T-cell depleted HLA-haploidentical HSCT in a child with neuromyelitis optica

Neuromyelitis optica is an immune-mediated disease characterized by a relapsing course, resulting in progressive disability. In children, given the long life expectancy, a disease-modifying treatment could be particularly desirable. Unfortunately, the currently available treatment strategies with this potential are scarce. Very limited data are available about the use of allogeneic hematopoietic stem cell transplantation (HSCT) for autoimmune neurological diseases. In this report, we present a pediatric case successfully treated with allogeneic HSCT from an HLA-haploidentical donor, after ex vivo TCR/CD19-depletion of the graft. To the best of our knowledge, this is the first case of a pediatric patient to benefit from such a treatment

Haematopoietic stem cell transplantation for severe autoimmune diseases in children : a review of current literature, registry activity and future directions on behalf of the autoimmune diseases and paediatric diseases working parties of the European Society for Blood and Marrow Transplantation

Although modern clinical management strategies have improved the outcome of paediatric patients with severe autoimmune and inflammatory diseases over recent decades, a proportion will experience ongoing or recurrent/relapsing disease activity despite multiple therapies often leading to irreversible organ damage, and compromised quality of life, growth/development and long-term survival. Autologous and allogeneic haematopoietic stem cell transplantation (HSCT) have been used successfully to induce disease control and often apparent cure of severe treatment-refractory autoimmune diseases (ADs) in children. However, transplant-related outcomes are disease-dependent and long-term outcome data are limited in respect to efficacy and safety. Moreover, balancing risks of HSCT against AD prognosis with continually evolving non-transplant options is challenging. This review appraises published literature on HSCT strategies and outcomes in individual paediatric ADs. We also provide a summary of the European Society for Blood and Marrow Transplantation (EBMT) Registry, where 343 HSCT procedures (176 autologous and 167 allogeneic) have been reported in 326 children (<18 years) for a range of AD indications. HSCT is a promising treatment modality, with potential long-term disease control or cure, but therapy-related morbidity and mortality need to be reduced. Further research is warranted to establish the position of HSCT in paediatric ADs via registries and prospective clinical studies to support evidence-based interspeciality guidelines and recommendations

Hematopoietic stem cell transplantation for neurological disorders: a focus on inborn errors of metabolism

Copyright © 2022 de Vasconcelos and Lacerda. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Hematopoietic stem cells have been investigated and applied for the treatment of certain neurological disorders for a long time. Currently, their therapeutic potential is harnessed in autologous and allogeneic hematopoietic stem cell transplantation (HSCT). Autologous HSCT is helpful in immune-mediated neurological diseases such as Multiple Sclerosis. However, clinical benefits derive more from the immunosuppressive conditioning regimen than the interaction between stem cells and the nervous system. Mainly used for hematologic malignancies, allogeneic HSCT explores the therapeutic potential of donor-derived hematopoietic stem cells. In the neurological setting, it has proven to be most valuable in Inborn Errors of Metabolism, a large spectrum of multisystem disorders characterized by congenital deficiencies in enzymes involved in metabolic pathways. Inborn Errors of Metabolism such as X-linked Adrenoleukodystrophy present with brain accumulation of enzymatic substrates that result in progressive inflammatory demyelination. Allogeneic HSCT can halt ongoing inflammatory neural destruction by replacing hematopoietic-originated microglia with donor-derived myeloid precursors. Microglia, the only neural cells successfully transplanted thus far, are the most valuable source of central nervous system metabolic correction and play a significant role in the crosstalk between the brain and hematopoietic stem cells. After transplantation, engrafted donor-derived myeloid cells modulate the neural microenvironment by recapitulating microglial functions and enhancing repair mechanisms such as remyelination. In some disorders, additional benefits result from the donor hematopoietic stem cell secretome that cross-corrects neighboring neural cells via mannose-6-phosphatase paracrine pathways. The limitations of allogeneic HSCT in this setting relate to the slow turnover of microglia and complications such as graft-vs.-host disease. These restraints have accelerated the development of hematopoietic stem cell gene therapy, where autologous hematopoietic stem cells are collected, manipulated ex vivo to overexpress the missing enzyme, and infused back into the patient. With this cellular drug vehicle strategy, the brain is populated by improved cells and exposed to supraphysiological levels of the flawed protein, resulting in metabolic correction. This review focuses on the mechanisms of brain repair resulting from HSCT and gene therapy in Inborn Errors of Metabolism. A brief mention will also be made on immune-mediated nervous system diseases that are treated with this approach.info:eu-repo/semantics/publishedVersio

Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis and immune-mediated neurological diseases : updated guidelines and recommendations from the EBMT autoimmune diseases working party (ADWP) and the joint accreditation committee of EBMT and ISCT (JACIE)

These updated EBMT guidelines review the clinical evidence, registry activity and mechanisms of action of haematopoietic stem cell transplantation (HSCT) in multiple sclerosis (MS) and other immune-mediated neurological diseases and provide recommendations for patient selection, transplant technique, follow-up and future development. The major focus is on autologous HSCT (aHSCT), used in MS for over two decades and currently the fastest growing indication for this treatment in Europe, with increasing evidence to support its use in highly active relapsing remitting MS failing to respond to disease modifying therapies. aHSCT may have a potential role in the treatment of the progressive forms of MS with a significant inflammatory component and other immune-mediated neurological diseases, including chronic inflammatory demyelinating polyneuropathy, neuromyelitis optica, myasthenia gravis and stiff person syndrome. Allogeneic HSCT should only be considered where potential risks are justified. Compared with other immunomodulatory treatments, HSCT is associated with greater short-term risks and requires close interspeciality collaboration between transplant physicians and neurologists with a special interest in these neurological conditions before, during and after treatment in accredited HSCT centres. Other experimental cell therapies are developmental for these diseases and patients should only be treated on clinical trials

Indications for haematopoietic cell transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2022

For over two decades, the EBMT has updated recommendations on indications for haematopoietic cell transplantation (HCT) practice based on clinical and scientific developments in the field. This is the eighth special EBMT report on the indications for HCT for haematological diseases, solid tumours and immune disorders. Our aim is to provide general guidance on HCT indications according to prevailing clinical practice in EBMT countries and centres. In order to inform patient decisions, these recommendations must be considered in conjunction with the risk of the disease, risk of HCT procedure and non-transplant strategies, including evolving cellular therapies. HCT techniques are constantly evolving and we make no specific recommendations, but encourage harmonisation of practice, where possible, to ensure experience across indications can be meaningfully aggregated via registry outputs. We also recommend working according to JACIE accreditation standards to maintain quality in clinical and laboratory components of practice, including benchmarking of survival outcomes. Since the last edition, the COVID-19 pandemic has affected clinical decision making and activity across indications. Although the full impact of the pandemic is yet to be determined, we recommend that decision making across indications is delivered with ongoing reference to EBMT and national COVID-19 guidance, in accordance with current local conditions

The EBMT Handbook

This Open Access edition of the European Society for Blood and Marrow Transplantation (EBMT) handbook addresses the latest developments and innovations in hematopoietic stem cell transplantation and cellular therapy. Consisting of 93 chapters, it has been written by 175 leading experts in the field. Discussing all types of stem cell and bone marrow transplantation, including haplo-identical stem cell and cord blood transplantation, it also covers the indications for transplantation, the management of early and late complications as well as the new and rapidly evolving field of cellular therapies. This book provides an unparalleled description of current practices to enhance readers’ knowledge and practice skills

Graft-versus-host disease and treatment with mesenchymal stromal cells

Graft-versus-host disease of both the acute (aGvHD) and chronic (cGvHD) variety remains a major cause of mortality and morbidity after allogeneic hematopoietic stem cell transplantation (HSCT). During the last 15 years, mesenchymal stromal cells (MSC) have been explored as a promising new treatment for aGvHD, but there are many questions to be answered in this young field. The aim of this thesis is to expand our understanding of MSC treatment and GvHD with a specific focus on safety, factors affecting the outcome of MSC therapy and the possibility of treating also cGvHD with MSC. In paper I we performed a long-term follow up study of the first patients treated with MSC, and reported on their outcome. We demonstrated a high frequency of infections and recommend the use of prophylactic drugs and close surveillance of patients during and following MSC treatment. Regarding factors affecting the outcome, we reported an association between low passage MSC and better clinical outcome, indicating that MSC lose some of their potency with extensive culturing. In paper II, we analysed autopsy reports and tissue samples from patients treated with MSC and could demonstrate that MSC do not appear to engraft in the patients. The risk of malignant transformation of donated MSC should therefore be very low. In paper III we demonstrated a correlation between vitamin D deficiency prior to HSCT and an increased incidence of cGvHD, indicating vitamin D deficiency as a possible risk factor for cGvHD. Paper IV reports on a clinical trial of MSC therapy in refractory cGvHD. Eleven patients were included; of whom nine received up to six repeated infusions of MSC and could be evaluated for response. Of these nine, six patients responded to MSC therapy with durable improvement in cGvHD symptoms and could significantly reduce systemic immunosuppression. To summarize, this thesis provides new data regarding the safety of MSC therapy and suggests that the use of MSC is relatively safe, provided that necessary precautions are taken regarding infectious complications. With this information at hand, we could move forward to expanding the use of MSC in conditions with less dire expectations than refractory aGvHD, such as cGvHD. The clinical study of MSC therapy in cGvHD is one of the largest reported worldwide and suggests that repeated infusions of MSC could be a valuable treatment option for these patients

The challenge of co-existence : from graft-versus-host disease to stable mixed chimerism after allogeneic hematopoietic stem cell transplantation

The only curative treatment strategy for many hematologic and inborn immunodeficiency disorders is an allogeneic hematopoietic stem cell transplantation (HSCT). The treatment involves replacing the entire hematopoietic system of the recipient. If successful, the underlying condition of the patient is resolved, the donor hematopoietic system engrafts and a tolerance between donor- and patient-derived cells is developed. Though the procedure of HSCT has been refined for decades, there are still several severe complications associated to it. Graft-versus-host disease (GVHD) is one of the most common and most feared complications post-HSCT, and is a result of donor graft-derived cells attacking recipient tissue. Despite improved GVHD treatment strategies, severe grade GVHD is still associated with high morbidity and mortality rates. A condition known as mixed chimerism (MC), where recipient hematopoietic cells co-exist with donor hematopoietic cells, may also be considered an adverse event early post-HSCT. This is certainly the case for patients with malignancies as it indicates a potential relapse. However, in rare cases where HSCT is performed due to non-malignant disorders, long-term stable MC may develop without any apparent signs of unfavourable symptoms. The papers in this thesis aim to provide a better understanding of the co-existence of graftand host-derived cells from an immunological perspective. I will focus on GVHD and longterm stable MC post-HSCT particularly. In Paper I, I aimed to identify predictive markers for acute GVHD development. Acute GVHD occurs relatively shortly post-HSCT with potential devastating effects. In this paper, I observed a reduced frequency in mucosal-associated-invariant T (MAIT) cells in donor grafts, given to patients who later developed acute GVHD. Moreover, I could identify a predictive role for high PD-1 and low CD127-expressing T cell frequencies in the donor grafts. Together with increased levels of TNFa in both the donor graft and in patient plasma prior to HSCT, these findings may putatively be used to predict acute GVHD development in patients at time of transplantation. In Paper II, I focused on chronic GVHD, a complication that usually develops later postHSCT presenting with symptoms from several organs. Patients may suffer from chronic GVHD for years, resulting in a diminished quality of life. In this paper, I was able to identify novel cellular subsets via mass cytometry that could be linked to the severity of chronic GVHD. These subsets could also be identified by conventional flow cytometry panels more suitable for routine laboratories. Additionally, similar to the study on acute GVHD, patients with more pronounced chronic GVHD were found to have fewer MAIT cells in their blood. Thus, Paper I and II indicate a potential role for MAIT cells in both acute and chronic GVHD. In Paper III and IV, the focus was long-term stable MC, which is defined as the presence of 5-95% recipient-derived cells, after ≥5 years post-HSCT in this study. Interestingly, patients with long-term stable MC had a similar quality of life, infectious disease burden and response to vaccines compared to patients with full donor chimerism (DC). Fluctuations in recipient chimerism tended to decrease and reach stable levels after around two to five years post-HSCT. Moreover, patients with MC appear to retain functional recipient-derived cells in multiple cellular subsets. Patients with MC also displayed increased levels of IgG3 and reduced lymphocyte expression of ZAP-70, though they were found to be similar to patients with DC in overall immune phenotype

Clinical and Cellular Response to Abatacept Therapy and Haematopoietic Stem Cell Transplantation in LRBA Deficiency

The lipopolysaccharide-responsive beige-like anchor (LRBA) gene comprises 58 exons, is located at chromosome 4q31, and encodes one of nine human BEACH proteins that participate in intracellular protein trafficking. Although ubiquitously expressed, LRBA is particularly vital to the function of regulatory T cells where it traffics CTLA4 to the cell surface, and prevents its lysosomal degradation. CTLA4 is an inhibitory receptor that competes with CD28 to bind CD80/CD86 on antigen presenting cells, thus preventing T cell activation. By interaction with CTLA4, LRBA plays an important role in maintaining immune homeostasis. Biallelic deleterious mutations throughout LRBA abolish expression of LRBA protein in almost all described cases, and cause a rare clinical syndrome characterised by cytopenia, inflammatory bowel disease, lymphadenopathy, and recurrent sinopulmonary disease. For reasons that are not completely understood, the spectrum of disease severity and manifestations is broad, ranging from asymptomatic individuals through to patients requiring profound immune suppression. Targeted therapy with the CTLA4-IgG fusion protein Abatacept has shown promise in some patients but cure is only possible through haematopoietic stem cell transplantation, a high-risk procedure with mixed early outcomes in LRBA deficiency. This thesis follows a cohort of 16 LRBA-deficient patients from diagnosis through to the introduction of Abatacept therapy, and finally bone marrow transplantation with reduced intensity conditioning. In-depth immune system interrogation was performed to characterise the impact of LRBA deficiency on T- and B-lymphocytes, as well as the innate immune system, which had not previously been studied in this disease. This study found that Abatacept therapy successfully modulates disease activity, both clinically and immunologically, but does not halt disease progression. Transplantation with reduced intensity conditioning can lead to complete disease remission with full donor chimerism, and correction of most immunological defects. A range of biological markers of disease activity were identified across the immune system, which can aid the monitoring of response to therapeutic interventions

Investigación de la distribución de los alelos HLA en poblaciones sanas y enfermas mediante la aplicación de nuevas metodologías de secuenciación

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Inmunología, Oftalmología y ORL, leída el 09/03/2021Increasing our knowledge of the HLA system, including both the complete sequence description and the assessment of its diversity at the worldwide human population-level, is of great importance for elucidating the molecular functional mechanisms of the immune system and its regulation in health and disease. Furthermore, assessment of HLA allelic and haplotypic diversity of each human population is essential in the clinical histocompatibility and transplantation setting as well as in the pharmacogenetics, immunotherapy and anthropology fields. Nevertheless, the inherent vast polymorphism and high complexity presented by the HLA system have been an important challenge for its unambiguous and in-depth (high-resolution) characterization by previously available legacy molecular HLA genotyping methods (e.g. SSP, SSO and even SBT). Recent application of novel next-generation sequencing (NGS) technology for high-resolution molecular HLA genotyping has enabled to obtain, at a high-throughput mode and larger scale, full-length and/or extended sequences and genotypes of all major HLA genes, thus overcoming most of these previous limitations. Objectives: I) Characterization of HLA allele and haplotype diversity of all major classical HLA genes (HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, -DQB1, -DRB1 and -DRB3/4/5) by application of NGS of a first representative cohort of the Spanish population that could also serve as a healthy control reference group. Respective statistical analyses were performed for this immunogenetic population data. II) Characterization of HLA allele and haplotype diversity of all major classical HLA genes (HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, -DQB1, -DRB1 and -DRB3/4/5) by application of NGS of a respective cohort of multiple sclerosis (MS) patients in the Spanish population (recruited at the Department of Neurology, Hospital Clínic, Barcelona, Catalonia, Spain). A first case-control study was carried out to examine HLA-disease associations with MS in these Spanish population cohorts as well as to attempt a fine-mapping of these allele and haplotype associations by full gene resolution level via NGS. In addition, a second analysis exercise (i.e. test case) of this case-control study was carried out using an alternative healthy control group dataset, exclusively from the Spanish northeastern region of Catalonia in this second case, to evaluate possible differences in the findings of HLA-disease association with MS due to plausible regional HLA genetic variation within mainland Spain (i.e. as a statistical way to try controlling for any possible existing population stratification)...El estudio del sistema HLA, incluyendo la descripción completa de su secuencia y de la diversidad de este complejo HLA a nivel poblacional, es de gran importancia de cara a poder entender los mecanismos moleculares y funciones del sistema inmune así como su regulación en individuos sanos y enfermos. Además, la caracterización exhaustiva de la diversidad de alelos y haplotipos HLA de cada población humana es esencial en el campo de la inmunología de trasplante e histocompatibilidad al igual que en las áreas de farmacogenética e inmunoterapia. El inmenso polimorfismo y gran complejidad que presenta el sistema HLA han sido hasta ahora importantes barreras de cara a poder caracterizarlo en gran detalle (por alta resolución) y sin ambigüedades mediante métodos de genotipaje HLA tradicionales disponibles (como son SSP, SSO o incluso SBT). La reciente aplicación de la novedosa tecnología de secuenciación masiva NGS para el genotipaje molecular HLA por alta resolución ha posibilitado obtener secuencias completas o mucho más extendidas para genotipos de los principales genes de HLA, superándose así estas previas limitaciones. Objetivos: I) Caracterización de la diversidad alélica y haplotípica de los principales genes HLA (HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, -DQB1, -DRB1 y -DRB3/4/5) mediante la aplicación de NGS en una primera cohorte representativa de la población española que, igualmente, constituirá una población control de referencia para estudios de asociación de HLA y enfermedades. También, respectivos análisis estadísticos se realizaron para estos resultados de genotipaje HLA. II) Caracterización de la diversidad alélica y haplotípica de los principales genes HLA (HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, -DQB1, -DRB1 y -DRB3/4/5) mediante la aplicación de NGS en una correspondiente cohorte de pacientes con esclerosis múltiple (EM) de la población española (reclutados y procedentes del Departamento de Neurología del Hospital Clínic (Barcelona, Cataluña)). Un primer estudio de asociación HLA tomando casos (pacientes EM) frente a controles sanos se llevó a cabo para examinar la asociación de genes HLA y la enfermedad de EM en estas cohortes de población española antes mencionadas. Así se buscaba realizar un mapeo fino de las respectivas asociaciones alélicas y haplotípicas de HLA mediante la gran resolución alélica proporcionada por esta metodología de secuenciación masiva. De modo adicional, y como un segundo ejercicio de análisis en este estudio de asociación HLA, se utilizó un grupo control sano alternativo al previo, que incluía individuos procedentes de la región de Cataluña (situada al noreste de España) exclusivamente en este caso, para evaluar así posibles diferencias dadas en la asociación de HLA con EM debido a la probable variación genética en HLA existente a nivel regional dentro del territorio de España...Fac. de MedicinaTRUEunpu