804). The cumulative incidence of severe acute graft-versus-host disease (GvHD) was higher after PTCY (15%, 9%-21%) than TCRαβ (6%, 2%-9%, P = .007), with no difference in chronic GvHD (PTCY, 11%, 6%-17%; TCRαβ, 7%, 3%-11%, P = .173). The 3-year GvHD-free EFS was 53% (44%-61%) after TCRαβ and 41% (32%-50%) after PTCY (P = .080). PTCY had significantly higher rates of veno-occlusive disease (14.4% vs TCRαβ 4.9%, P = .009), acute kidney injury (12.7% vs 4.6%, P = .032), and pulmonary complications (38.2% vs 24.1%, P = .017). Adenoviremia (18.3% vs PTCY 8.0%, P = .015), primary graft failure (10% vs 5%, P = .048), and second HSCT (17.4% vs 7.9%, P = .023) were significantly higher in TCRαβ. In conclusion, this study demonstrates that both approaches are suitable options in patients with IEIs, although they are characterized by different advantages and outcomes., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
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- 2024
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25. CD3 + TCRαβ/CD19 + -depleted stem cell boost and CD45RO + memory T-cell add-back as a successful salvage treatment for poor graft function unresponsive to eltrombopag, following a second allogenic HSCT.
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Ramanathan S, Roberts W, Nademi Z, Shenton G, Watson H, Matthews E, Carruthers K, Gennery AR, Hambleton S, Slatter M, and Lum SH
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- Humans, Antigens, CD19 immunology, Memory T Cells immunology, Receptors, Antigen, T-Cell, alpha-beta, CD3 Complex, Male, Leukocyte Common Antigens, Female, Lymphocyte Depletion, Transplantation, Homologous, Child, Hydrazines therapeutic use, Benzoates therapeutic use, Pyrazoles therapeutic use, Hematopoietic Stem Cell Transplantation methods, Salvage Therapy methods
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- 2024
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26. Wiskott-Aldrich syndrome: a study of 577 patients defines the genotype as a biomarker for disease severity and survival.
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Vallée TC, Glasmacher JS, Buchner H, Arkwright PD, Behrends U, Bondarenko A, Browning MJ, Buchbinder D, Cattoni A, Chernyshova L, Ciznar P, Cole T, Czogała W, Dueckers G, Edgar JDM, Erbey F, Fasth A, Ferrua F, Formankova R, Gambineri E, Gennery AR, Goldman FD, Gonzalez-Granado LI, Heilmann C, Heiskanen-Kosma T, Juntti H, Kainulainen L, Kanegane H, Karaca NE, Kilic SS, Klein C, Kołtan S, Kondratenko I, Meyts I, Nasrullayeva GM, Notarangelo LD, Pasic S, Pellier I, Pignata C, Misbah S, Schulz A, Segundo GR, Shcherbina A, Slatter M, Sokolic R, Soler-Palacin P, Stepensky P, van Montfrans JM, Ryhänen S, Wolska-Kuśnierz B, Ziegler JB, Zhao X, Aiuti A, Ochs HD, and Albert MH
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- Humans, Adolescent, Child, Male, Female, Child, Preschool, Adult, Retrospective Studies, Infant, Young Adult, Biomarkers, Hematopoietic Stem Cell Transplantation, Severity of Illness Index, Wiskott-Aldrich Syndrome Protein genetics, Follow-Up Studies, Middle Aged, Prognosis, Survival Rate, Wiskott-Aldrich Syndrome genetics, Wiskott-Aldrich Syndrome diagnosis, Wiskott-Aldrich Syndrome therapy, Genotype
- Abstract
Abstract: Wiskott-Aldrich syndrome (WAS) is a multifaceted monogenic disorder with a broad disease spectrum and variable disease severity and a variety of treatment options including allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT). No reliable biomarker exists to predict disease course and outcome for individual patients. A total of 577 patients with a WAS variant from 26 countries and a median follow-up of 8.9 years (range, 0.3-71.1), totaling 6118 patient-years, were included in this international retrospective study. Overall survival (OS) of the cohort (censored at HSCT or GT) was 82% (95% confidence interval, 78-87) at age 15 years and 70% (61-80) at 30 years. The type of variant was predictive of outcome: patients with a missense variant in exons 1 or 2 or with the intronic hot spot variant c.559+5G>A (class I variants) had a 15-year OS of 93% (89-98) and a 30-year OS of 91% (86-97), compared with 71% (62-81) and 48% (34-68) in patients with any other variant (class II; P < .0001). The cumulative incidence rates of disease-related complications such as severe bleeding (P = .007), life-threatening infection (P < .0001), and autoimmunity (P = .004) occurred significantly later in patients with a class I variant. The cumulative incidence of malignancy (P = .6) was not different between classes I and II. It confirms the spectrum of disease severity and quantifies the risk for specific disease-related complications. The class of the variant is a biomarker to predict the outcome for patients with WAS.
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- 2024
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27. NUDCD3 deficiency disrupts V(D)J recombination to cause SCID and Omenn syndrome.
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Chen R, Lukianova E, van der Loeff IS, Spegarova JS, Willet JDP, James KD, Ryder EJ, Griffin H, IJspeert H, Gajbhiye A, Lamoliatte F, Marin-Rubio JL, Woodbine L, Lemos H, Swan DJ, Pintar V, Sayes K, Ruiz-Morales ER, Eastham S, Dixon D, Prete M, Prigmore E, Jeggo P, Boyes J, Mellor A, Huang L, van der Burg M, Engelhardt KR, Stray-Pedersen A, Erichsen HC, Gennery AR, Trost M, Adams DJ, Anderson G, Lorenc A, Trynka G, and Hambleton S
- Subjects
- Humans, Animals, Mice, Male, Female, Infant, B-Lymphocytes immunology, Homeodomain Proteins genetics, Homeodomain Proteins immunology, T-Lymphocytes immunology, Child, Preschool, Mutation, Missense, Severe Combined Immunodeficiency genetics, Severe Combined Immunodeficiency immunology, V(D)J Recombination immunology, V(D)J Recombination genetics
- Abstract
Inborn errors of T cell development present a pediatric emergency in which timely curative therapy is informed by molecular diagnosis. In 11 affected patients across four consanguineous kindreds, we detected homozygosity for a single deleterious missense variant in the gene NudC domain-containing 3 ( NUDCD3 ) . Two infants had severe combined immunodeficiency with the complete absence of T and B cells (T
- B- SCID), whereas nine showed classical features of Omenn syndrome (OS). Restricted antigen receptor gene usage by residual T lymphocytes suggested impaired V(D)J recombination. Patient cells showed reduced expression of NUDCD3 protein and diminished ability to support RAG-mediated recombination in vitro, which was associated with pathologic sequestration of RAG1 in the nucleoli. Although impaired V(D)J recombination in a mouse model bearing the homologous variant led to milder immunologic abnormalities, NUDCD3 is absolutely required for healthy T and B cell development in humans.- Published
- 2024
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28. Extracorporeal photopheresis (ECP) in the treatment of chronic lung allograft dysfunction (CLAD): a prospective, multicentre, open-label, randomised controlled trial studying the addition of ECP to standard care in the treatment of bilateral lung transplant patients with CLAD (E-CLAD UK).
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Fisher AJ, White M, Goudie N, Kershaw A, Phillipson J, Bardgett M, Lally J, Bevin-Nicholls A, Chadwick T, Bryant A, Russell S, Smith H, Frisby L, Errington R, Carby M, Thompson R, Santhanakrishnan K, Parmar J, Lordan JL, Vale L, Hancock H, Exley C, Gennery AR, and Wason JM
- Subjects
- Adult, Female, Humans, Male, Middle Aged, Allografts, Graft Rejection, Lung physiopathology, Methoxsalen therapeutic use, Multicenter Studies as Topic, Primary Graft Dysfunction therapy, Prospective Studies, Quality of Life, Randomized Controlled Trials as Topic, Treatment Outcome, United Kingdom, Lung Transplantation, Photopheresis methods
- Abstract
Background: Long-term survival after lung transplantation is limited compared with other organ transplants. The main cause is development of progressive immune-mediated damage to the lung allograft. This damage, which can develop via multiple immune pathways, is captured under the umbrella term chronic lung allograft dysfunction (CLAD). Despite the availability of powerful immunosuppressive drugs, there are presently no treatments proven to reverse or reliably halt the loss of lung function caused by CLAD. The aim of the E-CLAD UK trial is to determine whether the addition of immunomodulatory therapy, in the form of extracorporeal photopheresis (ECP), to standard care is more efficacious at stabilising lung function in CLAD compared with standard care alone., Methods and Analysis: E-CLAD UK is a Phase II clinical trial of an investigational medicinal product (Methoxsalen) delivered to a buffy coat prepared via an enclosed ECP circuit. Target recruitment is 90 bilateral lung transplant patients identified as having CLAD and being treated at one of the five UK adult lung transplant centres. Participants will be randomised 1:1 to intervention plus standard of care, or standard of care alone. Intervention will comprise nine ECP cycles spread over 20 weeks, each course involving two treatments of ECP on consecutive days. All participants will be followed up for a period of 24 weeks.The primary outcome is lung function stabilisation derived from change in forced expiratory volume in one second and forced vital capacity at 12 and 24 weeks compared with baseline at study entry. Other parameters include change in exercise capacity, health-related quality of life and safety. A mechanistic study will seek to identify molecular or cellular markers linked to treatment response and qualitative interviews will explore patient experiences of CLAD and the ECP treatment.A patient and public advisory group is integral to the trial from design to implementation, developing material to support the consent process and interview materials., Ethics and Dissemination: The East Midlands-Derby Research Ethics Committee has provided ethical approval (REC 22/EM/0218). Dissemination will be via publications, patient-friendly summaries and presentation at scientific meetings., Trial Registration Number: EudraCT number 2022-002659-20; ISRCTN 10615985., Competing Interests: Competing interests: AJF has received honoraria for speaking at educational meetings organised by Mallinckrodt Pharmaceuticals., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2024
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29. Omenn Syndrome in Two Infants with Different Hypomorphic Variants in Janus Kinase 3.
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Tsilifis C, Spegarova JS, Good R, Griffin H, Engelhardt KR, Graham S, Hughes S, Arkwright PD, Hambleton S, and Gennery AR
- Subjects
- Humans, Infant, Interleukin-15, Interleukin-2, Interleukin-7, Leukocytes, Mononuclear, Janus Kinase 3 genetics, Severe Combined Immunodeficiency diagnosis, Severe Combined Immunodeficiency genetics, Severe Combined Immunodeficiency therapy
- Abstract
Biallelic null or hypomorphic variants in JAK3 cause SCID and less frequently Omenn syndrome. We investigated homozygous hypomorphic JAK3 mutations in two patients, and expression and function of a novel JAK3
R431P variant in Omenn syndrome. Immunophenotyping of PBMC from the patient with the novel JAK3R431P variant was undertaken, by flow cytometry and Phosflow after stimulation with IL-2, IL-7, and IL-15. JAK3 expression was investigated by Western blotting. We report two patients with homozygous hypomorphic JAK3 variants and clinical features of Omenn syndrome. One patient had a previously described JAK3R775H variant, and the second had a novel JAK3R431P variant. One patient with a novel JAK3R431P variant had normal expression of JAK3 in immortalised EBV-LCL cells but reduced phosphorylation of STAT5 after stimulation with IL-2, IL-7, and IL-15 consistent with impaired kinase activity. These results suggest the JAK3R431P variant to be hypomorphic. Both patients are alive and well after allogeneic haematopoietic stem cell transplantation. They have full donor chimerism, restitution of thymopoiesis and development of appropriate antibody responses following vaccination. We expand the phenotype of hypomorphic JAK3 deficiency and demonstrate the importance of functional testing of novel variants in disease-causing genes., (© 2024. The Author(s).)- Published
- 2024
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30. Expanding the PRAAS spectrum: De novo mutations of immunoproteasome subunit β-type 10 in six infants with SCID-Omenn syndrome.
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van der Made CI, Kersten S, Chorin O, Engelhardt KR, Ramakrishnan G, Griffin H, Schim van der Loeff I, Venselaar H, Rothschild AR, Segev M, Schuurs-Hoeijmakers JHM, Mantere T, Essers R, Esteki MZ, Avital AL, Loo PS, Simons A, Pfundt R, Warris A, Seyger MM, van de Veerdonk FL, Netea MG, Slatter MA, Flood T, Gennery AR, Simon AJ, Lev A, Frizinsky S, Barel O, van der Burg M, Somech R, Hambleton S, Henriet SSV, and Hoischen A
- Subjects
- Infant, Humans, Proteasome Endopeptidase Complex genetics, Proteasome Endopeptidase Complex metabolism, Mutation genetics, T-Lymphocytes metabolism, Mutation, Missense genetics, Severe Combined Immunodeficiency genetics, Severe Combined Immunodeficiency metabolism
- Abstract
Mutations in proteasome β-subunits or their chaperone and regulatory proteins are associated with proteasome-associated autoinflammatory disorders (PRAAS). We studied six unrelated infants with three de novo heterozygous missense variants in PSMB10, encoding the proteasome β2i-subunit. Individuals presented with T-B-NK± severe combined immunodeficiency (SCID) and clinical features suggestive of Omenn syndrome, including diarrhea, alopecia, and desquamating erythematous rash. Remaining T cells had limited T cell receptor repertoires, a skewed memory phenotype, and an elevated CD4/CD8 ratio. Bone marrow examination indicated severely impaired B cell maturation with limited V(D)J recombination. All infants received an allogeneic stem cell transplant and exhibited a variety of severe inflammatory complications thereafter, with 2 peri-transplant and 2 delayed deaths. The single long-term transplant survivor showed evidence for genetic rescue through revertant mosaicism overlapping the affected PSMB10 locus. The identified variants (c.166G>C [p.Asp56His] and c.601G>A/c.601G>C [p.Gly201Arg]) were predicted in silico to profoundly disrupt 20S immunoproteasome structure through impaired β-ring/β-ring interaction. Our identification of PSMB10 mutations as a cause of SCID-Omenn syndrome reinforces the connection between PRAAS-related diseases and SCID., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)
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- 2024
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31. Alemtuzumab, Dual Graft-versus-Host Disease Prophylaxis, and Lower CD3 + T Cell Doses Equalize Rates of Acute and Chronic Graft-versus-Host Disease in Pediatric Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation with Matched Unrelated Donor Peripheral Blood Stem Cells or Bone Marrow Grafts.
- Author
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Lum SH, James B, Ottaviano G, Ewins AM, Patrick K, Ali S, Carpenter B, Silva J, Tewari S, Furness C, Thomas A, Shenton G, Bonney D, Moppett J, Hambleton S, Gennery AR, Amrolia P, Gibson B, Hough R, Rao K, Slatter M, and Wynn R
- Subjects
- Adolescent, Child, Child, Preschool, Humans, Infant, Young Adult, Alemtuzumab therapeutic use, Bone Marrow, T-Lymphocytes, Unrelated Donors, Bronchiolitis Obliterans Syndrome, Graft vs Host Disease prevention & control, Hematopoietic Stem Cell Transplantation adverse effects, Peripheral Blood Stem Cells
- Abstract
Data comparing hematopoietic stem cell transplantation (HSCT) using bone marrow (BM) or peripheral blood stem cell (PBSC) grafts in children after alemtuzumab-based conditioning are lacking. We investigated whether in vivo T cell depletion using alemtuzumab could reduce the risk of severe acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD) after HSCT with matched unrelated donor (MUD) BM or PBSCs. This retrospective multicenter study included 397 children (BM group, n = 202; PBSC group, n = 195) who underwent first MUD HSCT at 9 pediatric centers in the United Kingdom between 2015 and 2019. The median age at transplantation was 7.0 years (range, .1 to 19.3 years), and the median duration of follow-up was 3.1 years (range, .3 to 7.5 years). The 3-year overall survival was 81% for the entire cohort (BM group, 80%; PBSC group, 81%). The incidence of grade II-IV aGVHD was significantly higher in the PBSC group (31%) compared to the BM group (31% versus 19%; P = .003), with no difference in the incidence of grade III-IV aGVHD (BM, 7%; PBSC, 12%; P = .17). CD3
+ T cell dose >5 × 108 /kg and the use of PBSCs were independent predictors of grade II-IV aGVHD. When considering CD3+ T cell dose and GVHD prophylaxis, PBSC transplantation with a calcineurin inhibitor (CNI) and mycophenolate mofetil (MMF) and a CD3+ T cell dose ≤5 × 108 /kg had a comparable grade II-IV aGVHD to BM transplantation plus a CNI (20% versus 18%; P = .52). PBSC transplantation was associated with a lower incidence of cGVHD compared to BM transplantation (6% versus 11%; P = .03). Within the limits of this study, we identified a potential strategy to reduce the risk of severe GVHD in pediatric PBSC recipients that includes a combination of in vivo T cell depletion using alemtuzumab and dual GVHD prophylaxis (with a CNI and MMF) and limiting the CD3+ T cell dose to ≤5 × 108 /kg., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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32. Inflammatory Complications in Chronic Granulomatous Disease.
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Grammatikos A and Gennery AR
- Abstract
Chronic granulomatous disease (CGD) is a rare inborn error of immunity that typically manifests with infectious complications. As the name suggest though, inflammatory complications are also common, often affecting the gastrointestinal, respiratory, urinary tracts and other tissues. These can be seen in all various types of CGD, from X-linked and autosomal recessive to X-linked carriers. The pathogenetic mechanisms underlying these complications are not well understood, but are likely multi-factorial and reflect the body's attempt to control infections. The different levels of neutrophil residual oxidase activity are thought to contribute to the large phenotypic variations. Immunosuppressive agents have traditionally been used to treat these complications, but their use is hindered by the fact that CGD patients are predisposed to infection. Novel therapeutic agents, like anti-TNFa monoclonal antibodies, anakinra, ustekinumab, and vedolizumab offer promise for the future, while hematopoietic stem cell transplantation should also be considered in these patients.
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- 2024
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33. JAK inhibitor treatment for inborn errors of JAK/STAT signaling: An ESID/EBMT-IEWP retrospective study.
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Fischer M, Olbrich P, Hadjadj J, Aumann V, Bakhtiar S, Barlogis V, von Bismarck P, Bloomfield M, Booth C, Buddingh EP, Cagdas D, Castelle M, Chan AY, Chandrakasan S, Chetty K, Cougoul P, Crickx E, Dara J, Deyà-Martínez A, Farmand S, Formankova R, Gennery AR, Gonzalez-Granado LI, Hagin D, Hanitsch LG, Hanzlikovà J, Hauck F, Ivorra-Cortés J, Kisand K, Kiykim A, Körholz J, Leahy TR, van Montfrans J, Nademi Z, Nelken B, Parikh S, Plado S, Ramakers J, Redlich A, Rieux-Laucat F, Rivière JG, Rodina Y, Júnior PR, Salou S, Schuetz C, Shcherbina A, Slatter MA, Touzot F, Unal E, Lankester AC, Burns S, Seppänen MRJ, Neth O, Albert MH, Ehl S, Neven B, and Speckmann C
- Subjects
- Child, Humans, Retrospective Studies, Prospective Studies, Treatment Outcome, Janus Kinase Inhibitors therapeutic use, Immunologic Deficiency Syndromes therapy
- Abstract
Background: Inborn errors of immunity (IEI) with dysregulated JAK/STAT signaling present with variable manifestations of immune dysregulation and infections. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but initially reported outcomes were poor. JAK inhibitors (JAKi) offer a targeted treatment option that may be an alternative or bridge to HSCT. However, data on their current use, treatment efficacy and adverse events are limited., Objective: We evaluated the current off-label JAKi treatment experience for JAK/STAT inborn errors of immunity (IEI) among European Society for Immunodeficiencies (ESID)/European Society for Blood and Marrow Transplantation (EBMT) Inborn Errors Working Party (IEWP) centers., Methods: We conducted a multicenter retrospective study on patients with a genetic disorder of hyperactive JAK/STAT signaling who received JAKi treatment for at least 3 months., Results: Sixty-nine patients (72% children) were evaluated (45 STAT1 gain of function [GOF], 21 STAT3-GOF, 1 STAT5B-GOF, 1 suppressor of cytokine signaling 1 [aka SOCS1] loss of function, 1 JAK1-GOF). Ruxolitinib was the predominantly prescribed JAKi (80%). Overall, treatment resulted in improvement (partial or complete remission) of clinical symptoms in 87% of STAT1-GOF and in 90% of STAT3-GOF patients. We documented highly heterogeneous dosing and monitoring regimens. The response rate and time to response varied across different diseases and manifestations. Adverse events including infection and weight gain were frequent (38% of patients) but were mild (grade I-II) and transient in most patients. At last follow-up, 52 (74%) of 69 patients were still receiving JAKi treatment, and 11 patients eventually underwent HSCT after receipt of previous JAKi bridging therapy, with 91% overall survival., Conclusions: Our study suggests that JAKi may be highly effective to treat symptomatic JAK/STAT IEI patients. Prospective studies to define optimal JAKi dosing for the variable clinical presentations and age ranges should be pursued., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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34. Allogeneic HSCT for Symptomatic Female X-linked Chronic Granulomatous Disease Carriers.
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Tsilifis C, Torppa T, Williams EJ, Albert MH, Hauck F, Soncini E, Kang E, Malech H, Schuetz C, von Bernuth H, Slatter MA, and Gennery AR
- Subjects
- Humans, Female, Retrospective Studies, Respiratory Burst, Neutrophils, Granulomatous Disease, Chronic diagnosis, Granulomatous Disease, Chronic genetics, Granulomatous Disease, Chronic therapy, Hematopoietic Stem Cell Transplantation
- Abstract
X-linked chronic granulomatous disease (XL-CGD) is an inherited disorder of superoxide production, causing failure to generate the oxidative burst in phagocytes. It is characterized by invasive bacterial and fungal infections, inflammation, and chronic autoimmune disease. While XL-CGD carriers were previously assumed to be healthy, a range of clinical manifestations with significant morbidity have recently been described in a subgroup of carriers with impaired neutrophil oxidative burst due to skewed lyonization. Allogeneic hematopoietic stem cell transplantation (HSCT) is the standard curative treatment for CGD but has rarely been reported in individual symptomatic carriers to date. We undertook a retrospective international survey of outcome of HSCT for symptomatic XL-CGD carriers. Seven symptomatic female XL-CGD carriers aged 1-56 years underwent HSCT in four centers, indicated for severe and recurrent infection, colitis, and autoimmunity. Two patients died from transplant-related complications, following donor engraftment and restoration of oxidative burst. All surviving patients demonstrated resolution of their neutrophil oxidative burst defect with concordant reduction in infection and inflammatory symptoms and freedom from further immunosuppressive therapy. In conclusion, allogeneic HSCT may cure the phagocyte defect in symptomatic XL-CGD carriers and improve their recurrent and disabling infective and inflammatory symptoms but risks transplant-related complications., (© 2023. The Author(s).)
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- 2023
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35. Outcome of Second Allogeneic HSCT for Patients with Inborn Errors of Immunity: Retrospective Study of 20 Years' Experience.
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Mehta P, Tsilifis C, Lum SH, Slatter MA, Hambleton S, Owens S, Williams E, Flood T, Gennery AR, and Nademi Z
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- Humans, Retrospective Studies, Adenoviridae, Chimerism, Graft vs Host Disease etiology, Severe Combined Immunodeficiency, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
A significant complication of HSCT is graft failure, although few studies focus on this problem in patients with inborn errors of immunity (IE). We explored outcome of second HSCT for IEI by a retrospective, single-centre study between 2002 and 2022. Four hundred ninety-three patients underwent allogeneic HSCT for severe combined immunodeficiency (SCID; n = 113, 22.9%) or non-SCID IEI (n = 380, 77.1%). Thirty patients (6.0%) required second HSCT. Unconditioned infusion or no serotherapy at first HSCT was more common in patients who required second transplant. Median interval between first and second HSCT was 0.97 years (range: 0.19-8.60 years); a different donor was selected for second HSCT in 24/30 (80.0%) patients. Conditioning regimens for second HSCT were predominately treosulfan-based (with thiotepa: n = 18, 60.0%; without, n = 6, 20.0%). Patients received grafts from peripheral blood stem cell (n = 25, 83.3%) or bone marrow (n = 5, 16.7%) with median stem cell dose 9.5 × 10
6 CD34 + cells/kilogram (range: 1.4-32.3). Median follow-up was 1.92 years (0.22-16.0). Overall survival was 80.8% and event-free survival was 64.7%. Four patients died, two of early-transplant related complications, and two of late sepsis post-second HSCT. Three patients required third HSCT; all are alive with 100% donor chimerism. Cumulative incidence of acute graft-versus-host disease was 28.4%, (all grade I-II). Viral reactivation was seen in 13/30 (43.3%) patients, including HHV6 (n = 6), CMV (n = 4), and adenovirus (n = 2). At latest follow-up, 25/26 surviving patients have donor chimerism ≥ 90% and 16/25 (64.0%) have discontinued immunoglobulin replacement. Second HSCT offers IEI patients with graft failure curative treatment with good overall survival and immunological recovery., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)- Published
- 2023
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36. An International Survey of Allogeneic Hematopoietic Cell Transplantation for X-Linked Agammaglobulinemia.
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Nishimura A, Uppuluri R, Raj R, Swaminathan VV, Cheng Y, Abu-Arja RF, Fu B, Laberko A, Albert MH, Hauck F, Bucciol G, Bigley V, Elcombe S, Kharya G, Pronk CJH, Wehr C, Neven B, Warnatz K, Meyts I, Morio T, Gennery AR, and Kanegane H
- Subjects
- Humans, Melphalan, Transplantation Conditioning methods, Hematopoietic Stem Cell Transplantation methods, Agammaglobulinemia diagnosis, Agammaglobulinemia therapy, Agammaglobulinemia etiology, Genetic Diseases, X-Linked therapy, Genetic Diseases, X-Linked etiology, Graft vs Host Disease etiology
- Abstract
Purpose: X-linked agammaglobulinemia (XLA) is an inborn error of immunity caused by variants in Bruton's tyrosine kinase (BTK). XLA patients require lifelong immunoglobulin replacement therapy (IgRT). Only few XLA patients are indicated for allogeneic hematopoietic cell transplantation (HCT) because of severe complications. Accordingly, the published transplantation experience in XLA is minimal. We aimed to collect clinical data of XLA patients who received HCT in an international framework and to establish appropriate transplantation criteria and methods for XLA patients., Methods: XLA patients were recruited through a questionnaire and a literature review. The data are on patient characteristics and transplantation methods and outcomes., Results: In this study, twenty-two XLA patients who underwent HCT were recruited. The indication for HCT was recurrent or life-threatening infection in sixteen patients, malignancy in three, and other factors in three. A myeloablative conditioning, reduced toxicity myeloablative conditioning (RT-MAC), and reduced intensity conditioning (RIC) were selected in four, ten, and eight patients, respectively. Engraftment was achieved in 21 patients (95%). In all patients, 2-year overall survival (OS) and event-free survival (EFS) were 86% and 77%, respectively. In patients who received RT-MAC or RIC using treosulfan, busulfan, or melphalan, 2-year OS and EFS were 82% and 71%, respectively. Finally, twenty-one patients (95%) obtained complete or stable high-level mixed chimerism (50-95%), and the 1-year discontinuation rate of IgRT was 89%., Conclusion: Based on the concept in which IgRT is the standard treatment for XLA, HCT may be an effective and safe alternative treatment option for XLA patients, and IgRT can be discontinued following transplantation. It is ideal to perform HCT in XLA patients for whom transplantation is indicated before they develop organ damage., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2023
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37. Too much of a good thing: a review of primary immune regulatory disorders.
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Tsilifis C, Slatter MA, and Gennery AR
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- Humans, Immune Tolerance, Hematopoietic Stem Cell Transplantation methods, Neoplasms
- Abstract
Primary immune regulatory disorders (PIRDs) are inborn errors of immunity caused by a loss in the regulatory mechanism of the inflammatory or immune response, leading to impaired immunological tolerance or an exuberant inflammatory response to various stimuli due to loss or gain of function mutations. Whilst PIRDs may feature susceptibility to recurrent, severe, or opportunistic infection in their phenotype, this group of syndromes has broadened the spectrum of disease caused by defects in immunity-related genes to include autoimmunity, autoinflammation, lymphoproliferation, malignancy, and allergy; increasing focus on PIRDs has thus redefined the classical 'primary immunodeficiency' as one aspect of an overarching group of inborn errors of immunity. The growing number of genetic defects associated with PIRDs has expanded our understanding of immune tolerance mechanisms and prompted identification of molecular targets for therapy. However, PIRDs remain difficult to recognize due to incomplete penetrance of their diverse phenotype, which may cross organ systems and present to multiple clinical specialists prior to review by an immunologist. Control of immune dysregulation with immunosuppressive therapies must be balanced against the enhanced infective risk posed by the underlying defect and accumulated end-organ damage, posing a challenge to clinicians. Whilst allogeneic hematopoietic stem cell transplantation may correct the underlying immune defect, identification of appropriate patients and timing of transplant is difficult. The relatively recent description of many PIRDs and rarity of individual genetic entities that comprise this group means data on natural history, clinical progression, and treatment are limited, and so international collaboration will be needed to better delineate phenotypes and the impact of existing and potential therapies. This review explores pathophysiology, clinical features, current therapeutic strategies for PIRDs including cellular platforms, and future directions for research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Tsilifis, Slatter and Gennery.)
- Published
- 2023
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38. Immunology of THymectomy And childhood CArdiac transplant (ITHACA): protocol for a UK-wide prospective observational cohort study to identify immunological risk factors of post-transplant lymphoproliferative disease (PTLD) in thymectomised children.
- Author
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Offor UT, Hollis P, Ognjanovic M, Parry G, Khushnood A, Long HM, Gennery AR, Bacon CM, Simmonds J, Reinhardt Z, and Bomken S
- Subjects
- Child, Humans, Herpesvirus 4, Human physiology, Thymectomy adverse effects, Prospective Studies, Risk Factors, Immunologic Factors, United Kingdom, Viral Load, Observational Studies as Topic, Epstein-Barr Virus Infections, Lymphoproliferative Disorders etiology, Heart Transplantation adverse effects
- Abstract
Introduction: Paediatric heart transplant patients are disproportionately affected by Epstein-Barr virus (EBV)-related post-transplant lymphoproliferative disease (PTLD) compared with other childhood solid organ recipients. The drivers for this disparity remain poorly understood. A potential risk factor within this cohort is the routine surgical removal of the thymus-a gland critical for the normal development of T-lymphocyte-mediated antiviral immunity-in early life, which does not occur in other solid organ transplant recipients. Our study aims to describe the key immunological differences associated with early thymectomy, its impact on the temporal immune response to EBV infection and subsequent risk of PTLD., Methods and Analysis: Prospective and sequential immune monitoring will be performed for 34 heart transplant recipients and 6 renal transplant patients (aged 0-18 years), stratified into early (<1 year), late (>1 year) and non-thymectomy groups. Peripheral blood samples and clinical data will be taken before transplant and at 3, 6, 12 and 24 months post-transplant. Single cell analysis of circulating immune cells and enumeration of EBV-specific T-lymphocytes will be performed using high-dimensional spectral flow cytometry with peptide-Major Histocompatibilty Complex (pMHC) I/II tetramer assay, respectively. The functional status of EBV-specific T-lymphocytes, along with EBV antibodies and viral load will be monitored at each of the predefined study time points., Ethics and Dissemination: Ethical approval for this study has been obtained from the North of Scotland Research Ethics Committee. The results will be disseminated through publications in peer-reviewed journals, presentations at scientific conferences and patient-centred forums, including social media., Trial Registration Number: ISRCTN10096625., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)
- Published
- 2023
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39. The "B" side of IL-7Rα-deficient SCID.
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Gennery AR
- Subjects
- Humans, Cell Differentiation, Receptors, Interleukin-7
- Published
- 2023
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40. Haematopoietic Stem Cell Transplantation for Chronic Granulomatous Disease.
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Slatter MA and Gennery AR
- Abstract
Chronic granulomatous disease (CGD) is an inborn error of immunity due to defects in the transport or function of subunits of nicotinamide adenine dinucleotide phosphate oxidase, the enzyme that generates the phagocyte respiratory burst responsible for intracellular killing of engulfed micro-organisms. Patients present with infectious or inflammatory complications. Common bacterial pathogens include Staphylococcus aureus and Burkholderia cepacia complex. Fungal pathogens include Aspergillus species, particularly Aspergillus fumigatus . Inflammatory complications most commonly manifest as inflammatory bowel disease or lung disease. Granulomata are the distinguishing histological feature. Haematopoietic stem cell transplantation (HSCT) was first considered for CGD in the early 1970's. Since then, refinements in transplant technique, donor selection, conditioning regimens, and graft engineering have widened the option of HSCT to most patients with CGD. This review charts the progress made in HSCT for CGD.
- Published
- 2023
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41. CD3 + TCRαβ/CD19 + -Depleted Mismatched Family or Unrelated Donor Salvage Stem Cell Transplantation for Graft Dysfunction in Inborn Errors of Immunity.
- Author
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Ramanathan S, Lum SH, Nademi Z, Carruthers K, Watson H, Flood T, Owens S, Williams E, Hambleton S, Gennery AR, and Slatter M
- Subjects
- Child, Humans, Infant, Receptors, Antigen, T-Cell, alpha-beta, Unrelated Donors, Retrospective Studies, Viremia, Herpesvirus 4, Human, Epstein-Barr Virus Infections, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation methods, Graft vs Host Disease
- Abstract
A minority of children experience significant graft dysfunction after undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for inborn errors of immunity (IEI). The optimal approach to salvage HSCT in this scenario is unclear with respect to conditioning regimen and stem cell source. This single-center retrospective case series reports the outcomes of salvage CD3
+ TCRαβ/CD19-depleted mismatched family or unrelated donor stem cell transplantation (TCRαβ-SCT) between 2013 and 2022 for graft dysfunction in 12 children with IEI. Outcomes of interest were overall survival (OS), event-free survival (EFS), graft-versus-host disease (GVHD)-free and event-free survival (GEFS), toxicities, GVHD, viremia and long-term graft function. In this retrospective audit of patients who underwent second CD3+ TCRαβ/CD19-depleted mismatched donor HSCT using treosulfan-based reduced-toxicity myeloablative conditioning, the median age at first HSCT was 8.76 months (range, 2.5 months to 6 years), and that at second TCRαβ-SCT was 3.6 years (range, 1.2 to 11 years). The median interval between first and second HSCTs was 1.7 years (range, 3 months to 9 years). The primary diagnoses were severe combined immunodeficiency (SCID) (n = 5) and non-SCID IEI (n = 7). Indications for second HSCT were primary aplasia (n = 1), secondary autologous reconstitution (n = 6), refractory acute GVHD (aGVHD) (n = 3), and secondary leukemia (n = 1). Donors were either haploidentical parental donors (n = 10) or mismatched unrelated donors (n = 2). All patients received TCRαβ/CD19-depleted peripheral blood stem cell (PBSC) grafts with a median CD34+ cell dose of 9.3 × 106 /kg (range, 2.8 to 32.3 × 106 /kg) and a median TCRαβ+ cell dose of 4 × 104 /kg (range, 1.3 to 19.2 × 104 /kg). All patients engrafted, with a median time neutrophil and platelet recovery of 15 days (range, 12 to 24 days) and 12 days (range, 9 to 19 days). One patient developed secondary aplasia, and 1 had secondary autologous reconstitution; both underwent a successful third HSCT. Four (33%) had grade II aGVHD, and none had grade III-IV aGVHD. No patients had chronic GVHD (cGVHD), but 1 patient developed extensive cutaneous cGVHD after their third HSCT using PBSCs and antithymocyte globulin. Nine (75%) had at least 1episode of blood viremia with human herpesvirus 6 (n = 6; 50%), adenovirus (n = 6; 50%), Epstein-Barr virus (n = 3; 25%), or cytomegalovirus (n = 3; 25%). The median duration of follow-up was 2.3 years (range, .5 to 10 years), and the 2-year OS, EFS, and GEFS were 100% (95% confidence interval [CI], 0 to 100%), 73% (95% CI, 37% to 90%), and 73% (95% CI, 37% to 90%), respectively. TCRαβ-SCT from mismatched family or unrelated donors, using a chemotherapy-only conditioning regimen, is a safe alternative donor salvage transplantation strategy for second HSCT in patients without a suitably matched donor., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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42. Gene silencing on a WHIM.
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Gennery AR
- Subjects
- Mice, Animals, Alleles, CRISPR-Cas Systems, Genetic Therapy, Primary Immunodeficiency Diseases genetics, Immunologic Deficiency Syndromes genetics, Warts genetics
- Published
- 2023
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43. What causes aplastic anaemia?
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Gale RP, Hinterberger W, Young NS, Gennery AR, Dvorak CC, Hebert KM, Heim M, Broglie L, and Eapen M
- Subjects
- Humans, Anemia, Aplastic etiology
- Published
- 2023
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44. Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome.
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Leiding JW, Vogel TP, Santarlas VGJ, Mhaskar R, Smith MR, Carisey A, Vargas-Hernández A, Silva-Carmona M, Heeg M, Rensing-Ehl A, Neven B, Hadjadj J, Hambleton S, Ronan Leahy T, Meesilpavikai K, Cunningham-Rundles C, Dutmer CM, Sharapova SO, Taskinen M, Chua I, Hague R, Klemann C, Kostyuchenko L, Morio T, Thatayatikom A, Ozen A, Scherbina A, Bauer CS, Flanagan SE, Gambineri E, Giovannini-Chami L, Heimall J, Sullivan KE, Allenspach E, Romberg N, Deane SG, Prince BT, Rose MJ, Bohnsack J, Mousallem T, Jesudas R, Santos Vilela MMD, O'Sullivan M, Pachlopnik Schmid J, Průhová Š, Klocperk A, Rees M, Su H, Bahna S, Baris S, Bartnikas LM, Chang Berger A, Briggs TA, Brothers S, Bundy V, Chan AY, Chandrakasan S, Christiansen M, Cole T, Cook MC, Desai MM, Fischer U, Fulcher DA, Gallo S, Gauthier A, Gennery AR, Gonçalo Marques J, Gottrand F, Grimbacher B, Grunebaum E, Haapaniemi E, Hämäläinen S, Heiskanen K, Heiskanen-Kosma T, Hoffman HM, Gonzalez-Granado LI, Guerrerio AL, Kainulainen L, Kumar A, Lawrence MG, Levin C, Martelius T, Neth O, Olbrich P, Palma A, Patel NC, Pozos T, Preece K, Lugo Reyes SO, Russell MA, Schejter Y, Seroogy C, Sinclair J, Skevofilax E, Suan D, Suez D, Szabolcs P, Velasco H, Warnatz K, Walkovich K, Worth A, Seppänen MRJ, Torgerson TR, Sogkas G, Ehl S, Tangye SG, Cooper MA, Milner JD, and Forbes Satter LR
- Subjects
- Child, Humans, Autoimmunity genetics, Cohort Studies, Gain of Function Mutation, Mutation, STAT3 Transcription Factor genetics, Cell Proliferation, Lymphocytes, Immune System Diseases, Immunologic Deficiency Syndromes genetics
- Abstract
Background: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity., Objective: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants., Methods: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3., Results: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate., Conclusion: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. All rights reserved.)
- Published
- 2023
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45. Editorial: Primary immune regulatory disorders: Coming of age.
- Author
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Gennery AR, Gonzalez-Granado LI, and Torgerson TR
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Published
- 2023
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46. Recent advances in graft-versus-host disease.
- Author
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Flinn AM and Gennery AR
- Abstract
Acute and chronic graft-versus-host disease (GVHD) continue to present a significant challenge to physicians, accounting for considerable haematopoietic stem cell transplant (HSCT)-related morbidity and mortality, particularly those patients with steroid-refractory disease. In this review, we discuss recent advances in understanding the underlying pathophysiology, prevention and management of acute and chronic GVHD. Barriers to progress include the difficulty in obtaining high-quality evidence with sufficient patient numbers to identify optimal preventative and treatment strategies, with the heterogeneity of multiple patient, donor, graft and transplant-related factors, in addition to limited availability of human tissue to study the underlying pathophysiology, particularly in steroid-refractory disease. Continued collaborative efforts to improve our understanding of the pathophysiology involved, particularly in steroid-refractory disease, identification of biomarkers to permit risk stratification, and further well-designed randomised clinical trials are essential to help physicians determine optimal GVHD preventative and treatment strategies for each individual patient., Competing Interests: The authors declare that they have no competing interests.Dr Holtan receives research funding from Incyte and Vitrac Therapeutics. She provides clinical trial adjudication services for CSL Behring.No competing interests were disclosed., (Copyright: © 2023 Gennery AR et al.)
- Published
- 2023
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47. Extracorporeal photopheresis as an immunomodulatory treatment modality for chronic GvHD and the importance of emerging biomarkers.
- Author
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Bojanic I, Worel N, Pacini CP, Stary G, Piekarska A, Flinn AM, Schell KJ, Gennery AR, Knobler R, Lacerda JF, Greinix HT, Pulanic D, and Crossland RE
- Subjects
- Humans, Biomarkers, Immunity, Photopheresis, Bronchiolitis Obliterans Syndrome, Graft vs Host Disease
- Abstract
Haematopoietic stem cell transplantation (HSCT) is the treatment of choice for malignant haematological diseases. Despite continuous improvements in pre- and post-transplantation procedures, the applicability of allo-HSCT is limited by life-threatening complications such as graft-versus-host disease (GvHD), engraftment failure, and opportunistic infections. Extracorporeal photopheresis (ECP) is used to treat steroid resistant GvHD with significant success. However, the molecular mechanisms driving its immunomodulatory action, whilst preserving immune function, require further understanding. As ECP is safe to administer with few significant adverse effects, it has the potential for earlier use in the post-HSCT treatment of GvHD. Thus, further understanding the immunomodulatory mechanisms of ECP action may justify more timely use in clinical practice, as well as identify biomarkers for using ECP as first line or pre-emptive GvHD therapy. This review aims to discuss technical aspects and response to ECP, review ECP as an immunomodulatory treatment modality for chronic GvHD including the effect on regulatory T cells and circulating vs. tissue-resident immune cells and consider the importance of emerging biomarkers for ECP response., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bojanic, Worel, Pacini, Stary, Piekarska, Flinn, Schell, Gennery, Knobler, Lacerda, Greinix, Pulanic and Crossland.)
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- 2023
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48. Hypomorphic RAG deficiency: impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT.
- Author
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Schuetz C, Gerke J, Ege M, Walter J, Kusters M, Worth A, Kanakry JA, Dimitrova D, Wolska-Kuśnierz B, Chen K, Unal E, Karakukcu M, Pashchenko O, Leiding J, Kawai T, Amrolia PJ, Berghuis D, Buechner J, Buchbinder D, Cowan MJ, Gennery AR, Güngör T, Heimall J, Miano M, Meyts I, Morris EC, Rivière J, Sharapova SO, Shaw PJ, Slatter M, Honig M, Veys P, Fischer A, Cavazzana M, Moshous D, Schulz A, Albert MH, Puck JM, Lankester AC, Notarangelo LD, and Neven B
- Subjects
- Infant, Newborn, Humans, Tissue Donors, T-Lymphocytes, Early Diagnosis, Cost of Illness, Retrospective Studies, Unrelated Donors, Transplantation Conditioning, Hematopoietic Stem Cell Transplantation adverse effects, Graft vs Host Disease diagnosis, Graft vs Host Disease etiology
- Abstract
Patients with hypomorphic mutations in the RAG1 or RAG2 gene present with either Omenn syndrome or atypical combined immunodeficiency with a wide phenotypic range. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but data are scarce. We report on a worldwide cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, 78% of whom experienced infections (29% active at HSCT), 72% had autoimmunity, and 18% had granulomas pretransplant. These complications are frequently associated with organ damage. Eight individuals (13%) were diagnosed by newborn screening or family history. HSCT was performed at a median of 3.4 years (range 0.3-42.9 years) from matched unrelated donors, matched sibling or matched family donors, or mismatched donors in 48%, 22%, and 30% of the patients, respectively. Grafts were T-cell depleted in 15 cases (25%). Overall survival at 1 and 4 years was 77.5% and 67.5% (median follow-up of 39 months). Infection was the main cause of death. In univariable analysis, active infection, organ damage pre-HSCT, T-cell depletion of the graft, and transplant from a mismatched family donor were predictive of worse outcome, whereas organ damage and T-cell depletion remained significant in multivariable analysis (hazard ratio [HR] = 6.01, HR = 8.46, respectively). All patients diagnosed by newborn screening or family history survived. Cumulative incidences of acute and chronic graft-versus-host disease were 35% and 22%, respectively. Cumulative incidences of new-onset autoimmunity was 15%. Immune reconstitution, particularly recovery of naïve CD4+ T cells, was faster and more robust in patients transplanted before 3.5 years of age, and without organ damage. These findings support the indication for early transplantation., (© 2023 by The American Society of Hematology.)
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- 2023
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49. Haploidentical CD3 + TCR αβ/CD19 + -depleted HSCT for MHC class II deficiency and persistent SARS-CoV-2 pneumonitis.
- Author
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Ramanathan S, Veramendi-Espinoza L, Shillitoe B, Flinn A, Owens S, Williams E, Emonts M, Hambleton S, Burton-Fanning S, Waugh S, Flood T, Gennery AR, Slatter M, and Nademi Z
- Abstract
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to coronavirus disease 2019 (COVID-19), which can range from a mild illness to a severe phenotype characterized by acute respiratory distress needing mechanical ventilation. Children with combined immunodeficiencies might be unable to mount a sufficient cellular and humoral immune response against COVID-19 and have persistent disease., Objective: Our aim was to describe a child with combined immunodeficiency and a favorable post-hematopoietic stem cell transplant (HSCT) course following a haploidentical HSCT in the presence of persistent SARS-CoV-2 infection., Methods: A 13-month-old girl with MHC class II deficiency developed persistent pre-HSCT SARS-CoV-2 infection. Faced with a significant challenge of balancing the risk of progressive infection due to an incompetent immune system with the danger of inflammatory pneumonitis peri-immune reconstitution after HSCT, the patient's physicians performed a maternal (with a recent history of COVID-19 infection) haploidentical HSCT. The patient received regdanvimab (after stem cell infusion) and remdesivir (before and after stem cell infusion)., Results: The patient exhibited a gradual increase in her cycle threshold values, implying a reduction in viral RNA with concomitant expansion in the CD3 lymphocyte subset and clinical and radiologic improvement., Conclusions: Combination of adoptive transfer of maternal CD45RO
+ memory addback T lymphocytes after haploidentical HSCT and use of regdanvimab (a SARS-CoV-2-neutralizing mAb) and remdesivir may have led to the successful outcome in our patient with severe immunodeficiency after she had undergone HSCT. This case highlights the role of novel antiviral strategies (mAbs and CD45RO+ memory T lymphocytes) in contributing to viral clearance in a challenging clinical scenario., (© 2022 The Authors.)- Published
- 2023
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50. Current Transition Practice for Primary Immunodeficiencies and Autoinflammatory Diseases in Europe: a RITA-ERN Survey.
- Author
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Israni M, Nicholson B, Mahlaoui N, Obici L, Rossi-Semerano L, Lachmann H, Hayward G, Avramovič MZ, Guffroy A, Dalm V, Rimmer R, Solis L, Villar C, Gennery AR, Skeffington S, Nordin J, Warnatz K, Korganow AS, Antón J, Cattalini M, Amin T, Berg S, Soler-Palacin P, Burns SO, and Campbell M
- Subjects
- Adult, Humans, Child, Adolescent, Young Adult, Europe epidemiology, Prevalence, Immunologic Deficiency Syndromes diagnosis, Immunologic Deficiency Syndromes epidemiology, Immunologic Deficiency Syndromes therapy, Autoimmune Diseases diagnosis, Autoimmune Diseases epidemiology, Autoimmune Diseases therapy, Hereditary Autoinflammatory Diseases
- Abstract
Background: Due to the absence of curative treatments for inborn errors of immunity (IEI), children born with IEI require long-term follow-up for disease manifestations and related complications that occur over the lifespan. Effective transition from pediatric to adult services is known to significantly improve adherence to treatment and long-term outcomes. It is currently not known what transition services are available for young people with IEI in Europe., Objective: To understand the prevalence and practice of transition services in Europe for young people with IEI, encompassing both primary immunodeficiencies (PID) and systemic autoinflammatory disorders (AID)., Methods: A survey was generated by the European Reference Network on immunodeficiency, autoinflammatory, and autoimmune diseases Transition Working Group and electronically circulated, through professional networks, to pediatric centers across Europe looking after children with IEI., Results: Seventy-six responses were received from 52 centers, in 45 cities across 17 different countries. All services transitioned patients to adult services, mainly to specialist PID or AID centers, typically transferring up to ten patients to adult care each year. The transition process started at a median age of 16-18 years with transfer to the adult center occurring at a median age of 18-20 years. 75% of PID and 68% of AID centers held at least one joint appointment with pediatric and adult services prior to the transfer of care. Approximately 75% of PID and AID services reported having a defined transition process, but few centers reported national disease-specific transition guidelines to refer to., Conclusions: Transition services for children with IEI in Europe are available in many countries but lack standardized guidelines to promote best practice., (© 2022. The Author(s).)
- Published
- 2023
- Full Text
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