Publications by authors named "Mario Abinun"

99 Publications

Outcome of Hematopoietic Stem Cell Transplantation in patients with Mendelian Susceptibility to Mycobacterial Diseases.

J Clin Immunol 2021 Aug 13. Epub 2021 Aug 13.

Children's Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne, UK.

Predisposition to mycobacterial infection is a key presenting feature of several rare inborn errors of intrinsic and innate immunity. Hematopoietic stem cell transplantation (HSCT) can be curative for such conditions, but published reports are few. We present a retrospective survey of the outcome of 11 affected patients (7 males, 4 females) who underwent HSCT between 2007 and 2019. Eight patients had disseminated mycobacterial infection prior to transplant. Median age at first transplant was 48 months (9 -192); three patients were successfully re-transplanted due to secondary graft failure. Donors were matched family (1), matched unrelated (3), and mismatched unrelated and haploidentical family (5 each). Stem cell source was peripheral blood (9), bone marrow (4), and cord blood (1). TCRαβ/CD19 + depletion was performed in 6. Conditioning regimens were treosulfan, fludarabine (4), with additional thiotepa (in 8), and fludarabine, melphalan (2); all had serotherapy with alemtuzumab (8) or anti T-lymphocyte globulin (6). Median hospital stay was 113 days (36-330). Three patients developed acute grade I-II skin and one grade IV skin graft versus host disease. Four patients had immune-reconstitution syndrome. Two reactivated cytomegalovirus (CMV), 1 Epstein-Barr virus, and 3 adenovirus post HSCT. Nine are alive, 1 died early post-transplant from CMV, and the other was a late death from pneumococcal sepsis. Patients with active mycobacterial infection at HSCT continued anti-mycobacterial therapy for almost 12 months. In conclusion, HSCT is a successful treatment for patients with mycobacterial susceptibility even with disseminated mycobacterial infection and in the absence of an HLA matched donor.
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http://dx.doi.org/10.1007/s10875-021-01116-1DOI Listing
August 2021

Haematopoietic stem cell transplantation in paediatric rheumatic disease.

Curr Opin Rheumatol 2021 09;33(5):387-397

Haematopoietic Stem Cell Transplantation Unit, Great North Children's Hospital, Newcastle upon Tyne Hospitals, National Health Service Foundation Trust, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.

Purpose Of Review: A small proportion of children affected by rheumatic diseases suffer from severe, progressive disease, resistant to conventional antirheumatic therapies and to biologic agents interfering with inflammatory cytokines, costimulatory molecules expressed on immune system cells and intracellular signalling pathways. Adding to the poor prognosis is a high risk from significant morbidity and mortality associated with long-term treatment with multiple, often combined anti-inflammatory and immunosuppressive agents. Carefully selected patients from this unfortunate group may benefit from treatment with haematopoietic stem cell transplantation.

Recent Findings: The majority of patients with severe paediatric rheumatic and autoinflammatory diseases treated with autologous and/or allogeneic haematopoietic stem cell transplantation achieved long-term remission. However, the incidence of disease relapse and transplant related morbidity and mortality is still significant.

Summary: Careful patient and donor selection, timing of the transplant earlier in the course of disease rather than the 'last resort' and choosing the most suitable conditioning regimen for each individual patient are the major factors favouring successful outcome. Close co-operation between the patients, their family, and involved medical teams is essential.
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http://dx.doi.org/10.1097/BOR.0000000000000823DOI Listing
September 2021

Hematopoietic Stem Cell Transplantation Resolves the Immune Deficit Associated with STAT3-Dominant-Negative Hyper-IgE Syndrome.

J Clin Immunol 2021 07 1;41(5):934-943. Epub 2021 Feb 1.

Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.

Autosomal dominant hyper-IgE syndrome caused by dominant-negative loss-of-function mutations in signal transducer and activator of transcription factor 3 (STAT3) (STAT3-HIES) is a rare primary immunodeficiency with multisystem pathology. The quality of life in patients with STAT3-HIES is determined by not only the progressive, life-limiting pulmonary disease, but also significant skin disease including recurrent infections and abscesses requiring surgery. Our early report indicated that hematopoietic stem cell transplantation might not be effective in patients with STAT3-HIES, although a few subsequent reports have reported successful outcomes. We update on progress of our patient now with over 18 years of follow-up and report on an additional seven cases, all of whom have survived despite demonstrating significant disease-related pathology prior to transplant. We conclude that effective cure of the immunological aspects of the disease and stabilization of even severe lung involvement may be achieved by allogeneic hematopoietic stem cell transplantation. Recurrent skin infections and abscesses may be abolished. Donor T17 cells may produce comparable levels of IL17A to healthy controls. The future challenge will be to determine which patients should best be offered this treatment and at what point in their disease history.
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http://dx.doi.org/10.1007/s10875-021-00971-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249289PMC
July 2021

HSCT is effective in patients with PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome.

J Allergy Clin Immunol 2021 07 15;148(1):250-255.e1. Epub 2020 Dec 15.

Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.

Background: Proline-serine-threonine phosphatase-interacting protein 1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome is a novel genetic disorder, causing hypercalprotectinemia and hyperzincemia with inflammatory complications accompanied by cytopenia. Immunosuppressive and/or anticytokine therapy is of limited effect.

Objectives: Because of cytokine production in nonhematopoietic tissues, the potential therapeutic effect of allogeneic hematopoietic stem cell transplantation (HSCT) in autoinflammatory disorders, including PAMI syndrome, has remained uncertain.

Methods: Five patients with PAMI syndrome underwent allogeneic HSCT with myeloablative (4) or reduced-intensity (1) conditioning regimens. Lack of PAMI disease control served as indication for the HSCT in 4 patients and myelodysplastic syndrome development in 1.

Results: All 5 patients engrafted; however, 1 patient at day +13 developed hemophagocytic syndrome, followed by graft rejection at day +17. After 5.5 months, a second HSCT was performed from an alternative donor. A further patient at day +116 developed an intense inflammatory syndrome with significant serositis and severe mitral and aortic valve regurgitation, controlled with adalimumab, tacrolimus, and prednisone. No other noninfectious inflammatory episodes, or acute or chronic graft-versus-host disease, occurred in any patient. At the last follow-up (median, 2.2 years), all 5 patients have predominantly or complete donor chimerism and adequate immune recovery and are free of any PAMI symptoms.

Conclusions: Allogeneic HSCT seems to be an effective option to cure cytopenia and severe autoinflammation in PAMI syndrome and may be a curative option for other proline-serine-threonine phosphatase-interacting protein 1-associated inflammatory disorders with poor therapeutic control.
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http://dx.doi.org/10.1016/j.jaci.2020.11.043DOI Listing
July 2021

Defective neutrophil development and specific granule deficiency caused by a homozygous splice-site mutation in SMARCD2.

J Allergy Clin Immunol 2021 06 3;147(6):2381-2385.e2. Epub 2020 Dec 3.

Immunity & Inflammation Theme, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; Great North Children's Hospital (GNCH), Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom. Electronic address:

Background: SMARCD2 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily D, member 2) has recently been shown to have a critical role in granulopoiesis in humans, mice, and zebrafish. Our patient presented with delayed cord separation, failure to thrive, and sepsis. Retrospective whole-exome sequencing confirmed a homozygous splice-site mutation in SMARCD2.

Objective: We sought to provide the second description of human SMARCD2 deficiency and the first functional analysis of human primary SMARCD2-deficient cells.

Methods: Heparinized venous blood and bone marrow were collected from the patient after obtaining informed consent. Patient leukocytes and CD34 cells were then isolated, phenotyped, and assessed functionally.

Results: Circulating neutrophils appeared phenotypically immature, lacking multilobed nuclei, and neutrophil granules lacked lactoferrin but showed normal levels of myeloperoxidase. Neutrophil oxidative burst was preserved in response to phorbol 12-myristate 13-acetate. Patient bone marrow-derived neutrophils and white blood cells showed a severely impaired chemotactic response. Furthermore, white blood cells showed defective in vitro killing of Staphylococcus aureus, consistent with a specific granule deficiency. Finally, patient bone marrow-derived CD34 cells showed markedly impaired in vitro expansion and differentiation toward the neutrophil lineage. Before her molecular diagnosis, our patient underwent hematopoietic stem cell transplantation and is well 8 years later.

Conclusions: This report highlights an important role for SMARCD2 in human myelopoiesis and the curative effect of hematopoietic stem cell transplantation for the hematopoietic features of SMARCD2 deficiency.
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http://dx.doi.org/10.1016/j.jaci.2020.11.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168953PMC
June 2021

Improved survival and graft function in ex vivo T-cell depleted haploidentical hematopoietic cell transplantation for primary immunodeficiency.

Bone Marrow Transplant 2021 05 24;56(5):1200-1204. Epub 2020 Nov 24.

Children's Haematopoietic Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne Hospital NHS Foundation Trust, Newcastle upon Tyne, UK.

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http://dx.doi.org/10.1038/s41409-020-01152-2DOI Listing
May 2021

Outcome of Non-hematological Autoimmunity After Hematopoietic Cell Transplantation in Children with Primary Immunodeficiency.

J Clin Immunol 2021 01 3;41(1):171-184. Epub 2020 Nov 3.

Children's Haematopoietic Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne Hospital NHS Foundation Trust, Clinical Resource Building, Floor 4, Block 2, Queen Victoria Road, Newcastle upon Tyne, NE1 4LP, UK.

Purpose: Knowledge of post-hematopoietic cell transplantation (HCT) non-hematological autoimmune disease (AD) is far from satisfactory.

Method: This multicenter retrospective study focuses on incidence, risk factors, and outcomes of post-HCT AD in 596 children with primary immunodeficiency (PID) who were transplanted from 2009 to 2018.

Results: The indications of HCT were severe combined immunodeficiency (SCID, n = 158, 27%) and non-SCID PID (n = 438, 73%). The median age at HCT was 2.3 years (range, 0.04 to 18.3 years). The 5-year overall survival for the entire cohort was 79% (95% cumulative incidence (CIN), 74-83%). The median follow-up of surviving patients was 4.3 years (0.08 to 14.7 years). The CIN of post-HCT AD was 3% (2-5%) at 1 year post-HCT, 7% (5-11%) at 5 years post-HCT, and 11% (7-17%) at 8 years post-HCT. The median onset of post-HCT AD was 2.2 years (0.12 to 9.6 years). Autoimmune thyroid disorder (n = 19, 62%) was the most common post-HCT AD, followed by neuromuscular disorders (n = 7, 22%) and rheumatological manifestations (n = 5, 16%). All patients but one required treatment for post-HCT AD. After multivariate analysis, age at transplant (p = 0.01) and T cell-depleted graft (p < 0.001) were significant predictors of post-HCT AD. None of the T cell-depleted graft recipients developed post-HCT AD. Patients with a lower CD3+ count at 6 months post-HCT had a significant higher incidence of post-HCT AD compared to disease controls. Graft-versus-host disease, viral infection, and donor chimerism had no association with post-HCT AD.

Conclusion: Post-HCT AD occurred in 11% at 8 years post-HCT and its occurrence was associated with older age at HCT and unmanipulated graft.
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http://dx.doi.org/10.1007/s10875-020-00895-3DOI Listing
January 2021

Pathobiologic Mechanisms of Neurodegeneration in Osteopetrosis Derived From Structural and Functional Analysis of 14 ClC-7 Mutants.

J Bone Miner Res 2021 03 29;36(3):531-545. Epub 2020 Nov 29.

Consiglio Nazionale delle Ricerche, Istituto di Biofisica (CNR-IBF), Dulbecco Telethon Laboratory, Genoa, Italy.

ClC-7 is a chloride-proton antiporter of the CLC protein family. In complex with its accessory protein Ostm-1, ClC-7 localizes to lysosomes and to the osteoclasts' ruffled border, where it plays a critical role in acidifying the resorption lacuna during bone resorption. Gene inactivation in mice causes severe osteopetrosis, neurodegeneration, and lysosomal storage disease. Mutations in the human CLCN7 gene are associated with diverse forms of osteopetrosis. The functional evaluation of ClC-7 variants might be informative with respect to their pathogenicity, but the cellular localization of the protein hampers this analysis. Here we investigated the functional effects of 13 CLCN7 mutations identified in 13 new patients with severe or mild osteopetrosis and a known ADO2 mutation. We mapped the mutated amino acid residues in the homology model of ClC-7 protein, assessed the lysosomal colocalization of ClC-7 mutants and Ostm1 through confocal microscopy, and performed patch-clamp recordings on plasma-membrane-targeted mutant ClC-7. Finally, we analyzed these results together with the patients' clinical features and suggested a correlation between the lack of ClC-7/Ostm1 in lysosomes and severe neurodegeneration. © 2020 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4200DOI Listing
March 2021

Hematopoietic Stem Cell Transplantation and Vasculopathy Associated With STAT3-Dominant-Negative Hyper-IgE Syndrome.

Front Pediatr 2020 10;8:575. Epub 2020 Sep 10.

Immunodeficiency Centre for Wales, University Hospital for Wales, Cardiff, United Kingdom.

Dominant negative mutations in the transcription-factor underlie the rare primary immunodeficiency Job's syndrome. Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) has shown promise in correction of the underlying immunological defect, with one report suggesting HSCT can prevent development of wider connective tissue complications. Here, we report the case of a 26 year old male who developed an acute ST-elevation myocardial infarction due to coronary artery ectasia and thrombosis, occurring despite pediatric allogeneic HSCT for STAT3-HIES and a predicted 10-year conventional cardiovascular risk of 0.1%. Vasculopathy associated with STAT3-HIES may persist or arise following HSCT and can precipitate life-threatening complications. This has implications for counseling and vascular surveillance, and highlights the need for further studies to determine the risk, pathogenesis, and optimal management of the vasculopathy associated with STAT3-HIES.
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http://dx.doi.org/10.3389/fped.2020.00575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511721PMC
September 2020

Outcome of autoimmune cytopenia after hematopoietic cell transplantation in primary immunodeficiency.

J Allergy Clin Immunol 2020 08 19;146(2):406-416. Epub 2020 May 19.

Children's Haematopoietic Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne Hospital National Health System Foundation Trust, Newcastle upon Tyne, United Kingdom; Translational and Clinical Research Institute, Newcastle upon Tyne Hospital National Health System Foundation Trust, Newcastle upon Tyne, United Kingdom.

Background: Post hematopoietic cell transplantation (HCT) autoimmune cytopenia (AIC) is a potentially life-threatening complication, but studies focusing on large cohorts of patients transplanted for primary immunodeficiency are lacking.

Objectives: This study sought to determine the incidence, risk factors, and outcomes of post-HCT AIC and B-lymphocyte function following rituximab.

Methods: We retrospectively studied 502 children with primary immunodeficiency who were transplanted at our center between 1987 and 2018.

Results: Thirty-six patients (9%) developed post-HCT AIC, with a median onset of 6.5 months post-HCT. On univariate analysis, pre-HCT AIC, mismatched donor, alemtuzumab, anti-thymocyte antiglobulin, and acute and chronic graft versus host disease were significantly associated with post-HCT AIC. After multivariate analysis, alemtuzumab (subdistribution hazard ratio, 9.0; 95% CI, 1.50-54.0; P = .02) was independently associated with post-HCT AIC. Corticosteroid and high-dose intravenous immunoglobulin achieved remission in 50% (n = 18), additional rituximab led to remission in 25% (n = 9), and the remaining 25% were treated with a combination of various modalities including sirolimus (n = 5), bortezomib (n = 3), mycophenolate mofetil (n = 2), splenectomy (n = 2), and second HCT (n = 3). The mortality of post-HCT AIC reduced from 25% (4 of 16) prior to 2011 to 5% (1 of 20) after 2011. The median follow-up of 5.8 years (range, 0.4 to 29.1 years) showed that 26 of 30 survivors (87%) were in complete remission, and 4 were in remission with ongoing sirolimus and low-dose steroids. Of the 17 who received rituximab, 7 had B-lymphocyte recovery, 5 had persistent low B-lymphocyte count and remained on intravenous immunoglobulin replacement, 2 had second HCT, and 3 died.

Conclusions: The frequency of post HCT AIC in our cohort was 9%, and the most significant risk factors for its occurrence were the presence of graft versus host disease and the use of alemtuzumab.
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http://dx.doi.org/10.1016/j.jaci.2020.04.053DOI Listing
August 2020

Improved transplant survival and long-term disease outcome in children with MHC class II deficiency.

Blood 2020 03;135(12):954-973

Children's Haematopoietic Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne Hospital NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.

MHC class II deficiency is a rare, but life-threatening, primary combined immunodeficiency. Hematopoietic cell transplantation (HCT) remains the only curative treatment for this condition, but transplant survival in the previously published result was poor. We analyzed the outcome of 25 patients with MHC class II deficiency undergoing first HCT at Great North Children's Hospital between 1995 and 2018. Median age at diagnosis was 6.5 months (birth to 7.5 years). Median age at transplant was 21.4 months (0.1-7.8 years). Donors were matched family donors (MFDs; n = 6), unrelated donors (UDs; n = 12), and haploidentical donors (HIDs; n = 7). Peripheral blood stem cells were the stem cell source in 68% of patients. Conditioning was treosulfanbased in 84% of patients; 84% received alemtuzumab (n = 14) or anti-thymocyte globulin (n = 8) as serotherapy. With a 2.9-year median follow-up, OS improved from 33% (46-68%) for HCT before 2008 (n = 6) to 94% (66-99%) for HCT after 2008 (n = 19; P = .003). For HCT after 2008, OS according to donor was 100% for MFDs and UDs and 85% for HIDs (P = .40). None had grade III-IV acute or chronic graft-versus-host disease. Latest median donor myeloid and lymphocyte chimerism were 100% (range, 0-100) and 100% (range, 64-100), respectively. Latest CD4+ T-lymphocyte number was significantly lower in transplant survivors (n = 14) compared with posttransplant disease controls (P = .01). All survivors were off immunoglobulin replacement and had protective vaccine responses to tetanus and Haemophilus influenzae. None had any significant infection or autoimmunity. Changing transplant strategy in Great North Children's Hospital has significantly improved outcomes for MHC class II deficiency.
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http://dx.doi.org/10.1182/blood.2019002690DOI Listing
March 2020

Allogeneic HSCT for Autoimmune Diseases: A Retrospective Study From the EBMT ADWP, IEWP, and PDWP Working Parties.

Front Immunol 2019 4;10:1570. Epub 2019 Jul 4.

ADWP-EBMT Chair; Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom.

This retrospective study assessed the use and long-term outcome of allogeneic hematopoietic stem cell transplantation (HSCT) in patients with severe autoimmune diseases (ADs), reported to the European Society for Blood and Marrow Transplantation (EBMT) registry. Between 1997 and 2014, 128 patients received allogeneic HSCT for various hematological ( = 49) and non-hematological ( = 79) refractory ADs. The median age was 12.7 years (0.2-62.2). Donors were syngeneic for seven, matched related for 46, unrelated for 51, haploidentical for 15, and cord blood for nine patients. The incidence of grades II-IV acute graft-vs.-host disease (GvHD) was 20.8% at 100 days. Cumulative incidence of chronic GvHD was 27.8% at 5-years. Non-relapse mortality (NRM) was 12.7% at 100-days. Overall survival (OS) and Progression-Free Survival (PFS) were 70.2 and 59.4% at 5-years, respectively. By multivariate analysis, age <18 years, males, and more recent year of transplant were found to be significantly associated with improved PFS. Reduced conditioning intensity was associated with a lower NRM. On a subgroup of 64 patients with detailed information a complete clinical response was obtained in 67% of patients at 1-year. This large EBMT survey suggests the potential of allogeneic HSCT to induce long-term disease control in a large proportion of refractory ADs, with acceptable toxicities and NRM, especially in younger patients.
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http://dx.doi.org/10.3389/fimmu.2019.01570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6622152PMC
October 2020

Two decades of excellent transplant survival for chronic granulomatous disease: a supraregional immunology transplant center report.

Blood 2019 06 5;133(23):2546-2549. Epub 2019 Apr 5.

Department of Paediatric Immunology and Haematopoietic Stem Cell Transplantation, Great North Children's Hospital, Newcastle upon Tyne Hospital National Health Service (NHS) Foundation Trust, Newcastle upon Tyne, United Kingdom.

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http://dx.doi.org/10.1182/blood.2019000021DOI Listing
June 2019

New graft manipulation strategies improve the outcome of mismatched stem cell transplantation in children with primary immunodeficiencies.

J Allergy Clin Immunol 2019 07 4;144(1):280-293. Epub 2019 Feb 4.

Molecular and Cellular Immunology Unit, University College London (UCL) Great Ormond Street Institute of Child Health, London, United Kingdom; Blood and Bone Marrow Transplant Unit, Great Ormond Street Hospital, London, United Kingdom.

Background: Mismatched stem cell transplantation is associated with a high risk of graft loss, graft-versus-host disease (GvHD), and transplant-related mortality. Alternative graft manipulation strategies have been used over the last 11 years to reduce these risks.

Objective: We investigated the outcome of using different graft manipulation strategies among children with primary immunodeficiencies.

Methods: Between 2006 and 2017, 147 patients with primary immunodeficiencies received 155 mismatched grafts: 30 T-cell receptor (TCR) αβ/CD19-depleted grafts, 43 cord blood (CB) grafts (72% with no serotherapy), 17 CD34 selection with T-cell add-back grafts, and 65 unmanipulated grafts.

Results: The estimated 8-year survival of the entire cohort was 79%, transplant-related mortality was 21.7%, and the graft failure rate was 6.7%. Posttransplantation viral reactivation, grade II to IV acute graft-versus-host disease (aGvHD), and chronic graft-versus-host disease (cGvHD) complicated 49.6%, 35%, and 15% of transplantations, respectively. Use of TCRαβ/CD19 depletion was associated with a significantly lower incidence of grade II to IV aGvHD (11.5%) and cGvHD (0%), although with a greater incidence of viral reactivation (70%) in comparison with other grafts. T-cell immune reconstitution was robust among CB transplants, although with a high incidence (56.7%) of grade II to IV aGvHD. Stable full donor engraftment was significantly greater at 80% among TCRαβ/CD19-depleted and CB transplants versus 40% to 60% among the other groups.

Conclusions: Rapidly accessible CB and haploidentical grafts are suitable alternatives for patients with no HLA-matched donor. Cord transplantation without serotherapy and TCRαβ/CD19-depleted grafts produced comparable survival rates of around 80%, although with a high rate of aGvHD with the former and a high risk of viral reactivation with the latter that need to be addressed.
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http://dx.doi.org/10.1016/j.jaci.2019.01.030DOI Listing
July 2019

Adjuvant rituximab, a potential treatment for the young patient with Graves' hyperthyroidism (RiGD): study protocol for a single-arm, single-stage, phase II trial.

BMJ Open 2019 01 21;9(1):e024705. Epub 2019 Jan 21.

Department of Paediatric Endocrinology, Institute of Genetic Medicine, Newcastle University, Great North Children's Hospital, Newcastle upon Tyne, UK.

Introduction: Graves' disease (Graves' hyperthyroidism) is a challenging condition for the young person and their family. The excess thyroid hormone generated by autoimmune stimulation of the thyroid stimulating hormone receptor on the thyroid gland can have a profound impact on well-being. Managing the young person with Graves' hyperthyroidism is more difficult than in older people because the side effects of conventional treatment are more significant in this age group and because the disease tends not to resolve spontaneously in the short to medium term. New immunomodulatory agents are available and the anti-B cell monoclonal antibody rituximab is of particular interest because it targets cells that manufacture the antibodies that stimulate the thyroid gland in Graves'.

Methods And Analysis: The trial aims to establish whether the combination of a single dose of rituximab (500 mg) and a 12-month course of antithyroid drug (usually carbimazole) can result in a meaningful increase in the proportion of patients in remission at 2 years, the primary endpoint. A single-stage, phase II A'Hern design is used. 27 patients aged 12-20 years with newly presenting Graves' hyperthyroidism will be recruited. Markers of immune function, including lymphocyte numbers and antibody levels (total and specific), will be collected regularly throughout the trial.

Discussion: The trial will determine whether the immunomodulatory medication, rituximab, will facilitate remission above and beyond that observed with antithyroid drug alone. A meaningful increase in the expected proportion of young patients entering remission when managed according to the trial protocol will justify consideration of a phase III trial.Ethics and dissemination The trial has received a favourable ethical opinion (North East - Tyne and Wear South Research Ethics Committee, reference 16/NE/0253, EudraCT number 2016-000209-35). The results of this trial will be distributed at international endocrine meetings, in the peer-reviewed literature and via patient support groups.

Trial Registration Number: ISRCTN20381716.
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http://dx.doi.org/10.1136/bmjopen-2018-024705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347892PMC
January 2019

Biallelic mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation.

Science 2018 08 19;361(6404):810-813. Epub 2018 Jul 19.

Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK.

RIPK1 (receptor-interacting serine/threonine kinase 1) is a master regulator of signaling pathways leading to inflammation and cell death and is of medical interest as a drug target. We report four patients from three unrelated families with complete RIPK1 deficiency caused by rare homozygous mutations. The patients suffered from recurrent infections, early-onset inflammatory bowel disease, and progressive polyarthritis. They had immunodeficiency with lymphopenia and altered production of various cytokines revealed by whole-blood assays. In vitro, RIPK1-deficient cells showed impaired mitogen-activated protein kinase activation and cytokine secretion and were prone to necroptosis. Hematopoietic stem cell transplantation reversed cytokine production defects and resolved clinical symptoms in one patient. Thus, RIPK1 plays a critical role in the human immune system.
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http://dx.doi.org/10.1126/science.aar2641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529353PMC
August 2018

Allogeneic hematopoietic stem cell transplantation for severe, refractory juvenile idiopathic arthritis.

Blood Adv 2018 04;2(7):777-786

Department of BMT, Great Ormond Street Hospital for Children, National Health Service (NHS) Foundation Trust, London, United Kingdom.

Patients with juvenile idiopathic arthritis (JIA) can experience a severe disease course, with progressive destructive polyarthritis refractory to conventional therapy with disease-modifying antirheumatic drugs including biologics, as well as life-threatening complications including macrophage activation syndrome (MAS). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative immunomodulatory strategy for patients with such refractory disease. We treated 16 patients in 5 transplant centers between 2007 and 2016: 11 children with systemic JIA and 5 with rheumatoid factor-negative polyarticular JIA; all were either refractory to standard therapy, had developed secondary hemophagocytic lymphohistiocytosis/MAS poorly responsive to treatment, or had failed autologous HSCT. All children received reduced toxicity fludarabine-based conditioning regimens and serotherapy with alemtuzumab. Fourteen of 16 patients are alive with a median follow-up of 29 months (range, 2.8-96 months). All patients had hematological recovery. Three patients had grade II-IV acute graft-versus-host disease. The incidence of viral infections after HSCT was high, likely due to the use of alemtuzumab in already heavily immunosuppressed patients. All patients had significant improvement of arthritis, resolution of MAS, and improved quality of life early following allo-HSCT; most importantly, 11 children achieved complete drug-free remission at the last follow-up. Allo-HSCT using alemtuzumab and reduced toxicity conditioning is a promising therapeutic option for patients with JIA refractory to conventional therapy and/or complicated by MAS. Long-term follow-up is required to ascertain whether disease control following HSCT continues indefinitely.
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http://dx.doi.org/10.1182/bloodadvances.2017014449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5894259PMC
April 2018

Non-posttransplant lymphoproliferative disorder malignancy after hematopoietic stem cell transplantation in patients with primary immunodeficiency: UK experience.

J Allergy Clin Immunol 2018 06 7;141(6):2319-2321.e1. Epub 2018 Mar 7.

Children's Haemopoietic Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne Hospital NHS Foundation Trust, Newcastle upon Tyne, United Kingdom; Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2018.02.038DOI Listing
June 2018

Treosulfan and Fludarabine Conditioning for Hematopoietic Stem Cell Transplantation in Children with Primary Immunodeficiency: UK Experience.

Biol Blood Marrow Transplant 2018 03 16;24(3):529-536. Epub 2017 Nov 16.

Great Ormond Street Hospital NHS Trust, London, United Kingdom.

We previously published results for 70 children who received conditioning with treosulfan and cyclophosphamide (n = 30) or fludarabine (n = 40) before undergoing hematopoietic stem cell transplantation (HSCT) for primary immunodeficiency (PID). Toxicity was lower and T cell chimerism was better in the patients receiving fludarabine, but cohort numbers were relatively small and follow-up was short. Here we report outcomes of 160 children who received homogeneous conditioning with treosulfan, fludarabine, and, in most cases, alemtuzumab (n = 124). The median age at transplantation was 1.36 years (range, .09 to 18.25 years). Donors included 73 matched unrelated, 54 1 to 3 antigen-mismatched unrelated, 12 matched sibling, 17 other matched family, and 4 haploidentical donors. Stem cell source was peripheral blood stem cells (PBSCs) in 70, bone marrow in 49, and cord blood in 41. Median duration of follow-up was 4.3 years (range, .8 to 9.4 years). Overall survival was 83%. No patients had veno-occlusive disease. Seventy-four patients (46%) had acute GVHD, but only 14 (9%) greater than grade II. Four patients underwent successful retransplantation for graft loss or poor immune reconstitution. Another patient experienced graft rejection and died. There was no association between T cell chimerism >95% and stem cell source, but a significant association was seen between myeloid chimerism >95% and use of PBSCs without an increased risk of significant GVHD compared with other sources. All 11 patients with severe combined immunodeficiency diagnosed at birth were alive at up to 8.7 years of follow-up. Long-term studies are needed to determine late gonadotoxic effects, and pharmacokinetic studies are needed to identify whether specific targeting is advantageous. The combination of treosulfan, fludarabine, and alemtuzumab is associated with excellent results in HSCT for PID.
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http://dx.doi.org/10.1016/j.bbmt.2017.11.009DOI Listing
March 2018

T-cell receptor αβ and CD19 cell-depleted haploidentical and mismatched hematopoietic stem cell transplantation in primary immune deficiency.

J Allergy Clin Immunol 2018 04 3;141(4):1417-1426.e1. Epub 2017 Aug 3.

Department of Immunology and BMT, Great North Children's Hospital, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom.

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is used as a therapeutic approach for primary immunodeficiencies (PIDs). The best outcomes have been achieved with HLA-matched donors, but when a matched donor is not available, a haploidentical or mismatched unrelated donor (mMUD) can be useful. Various strategies are used to mitigate the risk of graft-versus-host disease (GvHD) and rejection associated with such transplants.

Objective: We sought to evaluate the outcomes of haploidentical or mMUD HSCT after depleting GvHD-causing T-cell receptor (TCR) αβ CD3 cells from the graft.

Methods: CD3TCRαβ/CD19 depleted grafts were given in conditioned (except 3) children with PIDs. Treosulfan (busulfan in 1 patient), fludarabine, thiotepa, and anti-thymocyte globulin or alemtuzumab conditioning were used in 77% of cases, and all but 4 received GvHD prophylaxis.

Results: Twenty-five patients with 12 types of PIDs received 26 HSCTs. Three underwent transplantation for refractory GvHD that developed after the first cord transplantation. At a median follow-up of 20.8 months (range, 5 month-3.3 years), 21 of 25 patients survived and were cured of underlying immunodeficiency. Overall and event-free survival at 3 years were 83.9% and 80.4%, respectively. Cumulative incidence of grade II to IV acute GvHD was 22% ± 8.7%. No case of visceral or chronic GvHD was seen. Cumulative incidences of graft failure, cytomegalovirus, and/or adenoviral infections and transplant-related mortality at 1 year were 4.2% ± 4.1%, 58.8% ± 9.8%, and 16.1% ± 7.4%, respectively. Patients undergoing transplantation with systemic viral infections had poor survival in comparison with those with absent or resolved infections (33.3% vs 100%).

Conclusion: CD3TCRαβ and CD19 cell-depleted haploidentical or mMUD HSCT is a practical and viable alternative for children with a range of PIDs.
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http://dx.doi.org/10.1016/j.jaci.2017.07.008DOI Listing
April 2018

Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic /NEMO mutations.

Blood 2017 09 5;130(12):1456-1467. Epub 2017 Jul 5.

Department of Pediatrics and.

X-linked recessive ectodermal dysplasia with immunodeficiency is a rare primary immunodeficiency caused by hypomorphic mutations of the gene encoding the nuclear factor κB essential modulator (NEMO) protein. This condition displays enormous allelic, immunological, and clinical heterogeneity, and therapeutic decisions are difficult because NEMO operates in both hematopoietic and nonhematopoietic cells. Hematopoietic stem cell transplantation (HSCT) is potentially life-saving, but the small number of case reports available suggests it has been reserved for only the most severe cases. Here, we report the health status before HSCT, transplantation outcome, and clinical follow-up for a series of 29 patients from unrelated kindreds from 11 countries. Between them, these patients carry 23 different hypomorphic mutations. HSCT was performed from HLA-identical related donors (n = 7), HLA-matched unrelated donors (n = 12), HLA-mismatched unrelated donors (n = 8), and HLA-haploidentical related donors (n = 2). Engraftment was documented in 24 patients, and graft-versus-host disease in 13 patients. Up to 7 patients died 0.2 to 12 months after HSCT. The global survival rate after HSCT among NEMO-deficient children was 74% at a median follow-up after HSCT of 57 months (range, 4-108 months). Preexisting mycobacterial infection and colitis were associated with poor HSCT outcome. The underlying mutation does not appear to have any influence, as patients with the same mutation had different outcomes. Transplantation did not appear to cure colitis, possibly as a result of cell-intrinsic disorders of the epithelial barrier. Overall, HSCT can cure most clinical features of patients with a variety of mutations.
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http://dx.doi.org/10.1182/blood-2017-03-771600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5609334PMC
September 2017

Risks of serious infections in children treated with biologic response-modifying drugs.

Authors:
Mario Abinun

Rheumatology (Oxford) 2018 02;57(2):211-212

Primary Immunodeficiency Group, Institute of Cellular Immunology, Medical School, Newcastle University, Newcastle upon Tyne, UK.

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http://dx.doi.org/10.1093/rheumatology/kex228DOI Listing
February 2018

Hematopoietic stem cell transplantation in patients with gain-of-function signal transducer and activator of transcription 1 mutations.

J Allergy Clin Immunol 2018 02 7;141(2):704-717.e5. Epub 2017 Jun 7.

Canadian Center for Primary Immunodeficiency, Hospital for Sick Children, Toronto, Ontario, Canada.

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). A subset 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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http://dx.doi.org/10.1016/j.jaci.2017.03.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802430PMC
February 2018

Hematopoietic stem cell transplantation corrects osteopetrosis in a child carrying a novel homozygous mutation in the FERMT3 gene.

Bone 2017 04 14;97:126-129. Epub 2017 Jan 14.

Humanitas Clinical and Research Institute, Rozzano, Italy; CNR-IRGB, Milan Unit, Milan, Italy.

Osteopetrosis (OPT) is a rare skeletal disorder with phenotypic and genotypic heterogeneity: a variety of clinical features besides the bony defect may be present, and at least ten different genes are known to be involved in the disease pathogenesis. In the framework of this heterogeneity, we report the clinical description of a neonate, first child of consanguineous parents, who had osteoclast-rich osteopetrosis and bone marrow failure in early life, but no other usual classical features of infantile malignant OPT, such as visual or hearing impairments. Because of the severe presentation at birth, the patient received Hematopoietic Stem Cell Transplantation (HSCT) at 2months of age with successful outcome. Post-HSCT genetic investigation by means of exome sequencing identified a novel homozygous mutation in the Fermitin Family Member 3 (FERMT3) gene, which was predicted to disrupt the functionality of its protein product kindlin 3. Our report provides information relevant to physicians for recognizing patients with one of the rarest forms of infantile malignant OPT, and clearly demonstrates that HSCT cures kindlin 3 deficiency with severe phenotype.
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http://dx.doi.org/10.1016/j.bone.2017.01.012DOI Listing
April 2017

Hematopoietic stem cell transplant in patients with activated PI3K delta syndrome.

J Allergy Clin Immunol 2017 03 12;139(3):1046-1049. Epub 2016 Nov 12.

Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom; Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle upon Tyne University, Newcastle upon Tyne, United Kingdom.

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http://dx.doi.org/10.1016/j.jaci.2016.09.040DOI Listing
March 2017

Identification of Heterozygous Single- and Multi-exon Deletions in IL7R by Whole Exome Sequencing.

J Clin Immunol 2017 01 2;37(1):42-50. Epub 2016 Nov 2.

Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.

Purpose: We aimed to achieve a retrospective molecular diagnosis by applying state-of-the-art genomic sequencing methods to past patients with T-B+NK+ severe combined immunodeficiency (SCID). We included identification of copy number variations (CNVs) by whole exome sequencing (WES) using the CNV calling method ExomeDepth to detect gene alterations for which routine Sanger sequencing analysis is not suitable, such as large heterozygous deletions.

Methods: Of a total of 12 undiagnosed patients with T-B+NK+ SCID, we analyzed eight probands by WES, using GATK to detect single nucleotide variants (SNVs) and small insertions and deletions (INDELs) and ExomeDepth to detect CNVs.

Results: We found heterozygous single- or multi-exon deletions in IL7R, a known disease gene for autosomal recessive T-B+NK+ SCID, in four families (seven patients). In three families (five patients), these deletions coexisted with a heterozygous splice site or nonsense mutation elsewhere in the same gene, consistent with compound heterozygosity. In our cohort, about a quarter of T-B+NK+ SCID patients (26%) had such compound heterozygous IL7R deletions.

Conclusions: We show that heterozygous IL7R exon deletions are common in T-B+NK+ SCID and are detectable by WES. They should be considered if Sanger sequencing fails to detect homozygous or compound heterozygous IL7R SNVs or INDELs.
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http://dx.doi.org/10.1007/s10875-016-0343-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5226981PMC
January 2017

Infection-Related Death among Persons with Refractory Juvenile Idiopathic Arthritis.

Emerg Infect Dis 2016 10;22(10):1720-7

Severe infections are emerging as major risk factors for death among children with juvenile idiopathic arthritis (JIA). In particular, children with refractory JIA treated with long-term, multiple, and often combined immunosuppressive and antiinflammatory agents, including the new biological disease-modifying antirheumatic drugs (DMARDs), are at increased risk for severe infections and death. We investigated 4 persons with JIA who died during 1994-2013, three of overwhelming central venous catheter-related bacterial sepsis caused by coagulase-negative Staphylococus or α-hemolytic Streptococcus infection and 1 of disseminated adenovirus and Epstein-Barr virus infection). All 4 had active JIA refractory to long-term therapy with multiple and combined conventional and biological DMARDs. Two died while receiving high-dose systemic corticosteroids, methotrexate, and after recent exposure to anti-tumor necrosis factor-α biological DMARDs, and 2 during hematopoietic stem cell transplantation procedure. Reporting all cases of severe infections and especially deaths in these children is of paramount importance for accurate surveillance.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5038400PMC
http://dx.doi.org/10.3201/eid2210.151245DOI Listing
October 2016
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